Systematic review and metaanalysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer

Meta-analysis
Systematic review and meta-analysis of outcomes following
pathological complete response to neoadjuvant
chemoradiotherapy for rectal cancer
S. T. Martin, H. M. Heneghan and D. C. Winter
Institute for Clinical Outcomes, Research and Education (iCORE) and Department of Colorectal Surgery, St Vincent’s University Hospital,Dublin, IrelandCorrespondence to: Mr S. T. Martin, Department of Colorectal Surgery, St Vincent’s University Hospital, Elm Park, Dublin 4, Ireland(e-mail: drseanmartin@gmail.com) Background: Following neoadjuvant chemoradiotherapy (CRT) and interval proctectomy, 15 – 20 per
cent of patients are found to have a pathological complete response (pCR) to combined multimodal
therapy, but controversy persists about whether this yields a survival benefit. This systematic review
evaluated current evidence regarding long-term oncological outcomes in patients found to have a pCR
to neoadjuvant CRT.
Methods: Three major databases (PubMed, MEDLINE and the Cochrane Library) were searched. The
systematic review included all original articles reporting long-term outcomes in patients with rectal
cancer who had a pCR to neoadjuvant CRT, published in English, from January 1950 to March 2011.
Results: A total of 724 studies were identified for screening. After applying inclusion and exclusion
criteria, 16 studies involving 3363 patients (1263 with pCR and 2100 without) were included (mean
age 60 years, 65·0 per cent men). Some 73·4 per cent had a sphincter-saving procedure. Mean follow-up
was 55·5 (range 40–87) months. For patients with a pCR, the weighted mean local recurrence rate
was 0·7 (range 0–2·6) per cent. Distant failure was observed in 8·7 per cent. Five-year overall and
disease-free survival rates were 90·2 and 87·0 per cent respectively. Compared with non-responders, a
pCR was associated with fewer local recurrences (odds ratio (OR) 0·25; P = 0·002) and less frequent
distant failure (OR 0·23; P < 0·001), with a greater likelihood of being alive (OR 3·28; P = 0·001) and
disease-free (OR 4·33, P < 0·001) at 5 years.
Conclusion: A pCR following neoadjuvant CRT is associated with excellent long-term survival, with low
rates of local recurrence and distant failure.
Paper accepted 12 January 2012
Published online 23 February 2012 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.8702
Introduction
Currently, there is no level 1 evidence that a pathological complete response (pCR) confers a survival advantage Over the past decade neoadjuvant chemoradiotherapy and conflicting data exist, but are limited by small (CRT) followed by interval proctectomy has become the study numbers and short duration of follow-up. That standard of care for locally advanced rectal cancer, result- a pCR represents a good prognosis for patients with ing in improved local control without affecting long-term rectal cancer remains to be shown definitively. Despite an survival1–4. Many studies have shown that neoadjuvant apparent complete luminal and mural tumour response,up to 17 per cent of ypT0 tumours harbour disease CRT is associated with significant pathological downstag- in the mesorectal lymph nodes (ypN+)9. Similarly, ing of rectal cancers, with up to 20 per cent of patients approximately 8 per cent of patients with an apparent having complete tumour sterilization (defined as absence incomplete clinical response have a pCR10. The challenge of adenocarcinoma cells in the surgical resection specimen: remains to identify those patients with a clinical complete pathological stage after CRT (yp) T0 N0 M0)5–8.
response (cCR) who have a true pCR; it is likely  2012 British Journal of Surgery Society Ltd British Journal of Surgery 2012; 99: 918–928
Outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer
that combined radiological, biochemical and molecular Cochrane database search was performed by combining biological markers will be required to predict accurately the following search terms using the Boolean AND/OR the ypN status of ypT0 tumours. For selected patients operators: ‘rectal cancer’, ‘resection’ and ‘surgery’. For the with a cCR, transanal excision of the residual scar to PubMed and MEDLINE database searches, these same confirm the ypT0 status may suffice, followed by an keywords (and variants) were used as both text words expectant observational approach, obviating the need and Medical Search Headings (MeSH) terms, and were for radical surgery and possible permanent colostomy.
combined by using Boolean operators as follows: (‘rec- Whether patients with a pCR should undergo adjuvant tal cancer*’ OR ‘rectal tumor*’ OR ‘rectal tumour*’) chemotherapy also remains the subject of debate.
