Miranda Kusters

Corrie A M Marijnen

Cornelis J H Van De Velde
email: c.j.h.van_de_velde@lumc.nl

Harm J T Rutten

Max J Lahaye

Joo H Kim

Regina G H Beets-Tan

Geerard L Beets

Prof. C.J H Van De Velde

Patterns of local recurrence in rectal cancer; a study of the Dutch TME trial

Keywords: Local recurrence, rectal carcinoma, abdominoperineal resection, low anterior resection, distal margin, preoperative radiotherapy

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

M A N U S C R I P T A C C E P T E D ARTICLE IN PRESS

Introduction

Optimal local control is an important goal in the treatment of rectal cancer. Since the introduction of the total mesorectal excision (TME) local control has improved drastically, with further improvement through the addition of preoperative radiotherapy 1;2 . In the Dutch TME trial, surgeons were trained in TME-surgery by workshops and tutorials in order to achieve optimal surgical quality. Although locally advanced tumors were supposed to be excluded, only fixed tumors at rectal examination could be identified, since routine imaging was not mandatory at that time [START_REF] Kapiteijn | Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer[END_REF] . However, histological evaluation of the circumferential resection margins (CRM) suggested that a substantial proportion of advanced tumors had been included [START_REF] Nagtegaal | What is the role for the circumferential margin in the modern treatment of rectal cancer?[END_REF] . Suspected CRM involvement, T4 disease and massive lymph node involvement, all risk factors for local recurrence, can currently be well identified by preoperative MR imaging 4;5 . In the presence of these risk factors, nowadays a long course of neo-adjuvant (chemo)radiation would be given in order to achieve downsizing and downstaging before surgery [START_REF] Bosset | Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results--EORTC 22921[END_REF] .

The purpose of this study is to analyze the patterns of local recurrence in the TME trial, reconstructing the most likely mechanisms of local recurrence and the effect of preoperative radiotherapy.

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Patients and methods

Patients

Patients were selected from a large prospective randomized multi-center study that analyzed the effect of short-term preoperative radiotherapy (5 x 5 Gy) in patients operated with a total mesorectal excision (RT+TME), compared to patients with TME alone (TME). Inclusion criteria were primary adenocarcinoma of the rectum, without evidence of metastatic disease and tumor location within 15 cm from the anal verge. Patients with other malignant diseases or with fixed tumors were excluded.

Standardized techniques for surgery, radiotherapy and pathology were used [START_REF] Kapiteijn | Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer[END_REF] .

For the current study only the Dutch patients were selected and the following patients were excluded from the analysis: ineligible patients (n = 50), no resection (n = 37) and no tumor at operation (n = 26), leaving 1417 patients for analysis.

Methods

All patients with a local recurrence, defined as any rectal cancer recurrence in the small pelvis, were identified. Local recurrence was diagnosed either clinically, radiologically or histologically. All patients with a local recurrence were studied individually. Sources of information additional to the standard trial database items were the operative report, the histological report, specimen photographs when available, initial preoperative imaging when available, imaging of the local recurrences, and the clinical history and follow up after the diagnosis of the local recurrence. The data were reviewed case by case by a team consisting of 2 radiologists, 1 radiation oncologist and 2 surgeons.

Examining the images and data, the location of the recurrence was classified into one of the following subsites:

• Presacral: predominantly midline, in contact with sacral bone • Perineal: perineum, anal sphincter complex with surrounding perianal and ischiorectal space Although the distal margin for the low anterior resections and low Hartmann's was prospectively recorded, the database did not contain reliable information on the completeness of the mesorectum distally. For the patients with a local recurrence the operative reports were studied to define whether the distal mesorectum was transsected below the tumor, or if a distally complete mesorectal excision was performed.

Statistical analysis

Statistical analysis was performed using SPSS package (SPSS 12.0 for Windows; SPSS Inc, Chicago, IL). T-tests and chi-square tests were used to compare individual variables. Survival was estimated using the Kaplan-Meier method. Differences were assessed using the Log-Rank test. P-values were two-sided and considered statistically significant at a value of 0.05 or less. For local recurrence, cumulative incidences were calculated accounting for death as competing risk [START_REF] Putter | Tutorial in biostatistics: competing risks and multistate models[END_REF] . Similarly, cumulative incidences were calculated for subsite of local recurrence, with death and other types of local recurrence as competing risks, and for survival, with death due to other causes as competing risk.

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Results

Clinical and pathological characteristics

Clinical and pathological characteristics are listed in Table 1. Low tumor location, abdominoperineal resection (APR) surgery, higher TNM stage and involvement of the circumferential resection margin are associated with local recurrence, as previously reported [START_REF] Peeters | The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma[END_REF] . After a median follow-up of 7.0 years (range 2.5-9.8) 114 of the 1417 patients developed a local recurrence; 36 patients in the RT+TME group (5-year 4.6% LR-rate) and 78 patients in the TME group (5-year 11.0% LR-rate).

The mean time to local recurrence is 2.6 years in RT+TME group and 1.5 years in the TME group.

Nineteen of 36 patients (55%) in the RT+TME group had distant metastases at the time of local recurrence diagnosis. This was in 32 of 78 (41%) patients in the TME group (p = 0.264). If distant metastases diagnosed within 1 month of local recurrence diagnosis were also considered as occurring simultaneously, distant metastases rate was 74% in the RT+TME group and 40% in the TME group (p = 0.004) [START_REF] Van Den Brink | Clinical nature and prognosis of locally recurrent rectal cancer after total[END_REF] .

Patterns of local recurrence

The subsites of local recurrence are presented in Table 2. Presacral local recurrences (Figure ) occurred most in both randomisation groups (5-year local recurrence rate RT+TME: 2.0% and TME: 3.6%).

There was a significant difference between the two randomisation arms in the anastomotic subsite, with 0.7% 5-year local recurrence in the RT+TME group and 2.7% in the TME group (p = 0.003).

Lateral local recurrences comprised about 20% of all local recurrences.

Surgical aspects

Type of surgery

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In patients undergoing a LAR or Hartmann procedure, 67 of 981 developed a local recurrence (5-year 7.8% LR-rate). In contrast, 47 of 389 patients who underwent an APR developed a local recurrence (5year 11.7% LR-rate). In LAR patients, the majority of the recurrences was anastomotic 24/67 (36%) or presacral 19/67 (28%). In APR patients, presacral recurrences presented most often 21/47 (45%).

CRM involvement

In total, 267 patients had a positive CRM on pathology examination. Of those, 46 developed a local recurrence, indicating that CRM involvement is not the only factor explaining the occurrence of local relapses. Twenty-nine of the 267 patients (10.9%) with a positive CRM had a T1 or T2 tumor, suggesting that suboptimal surgery played a role in the occurrence of those relapses. In these 29 patients local recurrence rate was 12.4% after 5 years, whereas this was 23.6% in T3 or T4 tumors with a positive CRM (p = 0.217). Forty-one percent of these 29 patients had undergone a LAR, 59% had undergone an APR. In tumors operated by LAR with a negative CRM, local recurrence rate was 3.5% in N0 tumors and 12.5% in N+ tumors (p < 0.001). Similarly for tumors operated by APR with a negative CRM, local recurrence rate was 2.0% in N0 tumors and 18.0% in N+ tumors (p <0.001).

Distal margin

To investigate the influence of the distal margin on the occurrence of local recurrences, local relapses were stratified for distal margin and lymph node involvement by treatment arm in Table 3. TME alone in node positive disease resulted in considerable local recurrence rates when the distal margin was 2 cm or shorter. In node negative disease local recurrence rates were not significantly different for the separate margin groups. Radiotherapy resulted in small numbers of local recurrence, except when distal margins were less than 5 mm. For the patients with a local recurrence after LAR or Hartmann procedure, in 25 of 67 (37%) the distal mesorectum was transsected below the tumor, in 33 (49%) a distally complete mesorectal excision was performed, and in 9 (13%) it was unknown whether a complete or a partial mesorectal excision had been performed. In both partial and complete excision mean distal margin was 2.7 cm. In retrospect, 421 patients (30%) had at least one of the above-mentioned risk factors (IV stage: 87, T4: 51, N2: 236, CRM+: 267). Of those 421, 204 patients received RT+TME and 215 patients underwent TME only. The 5-year local recurrence rate was 17.0% and 24.6% respectively, indicating that the addition of short-term preoperative RT still resulted in an unacceptable high number of recurrences in this group. Sixty-six out of 114 local recurrences (58%) occurred in patients with risk factors; 23 (35%) were presacral, 18 (27%) were lateral, 14 (21%) were anterior and the remaining 11 were located in other areas. In 39 of these 66 (59%) the local recurrence occurred simultaneously with distant metastases.

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Forty-eight out of 114 local recurrences (42%) occurred in patients without risk factors. For patients without risk factors, 5-years LR-rates were 2.3% for the RT+TME group and 7.9% for the TME group (p < 0.001). Interestingly, in this group, a large percentage of the recurrences occurred in the anastomosis 18/48 (38%), whereas the percentage of presacral recurrences 17/48 (35%) was similar.

Compared to the group of patients with risk factors, lateral recurrences were seen in only 10% (5/48).

In 12 of these 48 (25%) the local recurrence appeared simultaneously with distant metastases. In this study we demonstrate that preoperative radiotherapy reduces local recurrences in all subsites and is especially effective in preventing in anastomotic recurrences. In addition, we found that shortterm preoperative radiotherapy reduces the number of recurrences caused by a too short distal margin.

Survival M A N U S C R I P T A C C E P T E D ARTICLE IN
Abdominoperineal resection mainly resulted in presacral local recurrences; even after resection with a negative circumferential resection margin, local relapse rate was high. Further, suboptimal selection and inclusion of many 'advanced tumours' in the TME trial is likely to be a factor most recurrences.

Low anterior resection

Apart from presacral recurrences, anastomotic recurrences are relatively frequent, especially in nonirradiated LAR patients. Table 3 suggests that node positive patients who did not undergo radiotherapy require a larger distal margin (more than 2 cm) than node negative patients, where a margin of 1 cm seems sufficient.

A complicating factor in analyzing the sphincter-saving procedures in the TME trial is that a total mesorectal excision down to the pelvic floor was not mandatory and surgeons were allowed to transsect the mesorectum 5 cm below the tumor. Unfortunately, it is unclear what proportion of the patients received a partial mesorectal excision in stead of a TME. However, the difference between node positive and node negative patients suggests that the risk is not so much in intramural spread as Chinese histological studies have reported that distal intramural spread is seen in about only 5% of rectal cancer patients, usually within 1 cm of the lower edge of the tumor 10-12 . Koh et al 13 , examining the distribution of mesorectal lymph nodes based on imaging and histopathology, hardly found any lymph nodes distal to the tumor. This in contrast to an anatomical cadaver study of Perez et al 14 , who found lymph nodes up to the distal third of the mesorectum. However, several studies reported distal mesorectal spread in 10-15% of rectal cancer patients, usually within 2-3 cm and more often in the form of small mesorectal deposits than involved nodes [10][11][12] .

Probably, the risk for mesorectal tumor deposits is larger in node positive than in node negative patients. Therefore, surgeons should be aware that in node positive patients a transsection of the mesorectum closer to the tumor carries a risk of leaving small tumor deposits behind. This should be kept in mind when for some reason a patient is not receiving preoperative radiotherapy; then a mesorectal transsection of 5 cm below the tumor is a wise precaution in these patients. But still, radiotherapy can prevent anastomotic recurrences, except when distal margins are less than 5 mm.

Abdominoperineal resection

APR-surgery has shown poor results in several reports, with higher local recurrence rates than after low anterior resections 15 . In this study, APR-surgery mainly resulted in presacral local recurrences.

It is known from the TME trial, that APR is associated with higher CRM involvement [START_REF] Nagtegaal | What is the role for the circumferential margin in the modern treatment of rectal cancer?[END_REF] . We previously speculated that tumor spill from these positive margins might cause these presacral local recurrences through force of gravity 16 .

Anatomical and radiological studies show that in the lowest part of the rectum the mesorectum tapers and terminates at the pelvic floor 17 . If a tumor is located in the distal third of the rectum, the surrounding mesorectum is very thin, especially on the ventral side 18 . Near the anal margin the visceral fascia (covering the mesorectum) blends with the parietal fascia (covering the levator ani muscle), forming the corrugator muscle, which separates the internal from the external sphincter. At

M A N U S C R I P T A C C E P T E D ARTICLE IN PRESS

13 this level a tumor that extends only a few millimeters beyond the muscular bowel wall is at risk for a positive margin when following the normal resection plane.

Even when negative margins are achieved, these low tumors seem to behave differently compared to proximal tumors. In this study, as much as 18.0% of the CRM-negative N+ tumors operated by APR developed a local recurrence. Apparently, in these low tumors tumor particles still seem to be left behind even when the circumferential margin seems sufficient, causing local recurrences at various subsites. Possibly, during surgery tumor cells are pushed into the lateral lymph flow routes during surgery, leaking back into the surgical volume after the resection 19 .

A wide APR, resecting the complete levator ani muscle, might provide better local control of low tumors 16;20 . Japanese surgeons advocate the lateral lymph node dissection. Another option, favored by Japanese and Western surgeons, is chemoradiation prior to surgery in low T3 tumors, as if they are true locally advanced disease 21 . This has been reported to result in downstaging and even sometimes the possibility for sphincter-saving surgery 21 . It also addresses the small tumor particles that are apparently left behind in patients without involved margins, be it in lateral nodes or somewhere else.

Risk factors

An involved or close circumferential resection margin (CRM) has repeatedly been confirmed as one of the most important risk factors for local recurrence [START_REF] Nagtegaal | What is the role for the circumferential margin in the modern treatment of rectal cancer?[END_REF] . In the TME trial CRM-positivity was 17% and even as much as 30% after an abdominoperineal resection 22 . CRM involvement results in a high local recurrence rate, even if the tumor was a T1 or T2 stage tumor. In this study 89.1% of CRM-positivity occurred in T3 or T4 tumors, indicating that it is mainly attributable to adverse tumor factors and not so much to bad surgery. In most cases, a long course of neo-adjuvant (chemo)radiation, rather than a short-course of radiotherapy, can probably downstage these tumors and lead to better results [START_REF] Bosset | Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results--EORTC 22921[END_REF] . Thus, nowadays, with good imaging and preoperative discussion in a multidisciplinary team, a positive margin is probably more a sign of inadequate surgical technique rather than unrecognized advanced disease 23 .

Apart from the CRM, T4 tumors, massive lymph node involvement (N2 disease) and synchronous metastases can be considered as a sign of aggressive tumor biology. Although difficult to prove, short-

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14 term preoperative radiotherapy may be insufficient to prevent local recurrences in this subgroup. We therefore analyzed patients without risk factors resulting in a hypothetical 5-year LR-rate of 2.0% for the RT+TME group and 7.2% for the TME group. We realize this post-factum distinction between 'risk factors' and 'no risk factors' is a hypothetical approach that may be due to subjective interpretation. However, it gives insight in the outcomes and patterns of local recurrence for current practice, where good preoperative imaging is available. Nowadays it would be unlikely that these 'more advanced' tumors would be only subjected to a short course of preoperative radiotherapy.

Lateral disease

Although the main lymphatic flow is upward in the mesorectum, involvement of lateral nodes outside the mesorectum does occur. This has been studied in detail by Japanese surgeons who have documented that in low rectal cancer in general there is a 10% chance of involved lateral nodes. In advanced distal cancer this percentage is even 15-20% 24-26 . In the TME trial lateral local recurrences represent about 20% of all local recurrences, a figure in accordance with an overview of Roels et al 27 .

We can conclude that lateral disease is responsible for a considerable amount of local relapse. We previously analyzed only low rectal tumors, when lateral lymph node spread is especially present, and noticed a significant difference between the RT+TME and TME arms. Thus, radiotherapy can probably sterilize lateral tumor particles in most of the cases 16 .

A problem however arises if positive lateral lymph nodes are not included in the radiation target volume, as in intensity modulated radiation therapy (IMRT). In contrast to the TME trial, in which the lateral lymph nodes were probably always irradiated, smaller areas only receive a high dose of local radiotherapy in IMRT, not including the lateral areas if they are not suspected to be involved.

Finally, once local recurrence has occurred, almost all RT+TME patients develop distant metastases within one year and few survive for two years. This can be explained by the fact that patients who develop local relapse after RT+TME, are a selection of patients with more aggressive disease [START_REF] Van Den Brink | Clinical nature and prognosis of locally recurrent rectal cancer after total[END_REF] . In TME-patients anastomotic local recurrences seem to behave more as true local disease, compared to local recurrences in the other subsites, also mentioned by other authors 28;29 . As a consequence,

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15 although these recurrences may appear 'easier' to resect, because of the higher chances of cure they should be treated with a maximal curative intent, including neoadjuvant treatment and surgery in an expert centre. In this study centrally situated recurrences were treated surgically more often than peripheral tumors and were less often metastasized, possibly explaining the better prognosis of these tumors.

Concluding, a short course preoperative radiotherapy prevents local recurrence in all subsites and is especially effective in preventing anastomotic recurrences. Surgical technique and attention to distal margin can play a role in preventing local recurrences. Abdominoperineal resection surgery mainly results in presacral local recurrences, which may be prevented by a wider resection. The majority of the recurrences however are related to the advanced nature of the disease, which can nowadays be identified with modern imaging techniques and consequently be treated with neoadjuvant chemoradiation.

6 •

 6 Anterior: predominantly midline, involving bladder, uterus, vagina, seminal vesicles or prostate • Anastomotic: after low anterior or low Hartmann, at the staple line • Lateral: pelvic sidewall, immediately behind posterior ischiac spine, in the obturator lymph node compartment or along iliac vessels

  Tumor aspectsTo evaluate the effect of radiotherapy on local recurrences mainly caused by surgery-related factors or mainly due to biological tumor factors, a hypothetical division was made. Patients with tumors mainly caused by biological agressive tumor behaviour were considered as patients with risk factors. The following factors were considered risk factors: TNM stage IV disease, T4 tumor, N2 disease (4 or more involved lymph nodes) or a positive CRM in T3 or T4 disease. All other patients were considered as patients without risk factors. In those patients suboptimal surgery possibly played a role in the aetiology of the local recurrence. For patients without risk factors, the 5-year local recurrence rate was 5.1%, whereas this figure was 21.0% for patients with risk factors (p < 0.001).

  M A N U S C R I P T A C C E P T E D ARTICLE IN PRESS 11 Discussion The present study aimed at reconstructing the mechanisms of local recurrence and to analyze the effect of short-term preoperative radiotherapy through studying the details of all patients with local relapse in the TME trial. Since this trial preoperative imaging, preoperative therapy, surgery and adjuvant treatment modalities have changed, but still these new data give insight in local recurrence genesis and help understanding how to prevent local relapse in current rectal cancer treatment. We have shown that presacral local recurrences are the most common type of local recurrence and have a poor prognosis in general. Anastomotic and anterior recurrences have a relatively good prognosis.

  spread, since it is unlikely that node positive disease results in more extensive intramural spread.

  or without preoperative radiotherapy. J Clin Oncol 2004; 22(19):3958-3964. (10) Zhao GP, Zhou ZG, Lei WZ, Yu YY, Wang C, Wang Z et al. Pathological study of distal mesorectal cancer spread to determine a proper distal resection margin. World J Gastroenterol 2005; 11(3):319-322. (11) Wang Z, Zhou Z, Wang C, Zhao G, Chen Y, Gao H et al. Microscopic spread of low rectal cancer in regions of the mesorectum: detailed pathological assessment with whole-mount sections. Int J Colorectal Dis 2005; 20(3):231-237. (12) Chen W, Shen W, Chen M, Cai G, Liu X. Study on the relationship between lymphatic vessel density and distal intramural spread of rectal cancer. Eur Surg Res 2007; 39(6):332-339. (13) Koh DM, Brown G, Temple L, Blake H, Raja A, Toomey P et al. Distribution of mesorectal lymph nodes in rectal cancer: in vivo MR imaging compared with histopathological examination. Initial observations. Eur Radiol 2005; 15(8):1650-1657. (14) Perez RO, Seid VE, Bresciani EH, Bresciani C, Proscurshim I, Pereira DD et al. Distribution of lymph nodes in the mesorectum: how deep is TME necessary? Tech Coloproctol 2008; 12(1):39-43. (15) Heald RJ, Moran BJ, Ryall RD, Sexton R, MacFarlane JK. Rectal cancer: the Basingstoke experience of total mesorectal excision, 1978-1997. Arch Surg 1998; 133(8):894-899. (16) Kusters M, Beets GL, van de Velde CJ, Beets-Tan RG, Marijnen CA, Rutten H et al. A comparison between the treatment of low rectal cancer in Japan and the Netherlands, with focus on the patterns of local recurrence. Ann Surg 2009; 249(2):229-35.

  Salerno G, Sinnatamby C, Branagan G, Daniels IR, Heald RJ, Moran BJ. Defining the rectum: surgically, radiologically and anatomically. Colorectal Dis 2006; 8 Suppl 3:5-9. (18) den Dulk M, Marijnen CA, Putter H, Rutten HJ, Beets GL, Wiggers T et al. Risk factors for adverse outcome in patients with rectal cancer treated with an abdominoperineal resection in the total mesorectal excision trial. Ann Surg 2007; 246(1):83-90. (19) Kusters M, Holman FA, Martijn H, Nieuwenhuijzen GA, Creemers GJ, Daniels-Gooszen AW et al. Patterns of local recurrence in locally advanced rectal cancer after intra-operative radiotherapy containing multimodality treatment. Radiother Oncol 2009; Epub ahead of print. (20) Holm T, Ljung A, Haggmark T, Jurell G, Lagergren J. Extended abdominoperineal resection with gluteus maximus flap reconstruction of the pelvic floor for rectal cancer. Br J Surg 2007; 94(2):232-238. (21) Valentini V, Coco C, Cellini N, Picciocchi A, Rosetto ME, Mantini G et al. Preoperative chemoradiation with cisplatin and 5-fluorouracil for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, sphincter preservation. Int J Radiat Oncol Biol Phys 1999; 45(5):1175-1184. (22) Nagtegaal ID, van de Velde CJ, Marijnen CA, van Krieken JH, Quirke P. Low rectal cancer: a call for a change of approach in abdominoperineal resection. J Clin Oncol 2005; 23(36):9257-9264. (23) Burton S, Brown G, Daniels IR, Norman AR, Mason B, Cunningham D. MRI directed multidisciplinary team preoperative treatment strategy: the way to eliminate positive circumferential margins? Br J Cancer 2006; 94(3):351-357. M A N U S C R I P T A C C E P T E D ARTICLE IN PRESS 20 (24) Steup WH, Moriya Y, van de Velde CJ. Patterns of lymphatic spread in rectal cancer. A topographical analysis on lymph node metastases. Eur J Cancer 2002; 38(7):911-918. (25) Moriya Y, Sugihara K, Akasu T, Fujita S. Patterns of recurrence after nerve-sparing surgery for rectal adenocarcinoma with special reference to loco-regional recurrence. Dis Colon Rectum 1995; 38(11):1162-1168. (26) Mori T, Takahashi K, Yasuno M. Radical resection with autonomic nerve preservation and lymph node dissection techniques in lower rectal cancer surgery and its results: the impact of lateral lymph node dissection. Langenbecks Arch Surg 1998; 383(6):409-415. (27) Roels S, Duthoy W, Haustermans K, Penninckx F, Vandecaveye V, Boterberg T et al. Definition and delineation of the clinical target volume for rectal cancer. Int J Radiat Oncol Biol Phys 2006; 65(4):1129-1142. (28) Moore HG, Shoup M, Riedel E, Minsky BD, Alektiar KM, Ercolani M et al. Colorectal cancer pelvic recurrences: determinants of resectability. Dis Colon Rectum 2004; 47(10):1599-1606. (29) Park JK, Kim YW, Hur H, Kim NK, Min BS, Sohn SK et al. Prognostic factors affecting oncologic outcomes in patients with locally recurrent rectal cancer: impact of patterns of pelvic recurrence on curative resection. Langenbecks Arch Surg 2009;

  Figure MR Image of a presacral local recurrence

  PRESS 10 Overall survival after local recurrence diagnosis per randomisation arm, stratified for subsite, is presented in Table 4. Overall survival is lower after local recurrence in the RT+TME group, compared to the TME group. The prognosis for anastomotic and anterior recurrences is generally better than for presacral and lateral recurrences.

Table 1

 1 Clinicopathologic characteristics

		All patients		Patients with local recurrence
		LR-	LR+	RT+	RT-
		N = 1303	N = 114	N = 36	N= 78
	Age (yrs)
	Median (range)	65 (26-83)	65 (23-92)	62 (26-82)	66 (43-83)
	Sex
	Male	837 (64)	69 (61)	23 (64)	46 (59)
	Female	466 (36)	45 (39)	13 (36)	32 (41)
	Distance from anus
	< 5 cm	387 (30)	48 (42)	20 (56)	28 (36)
	5 -10 cm	529 (40)	47 (41)	10 (28)	37 (47)
	> 10 cm	386 (30)	19 (17)	6 (16)	13 (17)
	Resection type
	APR	389 (30)	47 (41)	18 (50)	45 (58)
	LAR	843 (65)	61 (54)	16 (44)	29 (37)
	Hartmann	71 (5)	6 (5)	2 (6)	4 (5)
	T-stage
	T1	79 (6)	0 (0)	-	-
	T2	447 (34)	15 (13)	5 (14)	10 (12)
	T3	735 (56)	90 (79)	28 (78)	62 (80)
	T4	42 (4)	9 (8)	3 (8)	6 (8)
	N-stage
	N0	800 (61)	29 (26)	10 (28)	19 (24)
	N1	306 (24)	46 (40)	12 (33)	34 (44)
	N2	197 (15)	39 (34)	14 (39)	25 (32)
	CRM
	Negative	1082 (83)	68 (60)	17 (47)	51 (65)
	Positive	221 (17)	46 (40)	19 (53)	27 (35)
	Values in parenthesis are percentages
	LR = local recurrence
	RT = preoperative radiotherapy

Table 2

 2 Subsites of local recurrence

		RT+	RT-
		N = 713	N = 704
	Presacral	15 (2.0)	25 (3.6)
	Lateral	9 (1.1)	14 (1.9)
	Anterior	6 (0.7)	14 (1.9)
	Anastomosis	5 (0.7)	19 (2.7)
	Perineum	0 (0)	4 (0.6)
	Unknown	1 (0.1)	2 (0.3)
	TOTAL	36 (4.6)	78 (11.0)
	Values in parenthesis are 5-year LR-rates, by competing risks analysis
	RT = preoperative radiotherapy

Table 3

 3 Local recurrence rate according to distal margin and lymph node status

		RT-			RT+
	Distal Margin	N0	N+		N0	N+
	0 -5 mm	5.6	30.0		11.8	28.6
	6 -10 mm	8.8	34.6		0	0
	11 -20 mm	4.6	29.7		0	7.2
	> 21 mm	5.5	8.6		1.7	5.8
	TOTAL	5.6	19.4	<0.001	1.7	9.3	<0.001
	In LAR and Hartmann procedures. Values are 5-year local recurrence percentages

Table 4

 4 Overall survival after local recurrence diagnosisValues are overall survival percentages at two years after LR diagnosis

		RT+	RT-
		N = 36	N = 78
	Presacral	6.7 (1/15)	29.5 (8/25)
	Lateral	0 (0/9)	14.4 (2/14)
	Anterior	33.3 (2/6)	38.5 (5/14)
	Anastomosis	20.0 (1/5)	52.6 (10/19)
	Perineum	n.a.	0 (0/4)
	Unknown	0 (0/1)	50.0 (1/2)
	ALL	11.1 (4/36)	33.0 (25/78)


Cor N ; Verdouw
email: cor.verdouw@wur.nl

Lei

A J M Beulens

J H Trienekens

T Verwaart

Mastering demand and supply uncertainty with combined product and process configuration

Keywords: SUPPLY CHAIN MANAGEMENT, MASS CUSTOMIZATION, CONCURRENT ENGINEERING, CONFIGURATION, FLOWER configuration, supply chain management, mass customisation, concurrent engineering, ERP, flower industry

Mastering demand and supply uncertainty with combined product and process configuration

Introduction

Mastering both demand and supply uncertainty is a key challenge for many companies. Markets are increasingly turbulent and also the vulnerability of production and logistics processes is growing. The management of uncertainty has been addressed as an essential task of supply chain management (among others by [START_REF] Davis | Effective Supply Chain Management[END_REF]. The well-known bullwhip effect shows that amplification of demand uncertainty can be reduced by supply chain coordination [START_REF] Lee | Information distortion in a supply chain: The bullwhip effect[END_REF]. There are two main categories of supply chain uncertainties: i) inherent or high frequent uncertainties arising from mismatches of supply and demand, and ii) uncertainties arising from infrequent disruptions to normal activities such as natural disasters, strikes and economic disruptions (Van der [START_REF] Vorst | Identifying sources of uncertainty to generate supply chain redesign strategies[END_REF] Saad, 2005, Oke and[START_REF] Oke | Managing disruptions in supply chains: A case study of a retail supply chain[END_REF]. This paper is concerned with the first category of uncertainties, which can either be demand or supply related [START_REF] Lee | Aligning supply chain strategies with product uncertainties[END_REF].

For coping with the addressed uncertainties, Supply Chain Management (SCM) literature initially has focused on creating so-called lean supply chains that efficiently push products to the market. Lean supply chains build upon reduction of demand uncertainty, especially by product standardisation. Customers must choose from a fixed range of standard products that are made to forecast in high volumes. Business processes in lean supply chains can be highly automated by ERP systems [START_REF] Davenport | Enterprise systems and the supply chain[END_REF].

In the late 1990s, the then dominant approach of leanness was criticised more and more. It was argued that in volatile markets it is impossible to remove uncertainty. Companies therefore should accept differentiation and unpredictability, and focus on better uncertainty management. Agility was proposed as an alternative approach that aims for rapid response to unpredictable demand in a timely and costeffective manner [START_REF] Fisher | What is the right supply chain for your product?[END_REF][START_REF] Christopher | The Agile Supply Chain: Competing in Volatile Markets[END_REF]. It is founded on a mass customisation approach that combines the seemingly contradictory notions of flexible customisation with efficient standardisation [START_REF] Davis | From future perfect: Mass customizing[END_REF][START_REF] Pine | Making Mass Customization Work[END_REF][START_REF] Chandra | Mass Customization: A Supply Chain Approach[END_REF]. This by fabricating parts of the product in volume as standard components, while achieving distinctiveness through customer-specific assembly of modules [START_REF] Duray | Approaches to mass customization: configurations and empirical validation[END_REF].

Besides product modularity and flexible assembly systems (c.f. [START_REF] Molina | Next-generation manufacturing systems: key research issues in developing and integrating reconfigurable and intelligent machines[END_REF], product configurators are addressed as important enabling technologies [START_REF] Duray | Approaches to mass customization: configurations and empirical validation[END_REF], Zipkin, 2001[START_REF] Forza | Product configuration and inter-firm co-ordination: an innovative solution from a small manufacturing enterprise[END_REF]. Product configurators provide an interface for rapid and consistent translation of the customer's requirements into the product information needed for tendering and manufacturing [START_REF] Sabin | Product configuration frameworks -a survey[END_REF][START_REF] Forza | Product configuration and inter-firm co-ordination: an innovative solution from a small manufacturing enterprise[END_REF][START_REF] Tseng | Coordinating product configuration in the order fulfilment processing: an approach based on the binary tree algorithm[END_REF][START_REF] Reinhart | An approach for the offer specification process for customised products[END_REF].

Until then, SCM focused on strategies for coping with demand uncertainty. [START_REF] Lee | Aligning supply chain strategies with product uncertainties[END_REF] was one of the first who stressed the impact of supply uncertainty on supply chain design. Supply chains characterised by high supply uncertainty require the flexibility to deal with unexpected changes in the business processes. Disturbances of logistics, production or supply of materials should rapidly be observed and lead to process changes including re-planning and re-scheduling, purchasing new material, hiring alternative service providers, or negotiating new customer requirements. The rigid planning and scheduling systems of traditional ERP systems may cause problems in this type of supply chain (Akkermans et al., 2003, Zhao and[START_REF] Zhao | Implementation approach of ERP with mass customization[END_REF]. Modular software approaches, in particular Service-Oriented Architecture (SOA), have been proposed to overcome these limitations. In these approaches, process models guide the workflow planning and execution in run-time information systems. This puts the emphasis on process configuration to achieve the required backend flexibility. Process configuration supports a rapid and consistent specification of the workflow that is needed to fulfil specific customer orders (Schierholt, 2001, and others). For example, local deliveries from stock follow a different workflow than exports that are produced to order. Moreover, it supports reconfiguration of the workflow in case of unexpected supply events, e.g. components that were originally planned to be produced can be re-planned to be purchased.

Supply chains characterised by both uncertain demand and supply require a combination of responsiveness to changing demand and the flexibility to deal with unexpected changes in the business processes. Following [START_REF] Lee | Aligning supply chain strategies with product uncertainties[END_REF], we use the term agility to characterise these types of supply chains. In agile supply chains, demand requirements and supply capabilities, i.e. products and processes including resources, Formatted: English (U.K.) Formatted: English (U.K.) Formatted: English (U.K.) Formatted: English (U.K.) Formatted Formatted: English (U.K.) Formatted Formatted: English (U.K.) Formatted Formatted: English (U.K.) Formatted: Indent: First line: 36 pt Formatted Formatted: English (U.K.) Formatted: English (U.K.) Formatted Formatted Formatted Deleted: (Van der [START_REF] Vorst | Identifying sources of uncertainty to generate supply chain redesign strategies[END_REF][START_REF] Kleindorfer | Managing Disruption Risks in Supply Chains[END_REF][START_REF] Oke | Managing disruptions in supply chains: A case study of a retail supply chain[END_REF] Deleted: Present Deleted: z Deleted: [START_REF] Davenport | Enterprise systems and the supply chain[END_REF] Deleted: z Deleted: [START_REF] Fisher | What is the right supply chain for your product?[END_REF][START_REF] Christopher | The Agile Supply Chain: Competing in Volatile Markets[END_REF] Deleted: [START_REF] Davis | From future perfect: Mass customizing[END_REF][START_REF] Pine | Making Mass Customization Work[END_REF][START_REF] Chandra | Mass Customization: A Supply Chain Approach[END_REF] Deleted:

Deleted: [START_REF] Duray | Approaches to mass customization: configurations and empirical validation[END_REF], Zipkin, 2001[START_REF] Forza | Product configuration and inter-firm co-ordination: an innovative solution from a small manufacturing enterprise[END_REF] Deleted: [START_REF] Sabin | Product configuration frameworks -a survey[END_REF][START_REF] Forza | Product configuration and inter-firm co-ordination: an innovative solution from a small manufacturing enterprise[END_REF], Stormer, 2009) Deleted: (…, Deleted: z Deleted: (Akkermans et al., 2003, Zhao and[START_REF] Zhao | Implementation approach of ERP with mass customization[END_REF] Deleted: z should be continuously attuned. Therefore, both front-office and back-office systems need to be flexible and smoothly integrated. This paper explores the application of configurators to both products and processes to achieve this.

The majority of the existing configuration research focuses either on product or process configuration. However, interdependence among product and process configuration is relatively under-researched (c.f. Jiao et al., 2007, Chandra and[START_REF] Chandra | Role of flexibility in supply chain design and modeling--Introduction to the special issue[END_REF]. A literature review, which is presented hereafter, shows that available literature on this subject focuses on the definition domain, i.e. translation of customer requirements to an integrated design of products and manufacturing processes [START_REF] Jiao | Generic Bill-of-Materials-and-Operations for High-Variety Production Management[END_REF][START_REF] De Lit | An integrated approach for product family and assembly system design[END_REF][START_REF] Jiao | Coordinating product and process variety for mass customized order fulfilment[END_REF][START_REF] Bley | Variant-oriented Assembly Planning[END_REF]. However, the presence of supply uncertainty results in a high mutual dependence also after the definition phase. During configuration and execution, the effects of unforeseen backend events on the defined product and fulfilment processes must continuously be evaluated based on the actual state of the required resources. No research is found that provides an integrated consideration of the interdependences during definition, configuration and execution, neither that develops the corresponding information architecture for coordination of this interdependence using configurators.

The present research aims to contribute to this gap by assessing how configuration software can be used for combined product and process configuration to support mastering high uncertainty of both supply and demand. More specific, it aims to i) identify the interdependences between product and process configuration, ii) design an information architecture for coordination of this interdependence using configurators, and iii) identify configurator development strategies. Focus is on the order fulfilment cycle that starts with configuring orders in interaction with customers and ends with delivering the finished goods [START_REF] Lin | Reengineering the order fulfillment process in supply chain networks[END_REF]Shaw, 1998, Croxton, 2003).

In the remainder of this paper, we first give an account of the applied research method. Next, we introduce the problem context of the case study firm, which is a typical example of a company operating in agile supply chains. Subsequently, a literature overview is provided about the use of configurators for products and processes, and we define a typology of its interdependencies. The case-study results are then presented. The paper concludes by addressing challenges for future development and summarising the main findings.

Research method

The research used a design-oriented case study method to answer the research question addressed in the introduction. Design-oriented research aims to develop a body of generic knowledge that can be used in designing solutions to management problems [START_REF] Van Aken | Management research based on the paradigm of the design sciences: The quest for field-tested and grounded technological rules[END_REF]. It is a foundational methodology in information systems research [START_REF] Hevner | Design science in Information Systems research[END_REF]. Design-oriented research is typically involved with 'how' questions, i.e. how to design a model or system that solves a certain problem. A case study strategy fits best for this type of questions, in particular in case of complex phenomena that cannot be studied outside its context [START_REF] Benbasat | The Case Research Stratey in Studies of Information Systems[END_REF][START_REF] Yin | Case Study Research: Design and Methods[END_REF]. This characterises the present research, because it focuses on the interdependences between product configuration, process configuration and the planning and control of fulfilment. Therefore, we have chosen for an in-depth explorative case study research that puts the different related topic areas into context. In such a case study, it makes sense to focus on an extreme situation that clearly highlights the process of interest [START_REF] Eisenhardt | Building Theories from Case-Study Research[END_REF][START_REF] Yin | Case Study Research: Design and Methods[END_REF]. In present research, this is the existence of supply uncertainty in addition to demand uncertainty. Therefore, we searched within a sector that is inherently involved with high supply Formatted: English (U.K.) Formatted: English (U.K.) Formatted: Font: Italic, English (U.K.) Formatted: English (U.K.) Formatted: Font: Italic Formatted: English (U.K.) Formatted: Font: Italic, English (U.K.) Formatted: English (U.K.) Formatted: Font: Italic Formatted: Font: Italic Formatted: Font: Italic Formatted: English (U.K.) Formatted: English (U.K.) Formatted: English (U.K.) Formatted: English (U.K.) Formatted: English (U.K.) Formatted: English (U.K.) Formatted: Font: Italic, English (U.K.) Formatted: English (U.K.) Formatted: Font: Italic Formatted: English (U.K.) Formatted: English (U.K.) Formatted: English (U.K.)

Deleted:

Deleted: (Jiao et al., 2007, Chandra and[START_REF] Chandra | Role of flexibility in supply chain design and modeling--Introduction to the special issue[END_REF] Deleted: [START_REF] Jiao | Generic Bill-of-Materials-and-Operations for High-Variety Production Management[END_REF][START_REF] De Lit | An integrated approach for product family and assembly system design[END_REF][START_REF] Jiao | Coordinating product and process variety for mass customized order fulfilment[END_REF][START_REF] Bley | Variant-oriented Assembly Planning[END_REF] Deleted: l Deleted: [START_REF] Lin | Reengineering the order fulfillment process in supply chain networks[END_REF]Shaw, 1998, Croxton, 2003) Deleted: z Deleted: " Deleted: " Deleted: ' Deleted: [START_REF] Benbasat | The Case Research Stratey in Studies of Information Systems[END_REF][START_REF] Yin | Case Study Research: Design and Methods[END_REF] Deleted: z Deleted: , Deleted: l Deleted: [START_REF] Eisenhardt | Building Theories from Case-Study Research[END_REF][START_REF] Yin | Case Study Research: Design and Methods[END_REF] uncertainty, i.e. the Dutch flower industry. Firms in this sector face high supply uncertainty because of the dependence on the growth of living materials. Production processes are, therefore, vulnerable to weather conditions, pests and other uncontrollable factors. Next, we selected a firm within this sector that was characterised by high demand uncertainty. Additional criteria were product variety and practical reasons, in particular the firm's willingness to cooperate and the authors' familiarity in the domain.

Data collection is done in semi-structured open interviews with managers and employees of the case company, and additional desk research. In total, 14 persons have been interviewed in 9 interviews (5 managers and 9 employees). Division of roles:

• Management: Sales (1), Finance (1), Logistics (1), Production (1), CEO (1); • Employees: Order Processing (1), Planning (2), Expedition (1), ICT (1), Production Seedlings (2), Production Cuttings (2). The questionnaire comprises four main parts: supply chain structure, business processes, control and information management. Every section includes open questions both for mapping and evaluation (see appendix). Three in-depth interviews were held covering the complete questionnaire. The subsequent interviews focused on specific business processes and were combined with observation of the company's operations and systems.

The research was organised as follows. First we defined the dependence between product and process configuration in a typology of interdependencies based on literature review. Second, the case-study firm was investigated in interviews and additional desk research. Next, the investigation results were matched with the developed theoretical framework to define the basic design requirements. The researchers then designed a conceptual information architecture for combined support of both product and process configuration. The designed architecture was tested in a Proof of Feasibility implementation at Sofon, a Dutch configurator vendor, and evaluated by the management of both the case-study firm and Sofon. Finally, general development strategies were abstracted from the case findings based of the developed theoretical framework.

Configuration in the Dutch flower industry

This section introduces the case firm and its need for product and process configuration.

Dutch flower industry

The Dutch flower industry is traditionally a strong and innovative sector with a leading international competitive position and a great impact on the national economy. It is internationally renowned as a strong cluster [START_REF] Porter | Clusters and the New Economics of Competition[END_REF] that produces cut flowers and potted plants, mainly in greenhouses. Particularly production of potted plants has many similarities with manufacturing. It is also a form of discrete production, in which products are assembled from plants, flowerpots, decorations, labels and packaging. Fabrication of potted plants also has some features of continuous production, because of the process of continuous growth, but potted plants remain discrete units, traceable at single product level.

The extent to what processes are order-driven differs a lot, not only among different companies but also within firms. For the spot market, products are made to stock and distribution is either to order (usually via traders) or anticipatory (usually via auctions). For other cases, plants are often produced to forecast, while assembling, labelling and packaging are order-driven.

The flower industry is characterised by high uncertainty of both demand and supply. Supply uncertainty is high, because chains are vulnerable to product decay, weather conditions, pests, traffic congestion and other uncontrollable factors. Further, also demand uncertainty is high amongst others because of weather-dependent sales, changing consumer behaviour, and increasing global competition. This results in high variability of supply capabilities and demand requirements in terms of volume, time, service levels, quality and other product characteristics.

Case company profile

The case company is a global supplier of a wide range of young potted plants. It is a rapidly growing company, with 350 staff and with production locations in Holland, Brazil, Kenya, Israel and Zimbabwe. Annually, over 100 million young plants are delivered as input material to growers or wholesalers.

The firm is characterised by high product variety. It produces about 800 varieties in six main categories, including Begonia and Cyclamen. Besides, over 400 varieties are sourced from other producers to offer a complete assortment. Varieties differ, among others, in colour, shape, and growing characteristics. The firm propagates young plants in two basic ways: as seedlings or cuttings. Seedlings can be sold at different stages of the growing process. Cuttings can be sold rooted or unrooted; and in different sizes. All young plants can be delivered in different types of trays. Furthermore, delivery conditions vary. For example: due to product-inherent characteristics, some varieties can only be delivered in specific periods, and quality and prices are often time-dependent. Furthermore, royalties differ per variety and per continent.

Also process variety is high. Production differs between seedlings and cuttings. For seedlings, seeds are sourced from breeders, seeded in trays and budded. Budded seeds can be sold directly or grown further. