Neoadjuvant Chemoradiation and Local Excision for T2-3 ... - CiteSeerX

Annals of Surgical Oncology 15(3):712–720

DOI: 10.1245/s10434-007-9732-x

Neoadjuvant Chemoradiation and Local Excision for T2-3 Rectal Cancer Thomas Borschitz, MD,1 Daniel Wachtlin,2 Markus Mo¨hler, MD,3 Heinz Schmidberger, MD,4 and Theodor Junginger, MD1

1

Clinic of General and Abdominal Surgery, Johannes Gutenberg-University Hospital, Mainz, Germany 2 Coordination Center for Clinical Trials, Johannes Gutenberg-University, Mainz, Germany 3 First Department of Internal Medicine, Johannes Gutenberg-University Hospital, Mainz, Germany 4 Clinic of Radiation Oncology and Radiation Therapy, Johannes Gutenberg-University Hospital, Mainz, Germany

Background: Local excision (LE) of T1 low-risk (G1–2/L0/V0) rectal cancer is an established approach with local recurrence (LR) rates of 5%, whereas LE of ‡T2 high-risk tumors or inadequate resections (R1/RX/R £1 mm) showed high recurrence rates. Because of the favorable results after neoadjuvant chemoradiotherapy (nCRT) and radical surgery of disease that completely responds (CR) with almost absent LR even of T3–4 tumors, an extension of the indication for LE is controversially discussed, and therefore, we assessed this therapeutic option. Methods: Including our own data, seven studies about LE after nCRT of cT2–3 tumors (n = 237) were analyzed after a PubMed search for cT categories, tumor height, nCRT regimens, schedule and technique of surgery, complications, freedom of stoma, response rates (ypT0–3), length of follow-up, LR, and metastases. Results: Subgroups that we formed (retrospective vs. prospective/retractor vs. transanal endoscopic microsurgery) showed differences in the distribution of cT categories. However, neither the studies we considered nor our own patients showed LR in CR (ypT0). In addition, patients with ypT1 tumor consistently showed low LR rates of 2% (range, 0%–6%), whereas in ypT2 findings, less favorable LR rates of 6% to 20% were observed, and disease that did not respond to therapy (ypT3) displayed LR rates in up to 42%. Conclusions: Despite of a highly selected patient collective, an extended indication for LE of cT2–3 rectal cancer after nCRT may be considered. The strongest prognostic factors were a CR (ypT0) or responses on submucosa level (ypT1). These first results will have to be confirmed in a prospective trial with an appropriate sample size to ensure high statistical power. Key Words: Rectal cancer—Neoadjuvant chemoradiation—Local excision—Tumor response.

Conventional oncological surgery represents the treatment of choice of advanced (‡T2) rectal cancer. LR rates of 36 months were indicated by three trials. Most of 697 patients with rectal tumors undergoing LE at our specialized unit from 1985 to 2006 were treated with the TEM technique (Richard Wolf GmbH, Kittlingen, Germany) developed by Buess. A small number of tumors extending to the dentate line were operated by using a Park retractor. Five patients Ann. Surg. Oncol. Vol. 15, No. 3, 2008

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TABLE 1. Studies of local excision for rectal cancer after neoadjuvant chemoradiation Study

n

Kim et al.30

cT2 cT3 cT2 cT3 cT3

Ruo et al.32 33

Schell et al.

Hershman et al.29*

= = = = =

6 20 6 4 11

cT1–2 = 33

28

Bonnen et al.

cT3 = 26

Stipa et al.44

cT1 cT2 cT3 cT2 cT3 cT3 cT2 237

Lezoche et al.31  Borschitz (personal communication) Total

= = = = = = =

4 14 8 54 46 3 2

nCRT

Tumor height

Weeks to OP

Median (range) of follow-up

5-FU (100%) 45 Gy (100%) 5-FU/5-FU + Leu (80%) 36–50.4 Gy (100%) 5-FU + Leu (100%) 45 Gy (100%) Drug NS (30%) 39–45 Gy (100%) 5FU (100%) 45–52.5 Gy (100%) 5FU (100%) 45 Gy (100%)

Middle and lower rectum

NS

24 (6–77)

Lower rectum

4–6

29 (2–89)

Lower rectum

NS

48 (18–105)

Lower rectum

6–8

33 (3–120)

Lower rectum

NS

42 (5–109)

Middle and lower rectum

4

37 (25–118)

5FU (25%) 50.4 Gy (100%) 5FU (100%) 41–51.2 Gy (100%)

Middle and lower rectum

2 

55 (7–120)

Lower rectum

10 (8–17)

24 (12–79)

NS, not specified; nCRT, neoadjuvant chemoradiation; OP, operation; 5-FU, 5-fluorouracil; Leu, leucovorin. * Four conventional resections.   Prospective study.   Congress communication (10th World Congress of Endoscopic Surgery, September 13, 2006, Berlin).

TABLE 2. Data of the Mainz Centre Patient, sex, age (y), disease c/uT

nCRT

Complications after nCRT

Weeks to OP ypT

F 51 y

uT2N0 5-FU + Leu + 41 Gy None

17

M 75 y

cT3N0 5-FU + 50.4 Gy

None

8

M 56 y

uT3N0 5-FU + 50.4 Gy

Temporary sacral pain

8

M 58 y

uT2N0 5-FU + 50.4 Gy

9

M 70 y

uT3N+ 5-FU + 50.4 Gy

Temporary bowel pain polyuria Bleeding

9

Complications after TEM

ypT1Nx None G2L0V0R0 ypT2N0(0/2) Wound dehiscence G3L0V0R0 ypT0N0(0/1) Bleeding + wound G2L0V0R0 dehiscence ypT1Nx None G2L0V0R0 ypT1Nx Perianal abscess + fever G2V1L0R0

Follow-up LR/M 79

None

30

None

24

None

22

None

12

LR none; M, n=1

nCRT, neoadjuvant chemoradiation; TEM, transanal endoscopic microsurgery; OP, operation; Leu, leucovorin; LR, local recurrence; M, systemic metastases; 5-FU, 5-fluorouracil.

with a cT2/3 carcinoma declined to undergo a radical procedure, in particular if rectum extirpation was necessary (Table 2). These patients underwent nCRT with a median total radiation dose of 50.4 (41–50.4) Gy and continuous infusion of 5-FU. The time to surgery ranged 8 to 9 weeks after nCRT. One patient had previously received nCRT elsewhere and because of good tumor response refused to undergo a radical surgical procedure. Seventeen weeks passed before this patient decided to undergo LE. Complications Five investigators reported complications; none was severe, and all were managed without rectal resection or extirpation (Table 3).30–34 A temporary Ann. Surg. Oncol. Vol. 15, No. 3, 2008

stoma was required in one patient because of a perianal phlegmon.3 No study reported the need for a permanent colostomy. The most frequently complications included suture dehiscence and inflammatory changes (fever, dermatitis, phlegmons/abscesses). The incidence rate of transitory fecal incontinence reported by four investigators ranged 2% to 18%. Other complications were perianal bleeding and injury of the urethra, which were self-limiting or could be treated locally. A colostomy was necessary in one of our patients who developed a perianal phlegmonic abscess. Suture dehiscence occurred in two patients, one of whom exhibited peranal blood loss. However, neither patient required reoperation. The complications were associated with presacral pain, which required

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TABLE 3. Complications after nCRT and LE for rectal carcinoma Author

Wound dehiscence

Perianal phlegmon

Rectal bleeding

Transient incontinence

Urethral lesion

Perianal dermatitis

Fever

Kim et al.3 Ruo et al.32 Schell et al.33 Hershman et al.29 Bonnen et al.28 Stipa et al.44 Lezoche et al.31 Borschitz (personal communication)

1/26 (4%) 1/10 (10%) None NS NS None 11/100 (11%) 2/5 (40%)

None None None NS NS None 1/100 (1%) 1/5 (20%)

None None None NS NS None 1/100 (1%) 1/5 (20%)

1/26 (4%) None 2/11 (18%) NS NS 1/26 (4%) 2/100 (2%) None

None None None NS NS None 1/100(1%) None

7/26 (27%) None None NS NS None 1/100 (1%) None

None 1/10 (10%) None NS NS None None 2/5 (40%)

NS, not specified; nCRT, neoadjuvant chemoradiation; LE, local excision.

TABLE 4. Clinical T category in dependence on surgical procedure (retractor vs. TEM) and study type (retrospective vs. prospective) cT-stage

No.

All patients (7 studies1–8)

T1 T1–2 T2 T3 Total*

n n n n n

4 (2%) 33 (14%) 81 (34%) 119 (50%) 237*(100%)

= = = = =

Six retrospective studies1–3, 5–8 4 33 27 73 137

(3%) (24%) (20%) (53%) (100%)

One prospective study4 0 0 54 46 100

(0%) (0%) (54%) (46%) (100%)

Four retractor studies1,3,5,7 0 0 11 62 73

(0%) (0%) (15%) (85%) (100%)

Three TEM studies2,4,6,8 4 33 70 57 164

(2%) (20%) (43%) (35%) (100%)

2 retrospective TEM studies2,6,8 4 33 16 11 64

One prospective TEM study4

(6%) (52%) (25%) (17%) (100%)

0 0 54 46 100

(0%) (0%) (54%) (46%) (100%)

TEM, transanal endoscopic microsurgery. 1 Bonnen et al.28 2 Hershman et al.29 3 Kim et al.30 4 Lezoche et al.31 5 Schell et al.33 6 Stipa et al.44 7 Ruo et al.32 8 Borschitz (personal communication).

symptomatic pain therapy over several weeks. All of our patients had adequate sphincter function at follow-up and rated their quality of life as good. Clinical (cT) Staging Clinical staging before surgery of the 237 patients showed a cT1–2 tumor in 37 (16%), a cT2 in 81 (34%), and a cT3 category in 119 (50%) patients (Table 4).28–34 In the three investigated study groups (retrospective vs. prospective; retractor vs. TEM; TEM retrospective vs. TEM prospective), the total distribution of cT categories showed significant differences (P < .05) (Table 4). In the case of only one test variant, where the cT1, cT1–2, and cT2 findings were aggregated and compared with the cT3 findings, the comparison between retrospective and prospective data did not yield statistically significant differences (a = 5%). A statistical analysis based on the individual cT categories was considered inconsequential because of stochastic dependence. The separate analysis according to the method of data collection demonstrated that 27% cT1–2 and 20% cT2 findings were considered by six retrospective

investigations (Table 4).28–30,32–34 Conversely, no cT1–2 findings were included in the prospective study, compared with 54% cT2 findings.31 In contrast, the distribution of cT3 findings was nearly identical within these studies (53% in retrospective vs. 46% in prospective trials). Studying the study groups according to surgical technique revealed a predominance of cT1, cT1–2, and cT2 categories (65% vs. 15%) in the three TEM studies.29,31,34 In contrast, the four retractor studies showed more advanced (cT3) tumors (85% vs. 35%) (Table 4).28,30,32,33 Fifty-eight percent of cT1/1–2 findings were included in the two retrospective TEM studies,29,34 while no cT1/1–2 but 54% cT2 and 46% cT3 tumors were considered in the prospective investigation (Table 4).31

Restaging and ycT Categories after nCRT Three investigators reported their findings on the clinical response (ycT category) after nCRT.28,30,34 The proportion of clinical CR in the highly selected patients of the two retrospective retractor studies was 85% (22 of 26) and 89% (23 of 26), respectively,28,30 Ann. Surg. Oncol. Vol. 15, No. 3, 2008

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TABLE 5. Recurrences in dependence on postoperative ypT category, surgical procedure (retractor vs. TEM) and study type (retrospective vs. prospective) ypT stage T0 T1 T2 T3 T1–T3 Total*

LR/M Total LR M Total LR M Total LR M Total LR M Total LR M Total LR M

All patients (seven studies1–8 53 0/53 2/53 45 1/45 3/41 85 6/85 5/71 33 7/33 3/25 21 3/21 2/21 237* 17/237 15/211

(22%) (0%) (4%) (19%) (2%) (7%) (36%) (7%) (7%) (14%) (21%) (12%) (9%) (14%) (10%) (100%) (7%) (7%)

6 retrospective studies1–3, 5–8 50 0/50 2/50 21 1/21 3/17 31 3/31 3/17 14 5/14 0/6 21 3/21 2/21 137 12/137 10/111

(36%) (0%) (4%) (15%) (5%) (18%) (23%) (13%) (18%) (10%) (36%) (0%) (15%) (14%) (10%) (100%) (9%) (9%)

1 prospective study4 3 (3%) 0/3 (0%) 0/3 (0%) 24 (24%) 0/24 (0%) 0/24 (0%) 54 (54%) 3/54 (6%) 2/54 (4%) 19 (19%) 2/19 (11%) 3/19 (16%) – – 100 (100%) 5/100 (5%) 5/100 (5%)

4 retractor studies1, 3, 5, 42 0/42 2/42 3 0/3 1/3 5 1/5 2/5 2 0/2 0/2 21 3/21 2/21 73 4/73 7/73

(58%) (0%) (5%) (4%) (0%) (33%) (7%) (20%) (40%) (3%) (0%) (0%) (15%) (14%) (10%) (100%) (5%) (10%)

7

3 TEM studies2,

4, 6, 8

11 (7%) 0/11 (0%) 0/11 (0%) 42 (26%) 1/42 (3%) 2/38 (5%) 80 (49%) 5/80 (6%) 3/66 (5%) 31 (19%) 7/31 (23%) 3/23 (13%) – – 164 (100%) 13/164 (8%) 8/138 (6%)

2 TEM studies (retrospective)2,6,8 8 0/8 0/8 18 1/18 2/14 26 2/26 1/12 12 5/12 0/4

(7%) (0%) (0%) (28%) (6%) (14%) (41%) (8%) (8%) (19%) (42%) (0%)

64 (100%) 8/64 (13%) 3/64 (5%)

1 TEM study (prospective)4 3 0/3 0/3 24 0/24 0/24 54 3/54 2/54 19 2/19 3/19

(3%) (0%) (0%) (24%) (0%) (0%) (54%) (6%) (4%) (19%) (11%) (16%)

100 (100%) 5/100 (5%) 5/100 (5%)

TEM, transanal endoscopic microsurgery; LR, local recurrence; M, systemic metastasis. 1 Bonnen et al.28 2 Hershman et al.29 3 Kim et al.30 4 Lezoche et al.31 5 Schell et al.33 6 Stipa et al.44 7 Ruo et al.32 8 Borschitz (personal communication).

and in one retrospective TEM study was 27% (7 of 26).34 The tumor of one patient in our series showed complete response. No tumor was detected rectoscopically, digitally, or by ERUS (endorectal ultrasound)/MRI (magnetic resonance imaging). The available data did not permit a statistical analysis. Recurrence in Dependence on the Postoperative ypT Category A histological complete response (ypT0) was noted in 22% (53 of 237), a partial response at the submucosa level (ypT1) in 19% (45 of 237), and a slight (ypT2) or missing response (ypT3) in 36% (85 of 237) or 14% (33 of 237) of cases (Table 5). Two investigators did not differentiate data according to ypT categories but formed two subgroups.28,30 One comprised CR (ypT0); the other included patients with disease with partial, slight, or no response (ypT1–3). The proportion of disease in the latter group constituted 9% (21 of 237) of the total. All studies reported LR rates, with five additionally providing data on the time of the incidence.28,30–33 LR appeared after a mean of 23 (6–76) months.28,30–33 Data on the presence of systemic Ann. Surg. Oncol. Vol. 15, No. 3, 2008

metastases were reported by all but one of the seven studies.34 For the total patient population (ypT0–3), a rate of 7% was calculated for both the occurrence of LR (17 of 237) and systemic recurrence (15 of 211) (Table 5). None of the CR (ypT0) (0 of 53) had LR, and 4% (2 of 53) developed metastases. A response at the submucosa level (ypT1) was associated with LR in 2% (1 of 45) and with systemic progression in 7% (3 of 41) of patients (Table 5). Patients with residual tumor extending to the M. propria (ypT2) showed a LR (6 of 85) and a systemic recurrence (5 of 71) rate of 7% each, respectively. A LR rate of 21% (7 of 33) and a distant metastasis rate of 12% (3 of 25) were determined in patients whose disease did not respond to therapy (ypT3). Analogous to clinical staging, we carried out separate analyses of retrospective versus prospective trials, of the surgical technique used (retractor vs. TEM excision), and of retrospective TEM versus prospective TEM studies (Table 5). Two of these constellations (retrospective vs. prospective, and retractor vs. TEM) showed significant differences in the composition of the ypT categories (P < .05). A separate comparison of the individual ypT categories

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according to their distribution was not considered relevant in light of both the stochastic dependence and cumulative ypT1–3 findings. Retrospective Versus Prospective Data Collection Comparable to clinical staging, approximately 50% of patients (71 of 137) in the retrospective studies had ypT0 or ypT1 findings, compared with 27% (27 of 100) identified in the prospective investigation (Table 5). Independent of these distributions, the total LR (9% vs. 5%) and total metastasis rates (9% vs. 5%) found for the two types of data collection did not show any statistically significant differences at a significance level of a = 5%. Conventional Transanal Versus TEM Excision More than 50% (42 of 73) of patients included in the retractor studies experienced a histological complete remission, compared with 7% (11 of 164) of patients treated with TEM (Table 5). The distribution found in the retractor studies is contrasted by a large proportion (85%) of initial cT3 findings (Table 4). Comparable to the results obtained after the analysis of retrospective versus prospective studies, there were no statistically significant differences at the significance level a = 5% for the total LR or systemic metastases rates, nor was a difference observed for most ypT categories. The presence of metastases associated with ypT2 findings was the only exception, showing a significant difference (P = .0368) between TEM and retractor studies. Furthermore, the interpretability of statistically significant results is greatly limited for multiple testing because the probability of detecting a factually nonexistent difference increases significantly in relation to the number of tests carried out. A separate analysis of the TEM studies in dependence on the retrospective versus prospective data collection showed a similar distribution for the number of responses (ypT0–3), and this analysis failed to demonstrate a statistically significant difference (a = 5%) in the total or individual recurrence rates in regard to the corresponding ypT category (Table 5).

Recurrences in Dependence on Length of Follow-up Four studies reported a median follow-up of >36 months, while the follow-up period of patients in three investigations, including those of our series, ranged 36 Months

Local Systemic

17/237 (7%) 15/211 (7%)

6/74 (8%) 6/74 (8%)

11/163 (7%) 9/137 (7%)

DISCUSSION The aim of this study was to review the findings of nCRT and LE for T2–3 rectal carcinoma. In addition to the discussion of some experiences in our unit, a PubMed search was performed. Available for analysis were a total of 237 patients in seven studies, which permitted an assessment of the recurrence rates in relation to histopathological tumor response. Patients with systemic metastases were excluded, and lymph node status was provided by only a few authors. However, a clear distinction between cN0 or cN+ status is not incontestable, giving consideration to the fact that the detection of lymph node metastases has low sensitivity.37–50 Clinical staging before nCRT identified a T2/3 rectal carcinoma (T1 2%; T1–2 14%; T2 34%; T3 50%) in most studies.28–34 A separate review of retrospective versus prospective trials of studies that used retractor versus TEM or a combination revealed significant differences in the total distribution of the cT categories (P < .05), indicating the presence of heterogeneous inclusion criteria. The retrospectively performed retractor studies, comprised primarily of cT3 findings (85%), was contrasted with a 58% rate of CR (ypT0).28,30,32,33 However, these were not the only criteria reducing the positive predictive value of clinical findings regarding the expected success of nCRT and LE. The studies reported different therapeutic concepts, tumor locations, and intervals from completion of nCRT to surgery. Nevertheless, our analysis identified a number of similarities. These were predominance of cT2–3 carcinomas and the occurrences of LR. No studies documented LR in CR (ypT0). Patients with response at the submucosa level (ypT1) consistently showed low LR rates of 2% (0%–6%). Less clearly defined were the results of ypT2 findings, which ranged from 6% to 20% LR rates. Clearly unfavorable were the findings in patients whose disease did not respond to therapy (ypT3), for whom a mean LR rate of 21% was calculated. The widely divergent LR rates of ypT2 findings may be increased as a result of to nonuniform time intervals from nCRT to surgery. These ranged from 4 to 10 weeks in the retrospective trials, while up to 2 weeks was indicated by the prospective study (E. Ann. Surg. Oncol. Vol. 15, No. 3, 2008

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Lezoche, personal communication). The proportion of ypT2 and ypT3 findings was large in his study, reaching 54% and 19%, respectively, whereas LR rates of 6% (ypT2) and 11% (ypT3) were reported.31 It remains unknown whether an interval of >2 weeks would ameliorate the response rates. Several studies demonstrated a marked increase of CR on the condition that surgery was performed after 6 to 8 weeks instead of 2 to 3 weeks after nCRT.51–53 The present study confirms prior findings observed after nCRT and conventional resection. Almost no LR were reported for CR after nCRT of advanced (T3/4) tumors.11–13,15–20,24,25 Critical prognostic parameters are tumor response and tumor-free lymph nodes. LR and systemic recurrence rates ranging 0% to 23% and 8% to 22% were determined for this constellation.11–23 For disease that did not respond to therapy and for persistent nodal disease, far higher LR rates ranging from 16% to 58%, and metastases ranging from 35% to 58% were reported.11,13,15–23 nCRT followed by LE may represent a viable alternative to rectum extirpation in patients with low T2–3 rectal carcinoma. Despite an optimized surgical technique made available by total mesorectal excision, less favorable results were reported for tumors in the lower rectum.54–57 The distal mesorectum, described by Morson et al.58 as a ‘‘bare area,’’ attenuates distally and is characterized by a circumferential decrease in healthy tissue surrounding the tumor, leading to a loss of tissue layers and a restricted field of view. For this region, incomplete mesorectal excision has been suggested as the cause of higher LR rates.54–57 Local full-thickness excision may be performed as an adequate therapeutic measure for CR after nCRT. The described concept has been taken one step further by Habr-Gama et al.,59 who did not find a need for subsequent surgery in patients with clinically complete responses. In her retrospective, so far a unique long-term follow-up study, she reports a LR rate of only 3% in 100 patients. The question whether radical surgery, LE, or close-meshed follow-up alone may be appropriate in these patients still remains unanswered. It further needs to be clarified whether after nCRT with clinical confirmation of complete response, possibly remaining but vital tumor cells require surgical removal. These cells may have been damaged by irradiation and thus rendered unable to proliferate. Alternatively, some tumor cells surviving nCRT may represent resistant hypoxic clones that build the basis for development of recurrence later on.51–53 Ann. Surg. Oncol. Vol. 15, No. 3, 2008

Furthermore, LE of patients with cT1 response to nCRT with a confirmed ypT1 finding may also represent an appropriate therapy. However, the situation with ypT2 resection findings is not as clear because of the wide range of LR (6% to 20%) with a mean rate of 7%. A separation in pT2 low-risk (G1–2/L0/V0) and high-risk tumors and a strictly defined time point for surgery between 6 to 8 weeks after completion of nCRT may help to clarify these heterogeneous findings in the future. Unexpected histological nonresponse is an indication for immediate radical reoperation, analogous to primary LE of uT1 lowrisk tumors and unexpected prognostically unfavorable results without nCRT.60–64 A high-risk situation (G3–4/L1/V1) or advanced carcinoma (‡pT2) is associated with a high incidence of LR.60–64 For these findings, much evidence indicates that immediate reoperation (within 4 weeks) yields comparable to those obtained after primary radical surgery.60,61,65–68 Patients with disease that does not respond clinically should undergo primary radical surgery. In summary, the findings of this study strongly support the proposition that the indication for LE after nCRT may be extended to distal cT2–3 rectal carcinoma. The strongest prognostic parameter for favorable oncological results is an effective tumor response without residual tumor (ypT0) or with response to at least the submucosa level (ypT1) in the excised specimen. For ypT2 tumors, the interpretation of the heterogeneous results should be performed with caution. But maybe an extrapolation is possible from LE alone, without nCRT. LE is not adequate in patients whose tumors exhibit no response or weak response to nCRT. These patients should be treated conventionally—that is, with radical surgery. However, the P values determined for the subgroups in particular have only limited statistical power and are not robust, a result of the small sample size. The comparability of the data is further encumbered by different patient selection and unequal therapeutic regimes. To verify these results and to answer remaining open questions, we are currently launching a prospective randomized multicenter study in Germany with a sufficient number of patients and the statistical power necessary to permit firm conclusions to be drawn. ACKNOWLEDGMENTS The authors thank Drs. Monika Seibert-Grafe and Rolf Meinert from the Coordination Center for Clinical Trials Mainz for helpful discussions and

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critically reading the manuscript. In addition, the authors thank the CHIR-Net for support (BMBF grant 01GH0602).

REFERENCES 1. Bernardshaw SV, Ovrebo K, Eide GE, et al. Treatment of rectal cancer: reduction of local recurrence after the introduction of TME—experience from one University Hospital. Dig Surg 2006; 23:51–9. 2. Carlsen E, Schlichting E, Guldvog I, et al. Effect of the introduction of total mesorectal excision for the treatment of rectal cancer. Br J Surg 1998; 85:526–9. 3. Goldberg S, Klas JV. Total mesorectal excision in the treatment of rectal cancer: a view from the USA. Semin Surg Oncol 1998; 15:87–90. 4 Kapiteijn E, van de Velde CJ. The role of total mesorectal excision in the management of rectal cancer. Surg Clin North Am 2002; 82:995–1007. 5. Kapiteijn E, Putter H, van de Velde CJ. Cooperative investigators of the Dutch ColoRectal Cancer Group. Impact of the introduction and training of total mesorectal excision on recurrence and survival in rectal cancer in The Netherlands. Br J Surg 2002; 89:1142–9. 6. Mahteme H, Pahlman L. Good colorectal cancer surgery. Tech Coloproctol 2005; 9:1–7. 7. Martling AL, Holm T, Rutqvist LE, et al. Effect of a surgical training programme on outcome of rectal cancer in the County of Stockholm. Stockholm Colorectal Cancer Study Group, Basingstoke Bowel Cancer Research Project. Lancet 2000; 356:93–6. 8. Moore E, Heald RJ, Cecil TD, et al. Almost all five year disease free survivors are cured following rectal cancer surgery, but longer term follow-up detects some late local and systemic recurrences. Colorectal Dis 2005; 7:403–5. 9. Piso P, Dahlke MH, Mirena P, et al. Total mesorectal excision for middle and lower rectal cancer: a single institution experience with 337 consecutive patients. J Surg Oncol 2004; 86:115–21. 10. Wibe A, Carlsen E, Dahl O, et al. The Norwegian Rectal Cancer Group. Nationwide quality assurance of rectal cancer treatment. Colorectal Dis 2006; 8:224–9. 11. Bedrosian I, Rodriguez-Bigas MA, Feig B, et al. Predicting the node-negative mesorectum after preoperative chemoradiation for locally advanced rectal carcinoma. J Gastrointest Surg 2004; 8:56–62. 12. Brown CL, Ternent CA, Thorson AG, et al. Response to preoperative chemoradiation in stage II and III rectal cancer. Dis Colon Rectum 2003; 46:1189–93. 13. Chan AK, Wong A, Jenken D, et al. Posttreatment TNM staging is a prognostic indicator of survival and recurrence in tethered or fixed rectal carcinoma after preoperative chemotherapy and radiotherapy. Int J Radiat Oncol Biol Phys 2005; 61:665–77. 14. Fietkau R, Barten M, Klautke G, et al. Postoperative chemotherapy may not be necessary for patients with ypN0-category after neoadjuvant chemoradiotherapy of rectal cancer. Dis Colon Rectum 2006; 49:1284–92. 15. Garcia-Aguilar J, de Hernandez 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 2003; 46:298–304. 16. 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

17.

18.

19. 20.

21.

22.

23.

24.

25. 26. 27. 28.

29. 30. 31.

32.

33.

34. 35.

719

for sterilisation of pelvic lymph nodes, a low risk of local recurrence and the appropriateness of local excision?. Int J Colorectal Dis 2006; 21:11–7. Onaitis MW, Noone RB, Hartwig M, et al. Neoadjuvant chemoradiation for rectal cancer: analysis of clinical outcomes from a 13-year institutional experience. Ann Surg 2001; 233:778–85. Reerink O, Verschueren RC, Szabo BG, et al. A favourable pathological stage after neoadjuvant radiochemotherapy in patients with initially irresectable rectal cancer correlates with a favourable prognosis. Eur J Cancer 2003; 39:192–5. Rodel C, Martus P, Papadoupolos T, et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 2005; 23:8688–96. Theodoropoulos G, Wise WE, Padmanabhan A, et al. T-level downstaging and complete pathologic response after preoperative chemoradiation for advanced rectal cancer result in decreased recurrence and improved disease-free survival. Dis Colon Rectum 2002; 45:895–903. Tulchinsky H, Rabau M, Shacham-Shemueli E, et al. Can rectal cancers with pathologic T0 after neoadjuvant chemoradiation (ypT0) be treated by transanal excision alone?. Ann Surg Oncol 2006; 13:347–52. 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; 62:752–60. Coco C, Valentini V, Manno A, et al. Long-term results after neoadjuvant radiochemotherapy for locally advanced resectable extraperitoneal rectal cancer. Dis Colon Rectum 2006; 49:311–8. Gavioli M, Luppi G, Losi L, et al. Incidence and clinical impact of sterilized disease and minimal residual disease after preoperative radiochemotherapy for rectal cancer. Dis Colon Rectum 2005; 48:1851–7. Habr-Gama A. Assessment and management of the complete clinical response of rectal cancer to chemoradiotherapy. Colorectal Dis 2006; 8:21–4. Rengan R, Paty P, Wong WD, et al. Distal cT2N0 rectal cancer: is there an alternative to abdominoperineal resection?. J Clin Oncol 2005; 23:4905–12. Gimbel MI, Paty PB. A current perspective on local excision of rectal cancer. Clin Colorectal Cancer 2004; 4:26–35. Bonnen M, Crane C, Vauthey JN, et al. Long-term results using local excision after preoperative hemoradiation among selected T3 rectal cancer patients. Int J Radiat Oncol Biol Phys 2004; 60:1098–105. Hershman MJ, Myint AS, Makin CA. Multi-modality approach in curative local treatment of early rectal carcinomas. Colorectal Dis 2003; 5:445–50. Kim CJ, Yeatman TJ, Coppola D, et al. Local excision of T2 and T3 rectal cancers after downstaging chemoradiation. Ann Surg 2001; 234:352–8. Lezoche E, Guerrieri M, Paganini AM, et al. Long-term results in patients with T2–3 N0 distal rectal cancer undergoing radiotherapy before transanal endoscopic microsurgery. Br J Surg 2005; 92:1546–52. Ruo L, Guillem JG, Minsky BD, et al. Preoperative radiation with or without chemotherapy and full-thickness transanal excision for selected T2 and T3 distal rectal cancers. Int J Colorectal Dis 2002; 17:54–8. Schell SR, Zlotecki RA, Mendenhall WM, et al. Transanal excision of locally advanced rectal cancers downstaged using neoadjuvant chemoradiotherapy. J Am Coll Surg 2002; 194:584–90. Stipa F, Lucandri G, Ferri M, et al. Local excision of rectal cancer with transanal endoscopic microsurgery (TEM). Anticancer Res 2004; 24:1167–72. Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual 6th ed. New York: Springer-Verlag; 2002.

Ann. Surg. Oncol. Vol. 15, No. 3, 2008

720

T. BORSCHITZ ET AL.

36. Sobin LH, Wittekind CH. UICC TNM Classification of Malignant Tumours 6th ed. New York: John Wiley 2002. 37. Bartram C, Brown G. Endorectal ultrasound and magnetic resonance imaging in rectal cancer staging. Gastroenterol Clin North Am 2002; 31:827–39. 38. Beets-Tan RG, Beets GL. Rectal cancer: review with emphasis on MR imaging. Radiology 2004; 232:335–46. 39. Bipat S, Glas AS, Slors FJ, et al. Rectal cancer: local staging and assessment of lymph node involvement with endoluminal US, CT, and MR imaging—a meta-analysis. Radiology 2004; 232:773–83. 40. Brown G, Davies S, Williams GT, et al. Effectiveness of preoperative staging in rectal cancer: digital rectal examination, endoluminal ultrasound or magnetic resonance imaging?. Br J Cancer 2004; 91:23–9. 41. Garcia-Aguilar J, Pollack J, Lee SH, et al. Accuracy of endorectal ultrasonography in preoperative staging of rectal tumors. Dis Colon Rectum 2002; 45:10–5. 42. Junginger T, Hermanek P, Oberholzer K, et al. Rectal carcinoma: is too much neoadjuvant therapy performed? Proposals for a more selective MRI based indication. Zentralbl Chir 2006; 131:275–84. 43. Heald RJ, OÕNeill BD, Moran B, et al. MRI in predicting curative resection of rectal cancer: new dilemma in multidisciplinary team management. BMJ 2006; 333:808. 44. Kim JC, Kim HC, Yu CS, et al. Efficacy of 3-dimensional endorectal ultrasonography compared with conventional ultrasonography and computed tomography in preoperative rectal cancer staging. Am J Surg 2006; 192:89–97. 45. Kneist W, Terzic A, Burghardt J, et al. Selection of patients with rectal tumors for local excision based on preoperative diagnosis. Results of a consecutive evaluation study of 552 patients. Chirurg 2004; 75:168–75. 46. Koh DM, Brown G, Husband JE. Nodal staging in rectal cancer. Abdom Imaging 2006; 31:652–9. 47. Kramann B, Hildebrandt U. Computed tomography versus endosonography in the staging of rectal carcinoma: a comparative study. Int J Colorectal Dis 1986; 1:216–8. 48. Maretto I, Pomerri F, Pucciarelli S, et al. The potential of restaging in the prediction of pathologic response after preoperative chemoradiotherapy for rectal cancer. Ann Surg Oncol 2007; 14:455–61. 49. Mathur P, Smith JJ, Ramsey C, et al. Comparison of CT and MRI in the pre-operative staging of rectal adenocarcinoma and prediction of circumferential resection margin involvement by MRI. Colorectal Dis 2003; 5:396–401. 50. Siddiqui AA, Fayiga Y, Huerta S. The role of endoscopic ultrasound in the evaluation of rectal cancer. Int Semin Surg Oncol 2006; 3:36. 51. Kaminsky-Forrett MC, Conroy T, Luporsi E, et al. Prognostic implications of downstaging following preoperative radiation therapy for operable T3–T4 rectal cancer. Int J Radiat Oncol Biol Phys 1998; 42:935–41. 52. 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 1999; 17:2396.

Ann. Surg. Oncol. Vol. 15, No. 3, 2008

53. Glehen O, Chapet O, Adham M, et al. Lyons Oncology Group. Long-term results of the Lyons R90-01 randomized trial of preoperative radiotherapy with delayed surgery and its effect on sphincter-saving surgery in rectal cancer. Br J Surg 2003; 90:996–8. 54. Marr R, Birbeck K, Garvican J, et al. The modern abdominoperineal excision: the next challenge after total mesorectal excision. Ann Surg 2005; 242:74–82. 55. Nagtegaal ID, van de Velde CJ, van der Worp E, et al. Cooperative Clinical Investigators of the Dutch Colorectal Cancer Group. Macroscopic evaluation of rectal cancer resection specimen: clinical significance of the pathologist in quality control. J Clin Oncol 2002; 20:1729–34. 56. Tekkis PP, Heriot AG, Smith J, et al. Association of Coloproctology of Great Britain and Ireland. Comparison of circumferential margin involvement between restorative and nonrestorative resections for rectal cancer. Colorectal Dis 2005; 7:369–74. 57. Wibe A, Syse A, Andersen E, et al. Norwegian Rectal Cancer Group. Oncological outcomes after total mesorectal excision for cure for cancer of the lower rectum: anterior vs. abdominoperineal resection. Dis Colon Rectum 2004; 47:48– 58. 58. Morson BC, Vaughan EG, Bussey HJR. Pelvic recurrence after excision of rectum for carcinoma. Br Med J 1963; ii:13–8. 59. Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 2004; 240:711–7. 60. Borschitz T, Junginger T. Value of local surgical therapy of rectal cancer. A literature analysis. Zentralbl Chir 2003; 128:1066–74. 61. Borschitz T, Heintz A, Junginger T. The influence of histopathologic criteria on the long-term prognosis of locally excised pT1 rectal carcinomas: results of local excision (transanal endoscopic microsurgery) and immediate reoperation. Dis Colon Rectum 2006; 49:1492–506. 62. Borschitz T, Heintz A, Junginger T. Transanal endoscopic microsurgical excision of pT2 rectal cancer: results and possible indications. Dis Colon Rectum 2007; 50:292–301. 63. Sengupta S, Tjandra JJ. Local excision of rectal cancer: what is the evidence?. Dis Colon Rectum 2001; 44:1345–61. 64. Sharma A, Hartley J, Monson JR. Local excision of rectal tumours. Surg Oncol 2003; 12:51–61. 65. Baron PL, Enker WE, Zakowski MF, et al. Immediate vs. salvage resection after local treatment for early rectal cancer. Dis Colon Rectum 1995; 38:177–81. 66. Guillem JG, Chessin DB, Jeong SY, et al. Contemporary applications of transanal endoscopic microsurgery: technical innovations and limitations. Clin Colorectal Cancer 2005; 5:268–73. 67. Hahnloser D, Wolff BG, Larson DW, et al. radial resection after local excision of rectal cancer: an oncologic compromise?. Dis Colon Rectum 2005; 48:429–37. 68. Nakagoe T, Ishikawa H, Sawai T, et al. Long-term outcomes of radical surgery after gasless video endoscopic transanal excision of T1/T2 rectal cancers. Eur J Surg Oncol 2004; 30:638–42.