AND (‘chemoradiotherapy’ OR ‘neoadjuvant therapy*’ The aim of this systematic review was to evaluate the OR ‘pre-operative chemoradiotherapy’) AND (‘pathologic oncological outcomes of patients with a pCR after neoad- complete response*’ OR ‘tumour regression grade*’). The juvant therapy followed by interval proctectomy. The search was limited to original papers based on human stud- primary outcomes of interest were rates of local recur- ies, and there was no restriction on the date of publication.
rence, distant recurrence, 5-year overall survival and 5-yeardisease-free survival (DFS). These data were then com- Study selection
pared with those of patients having an incomplete or noresponse to neoadjuvant therapy.
Only articles published in the English language betweenJanuary 1950 and March 2011 were included for review.
Included were studies of patients with rectal tumours who underwent neoadjuvant CRT and radical rectal This review was conducted according to the Preferred resection, which reported oncological outcomes and Reporting Items for Systematic Reviews and Meta- survival endpoints. Patients who had transanal excision of tumours and those who did not proceed to surgery wereexcluded from analysis. Only studies that included patientswith pathologically verified rectal cancer were included.
Search strategy for identification of studies
A minimum mean (or median) follow-up of 40 months A systematic literature search of the Cochrane Library, and a minimum cohort of 40 patients was required for PubMed and MEDLINE databases was performed. The all included studies. Studies including recurrent lesions Citations identified for screening n = 724 Rejected (met exclusion criteria) n = 674 Rejected (did not meet inclusion criteria) n = 28 Additional studies identified from bibliographies and Rejected (duplicate/kin studies, insufficient data for pooling, or additional studies did not meet inclusion Fig. 1 Flow chart illustrating study screening and selection process
 2012 British Journal of Surgery Society Ltd British Journal of Surgery 2012; 99: 918–928
S. T. Martin, H. M. Heneghan and D. C. Winter
or lesions that had already been treated surgically were Assessment of methodological quality of studies
excluded. Other excluded studies were those reporting All eligible studies were assessed for methodological quality on the technique or feasibility only. Multiple publications by two independent reviewers. The Newcastle–Ottawa involving the same series of patients (or duplicate patient Quality Assessment Scale for non-randomized cohort populations) were identified and grouped together; only studies was applied by two reviewers to determine the the most recent or parent study was included in this review overall quality of each eligible study. Points were awarded to avoid double-counting of patients. Where there was for patient selection (maximum 4 points), comparability uncertainty about duplicate patient groups (same group or of cohorts (maximum 2 points) and outcome assessment institution reporting outcomes for a similar period, without (maximum 3 points), and summed to give an overall clear indication that the smaller report was a substudy or quality rating with a maximum of 9 points12. Details interim results), a consensus was reached among the review of the scoring system are shown Table S1 (supporting authors regarding its inclusion or exclusion.
Table 1 Baseline characteristics of studies included in the systematic review
*Values in parentheses are percentages. †All received long-course radiotherapy. ‡Only patients with a pathological complete response (pCR) reported.
§Only 58 per cent of patients received 5-fluorouracil (5-FU). ¶Excluding reference 15. TNM, tumour node metastasis; NR, not reported.
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Outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer
Data collection and statistical analysis
outcomes in those with a pCR versus patients with anincomplete or no response to neoadjuvant CRT), study Data extracted from selected studies included: year of characteristics and patient outcomes were obtained for all publication, authors’ institution, number of patients and baseline characteristics, preoperative stage of disease, Where possible, pooled analyses were performed using details of neoadjuvant and adjuvant therapy, distance of the DerSimonian–Laird random-effects model to compute tumour from the anal verge, interval to surgery, type odds ratios (ORs) with 95 per cent confidence intervals of surgery, pCR rate, duration of follow-up, survival (c.i.). The decision to use a random-effects model was statistics (5-year overall survival and DFS), local recurrence made in advance as a degree of heterogeneity between and distant recurrence rates. Statistical analyses were studies was anticipated. The P value for overall effect was performed only on the extracted data from the selected calculated by means of the Z test and significance was set at P < 0·050. The pooled ORs and 95 per cent c.i.
Basic descriptive statistics (percentages and weighted are presented graphically as forest plots. Each study is means) were used to summarize the patient, study and represented as a square on the chart area, the area of which outcomes data. Weighted means were calculated for is proportional to the weight of the study (the inverse of oncological outcomes across all studies. Where studies the study variance). The summary measure is represented reported results by sex, age or disease stage, the overall by a diamond, the width of which corresponds to the results were calculated using the proportional mix of sexes 95 per cent c.i. The degree of heterogeneity is presented as (or other variable) and individual scores. In studies with a the Q and I2 statistics. The I2 index of heterogeneity control group (for example comparative studies comparing represents the percentage of the total variation, due Table 2 Outcomes in 1263 patients with a pathological complete response, determined at a mean follow-up of 55.5 months
*Three of 165 patients had metastases at surgery and did not undergo resection. Patients who had transanal excision (TAE) or no resection were excludedfrom the weighted means analysis. (L)AR, (low) anterior resection; APR, abdominoperineal resection; (T)PC, (total) proctocolectomy; CAA, coloanalanastomosis; IPAA, ileal pouch–anal anastomosis.
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S. T. Martin, H. M. Heneghan and D. C. Winter
to variation between studies. An I2 value of 0 per cent thorough review of the remaining 22 publications, a further indicates no heterogeneity, 25 per cent low heterogeneity, eight eligible studies were identified from bibliographies 50 per cent moderate heterogeneity and 75 per cent high and related citations. Of these 30 primary studies, 16 heterogeneity between studies13. The software package contained sufficient detail or met the criteria to merit inclusion in this review (Fig. 1).
(BioSTAT, Englewood, New Jersey, USA) was used toperform the meta-analysis and generate forest plots.
Study characteristics
The data set consisted of 16 original studies5,6,8,14–26.
The majority were from Europe (6) or the USA (5); Search yields and data retrieval
three were from Asia and one each from Canada andAustralia. Regarding study design, the majority (14) were The initial literature search yielded 724 citations, of which retrospective comparative or case studies; only two were 674 studies were excluded after initial screening of titles documented as prospective cohort studies. These studies and abstracts. Of the 50 papers reviewed in full, 28 were are summarized in Table 1 and study quality is outlined in rejected because they did not fulfil the inclusion criteria. On Table S1 (supporting information).
Test for heterogeneity: Q = 1·9, 8 d.f., P = 0·981, I2 = 0% a Local recurrence
Test for heterogeneity: Q = 14·63, 8 d.f., P = 0·067, I2 = 45% b Distant recurrence
Fig. 2 Forest plots showing a local recurrence and b distant disease recurrence in patients with versus those without a pathological
complete response (pCR) to chemoradiotherapy. A random-effects model was used for meta-analysis. Odds ratios are shown with
95 per cent confidence intervals
 2012 British Journal of Surgery Society Ltd British Journal of Surgery 2012; 99: 918–928
Outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer
Patient characteristics
rate for the entire cohort was 24·4 (range 10·3–91·3)per cent.
All patients had biopsy-proven rectal adenocarcinoma The 16 studies included 3363 patients who had undergoneneoadjuvant CRT followed by interval proctectomy for before starting therapy. The most consistent method of rectal cancer. The mean age of included patients was reporting disease stage was the American Joint Committee 60 years and 65·0 per cent were men. Some 1263 had a on Cancer tumour node metastasis (TNM) staging system.
pCR, and 2100 had an incomplete or no response. One The stage was clearly documented in 11 of 16 studies; three study reported data only from 536 patients who had a studies reported that all patients had stage II/III disease, pCR to neoadjuvant CRT15. Excluding this study from without subclassification. Among studies that described the pooled estimates and meta-analysis, the mean pCR TNM stage, 34·1 per cent of patients had clinical stage Test for heterogeneity: Q = 27·6, 11 d.f., P = 0·004, I2 = 60% a Overall survival
Test for heterogeneity: Q = 25·0, 11 d.f., P = 0·009, I2 = 56% b Disease-free survival
Fig. 3 Forest plots showing a overall and b disease-free survival in patients with versus those without a pathological complete response
(pCR) to chemoradiotherapy. A random-effects model was used for meta-analysis. Odds ratios are shown with 95 per cent confidence
intervals
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S. T. Martin, H. M. Heneghan and D. C. Winter
II and 64·8 per cent had clinical stage III disease. Clinical Discussion
staging was achieved by a combination of pelvic magneticresonance imaging, endoanal ultrasonography and com- Neoadjuvant CRT produces a pCR in 15–20 per centof patients with locally advanced rectal cancer5–8. Data puted tomography. Mean distance of tumours from the from this review show that local recurrence rates anal verge, measured at proctoscopy, was 53·6 mm.
(0·7 per cent), 5-year overall survival (90·2 per cent) and All patients received neoadjuvant CRT consisting of DFS (87·0 per cent) are comparable with those after R0 long-course radiotherapy (45 Gy in 7 studies and 50–50·4 proctectomy for stage I rectal cancer27.
Gy in 9). A variety of chemotherapeutic regimens were The effect of pCR on local recurrence after surgical used to radiosensitize, with 5-fluorouracil (5-FU) being excision is dramatic. With the advent of neoadjuvant used in all 16 studies (Table 1). A restorative sphincter- CRT and optimization of surgical technique, including saving procedure was performed in 73·4 per cent of widespread adoption of total mesorectal excision, local patients, 22·7 per cent had an abdominoperineal resec- recurrence rates have fallen dramatically after R0 resec- tion and 3·9 per cent an alternative procedure (low Hart- tion of locally advanced rectal cancer1,28–31. With surgery mann’s, pelvic exenteration, total proctocolectomy, ante- alone, local failure after rectal cancer surgery tends to occur rior resection or transanal excision). Information on adju- before distant failure and predominantly within the first vant chemotherapy was available for 13 of 16 studies; 2 years32–35. However, data exist to suggest that neoadju- 61·4 per cent of patients in the pCR cohort received adju- vant CRT before radical surgery delays the development of pelvic recurrence36,37. Even with close surveillance andearly detection of local recurrence, many patients are notamenable to curative resection. For those who are, survival Oncological outcomes
rates after radical salvage surgery remain suboptimal38–40.
Capirci and colleagues15 have published the largest expe- Mean follow-up was 55·5 months and seven studies rience of patients with a pCR following neoadjuvant CRT; reported follow-up of 5 years or more. Oncological out- after a median follow-up of 46 months, they reported a comes are summarized in Table 2. Tumour recurrence in local failure rate of 0·9 per cent with distant failure occur- the pelvis (presacral, pelvic side wall or anastomotic) was ring in 8·9 per cent of those undergoing radical surgery considered a local recurrence, and diagnosed by a com- after neoadjuvant CRT. Median time to detection of pelvic bination of clinical, histopathological, biochemical and recurrence was 26 months. Maas and co-workers41 recently radiological abnormalities. Recurrence of disease outside published a comparative study addressing oncological out- the pelvis was considered a distant recurrence. Outcomes comes for patients with and without a pCR to neoadjuvant of patients who had a pCR are compared with those of CRT. The 5-year crude DFS rate in patients with a pCR incomplete responders in Table S2 (supporting informa- was 83·3 per cent compared with 65·6 per cent for incom- tion). Twelve studies reported a 5-year local recurrence rate plete responders. Five-year local recurrence rates were 2·8 of 0 per cent among patients who had a pCR. The overall versus 9·7 per cent, and the rate of distant metastasis was weighted mean local recurrence rate among all studies was 11·2 versus 25·2 per cent. These data are similar to the 0·7 (range 0–2·6) per cent. Those with a pCR were almost findings reported here. Many of the studies included in four times less likely to develop local failure compared with the Maas article were not included in the present review incomplete responders (OR 0·25, 0·10 to 0·59; P = 0·002) as Maas and co-workers included updated data and unpub- (Fig. 2a). Distant failure or metastasis was noted in lished personal contributions from authors of published 8·7 per cent of patients who had a pCR, at median follow- previously studies; these data were unavailable to the up of 55·5 months. A pCR was associated with a greater than fourfold decrease in the likelihood of developing The present finding of a local recurrence rate of distant failure (OR 0·23, 0·11 to 0·47; P < 0·001) (Fig. 2b).
0·7 per cent at median follow-up of 55·5 months suggests The 5-year overall survival rate for patients with a pCR that a pCR after neoadjuvant CRT practically eradicates was 90·2 per cent; these patients had a 3·3-fold overall the risk of local recurrence following surgery. Many data survival advantage compared with incomplete responders have emerged to support the contention that a pCR also (OR 3·28, 1·66 to 6·51; P = 0·001) (Fig. 3a). A 5-year DFS improves oncological outcomes in terms of distant failure.
rate of 87·0 per cent was noted in those with a pCR. This Of the studies included in this analysis, all but one19 showed group was 4·3 times more likely to be disease-free at 5 years a survival advantage for patients who had a pCR compared than non-responders (OR 4·33, 2·31 to 8·09; P < 0·001) with those who had an incomplete or no response to neoadjuvant CRT5,6,8,14–18,20–26. In an analysis of 106  2012 British Journal of Surgery Society Ltd British Journal of Surgery 2012; 99: 918–928
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patients treated with neoadjuvant CRT before radical The major implication of a pCR to neoadjuvant CRT, surgery, Pucciarelli and colleagues19 did not find a survival in terms of oncological outcomes, is that the patient benefit associated with a pCR. Their data suggested that may become eligible for less radical surgical resection clinical T category and neoadjuvant chemotherapeutic or an expectant ‘watch and wait’ approach. In selected regimens were the most accurate predictors of outcome patients who appear to have a complete luminal/mural following neoadjuvant therapy. However, a small number response, many observers recommend transanal excision of patients in that study did have a pCR (19, 17·9 per cent) of the tumour scar to ensure ypT0 status with observation and follow-up was relatively short at 40 months. Onaitis of the mesorectal lymph nodes48–54. Habr-Gama and and colleagues42 similarly did not demonstrate a local colleagues10 advocated an expectant policy for patients with recurrence or survival advantage for 30 patients who had a a cCR after neoadjuvant CRT. In a series of 265 patients, 71 pCR, compared with 110 who had an incomplete or absent (26·8 per cent) had a cCR; of these, only 2·8 per cent had response; however, interpretation of these data is tempered an endoluminal recurrence, which was treated successfully by limited follow-up of 27 months. The study by Onaitis with transanal excision or brachytherapy. No pelvic et al. was not included in the present review as it did not recurrences were observed, but 4·2 per cent developed distant metastases. Ten-year overall survival and DFS Although local recurrence appears to be eradicated rates in patients who achieved a cCR were 100 and almost completely by a pCR, distant failure is not. In this 86 per cent10. However, patients displaying an apparent review 8·7 per cent of patients developed metastatic dis- cCR after neoadjuvant CRT may still have disease in ease despite achieving a pCR. This rate of distant failure, the mesorectal lymph nodes. It has been reported that despite the apparent disappearance of the primary tumour, 2–27 per cent of ypT0 tumours are ypN+9,55–59.
may be an indication that adjuvant chemotherapy is war- The ability to identify patients with a cCR who are ranted in these patients. The primary role of 5-FU as part also likely to have a pCR would have major clinical of a neoadjuvant regimen is to radiosensitize the primary implications. If such information were available and tumour. In itself, neoadjuvant 5-FU provides very little accurate, it could obviate the need for radical surgery chemotherapeutic benefit. Although the primary tumour and possibly a permanent stoma in selected patients. It is may be sterilized completely following CRT, viable distant hoped that advances in radiological imaging, molecular micrometastatic cells may not respond and could provoke biology and biochemical markers may facilitate this.
distant failure. Thus, the challenge remains to identify Outcomes following salvage surgery for local endoluminal patients with a pCR who can potentially benefit from recurrence of disease are comparable with those of adjuvant chemotherapy. Many groups are now explor- primary surgery after neoadjuvant CRT. However, when ing the possibility of increasing the pCR rate followingneoadjuvant CRT. Administration of additional radio- an expectant observational approach fails, survival is therapy (‘boost dose’), concomitant non-radiosensitizing significantly compromised by systemic failure60.
infusional chemotherapy43, chemotherapy before neo- This review has several limitations. There is concern adjuvant CRT44 and use of alternative chemotherapeu- regarding outcome reporting bias given that not every tic agents for radiosensitization24,45 have all been shown to study reported all four oncological outcomes (local recurrence, distant recurrence, overall survival and DFS).
Increasing the interval to surgery has also been Similarly, with regard to publication bias, a sensitivity postulated to increase the pCR rate by facilitating analysis suggested that there might be three missing prolonged tumour necrosis. Tulchinsky and colleagues studies reporting data on overall survival and DFS, et al.46 found that increasing the interval to surgery to but imputing data from these studies would not have more than 7 weeks improved the pCR rate to 35 per cent, altered the point estimates significantly (according to a compared with 17 per cent in those undergoing surgery ‘trim and fill’ analysis). All patients received long-course within 7 weeks; interval to surgery was prognostic of overall radiotherapy and, although a variety of radiosensitizing survival and DFS on multivariable analysis. Similarly, chemotherapeutic regimens were employed, 5-FU was Kalady and co-workers47 found that increasing the interval used in all patients. Data on adjuvant chemotherapy to more than 8 weeks was associated with a higher were incomplete; however, in the 12 studies reporting rate of pCR, and improved local control and overall its use, 61·4 per cent of patients received adjuvant therapy.
survival. A National Institutes of Health study is currently It would be of interest to know what proportion of patients investigating the optimal delay to surgery after neoadjuvant experiencing local and distant failure received adjuvant CRT, with intervals ranging from 6 to 24 weeks7.
chemotherapy, but these data were not reported.
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The challenge remains to identify those with a cCR response to preoperative chemoradiation. Ann Surg 2010; and a ‘true pCR’ who may be spared radical surgery 251: 261–264.
and, similarly, patients with a pCR who may benefit from 9 Bedrosian I, Rodriguez-Bigas MA, Feig B, Hunt KK, Ellis L, adjuvant chemotherapy to minimize the risk of subsequent Curley SA et al. Predicting the node-negative mesorectum local or distant failure. It is concluded that a pCR is after preoperative chemoradiation for locally advanced rectal associated with excellent long-term oncological outcomes, carcinoma. J Gastrointest Surg 2004; 8: 56–62.
10 Habr-Gama A, Perez RO, Nadalin W, Sabbaga J, Ribeiro U almost eradicating local failure and achieving low rates of Jr, Silva e Sousa AH Jr et al. Operative versus nonoperative distant failure with high rates of overall survival and DFS.
treatment for stage 0 distal rectal cancer followingchemoradiation therapy: long-term results. Ann Surg 2004; Acknowledgements
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11 Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred The authors thank Jeff Hammel for statistical guidance in reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535.
Disclosure: The authors declare no conflict of interest.
12 Stang A. Critical evaluation of the Newcastle–Ottawa scale for the assessment of the quality of nonrandomized studies in
meta-analyses. Eur J Epidemiol 2010; 25: 603–605.
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Supporting information
Additional supporting information may be found in the online version of this article: Table S1 Newcastle–Ottawa Quality Assessment Scale score for studies included in the review (Word document)
Table S2 Oncological outcomes of patients who had a pathological complete response to neoadjuvant
chemoradiotherapy versus those who did not (mean follow-up 55·5 months) (Word document)
Please note: John Wiley & Sons Ltd is not responsible for the functionality of any supporting materials suppliedby the authors. Any queries (other than missing material) should be directed to the corresponding author for thearticle.
 2012 British Journal of Surgery Society Ltd British Journal of Surgery 2012; 99: 918–928

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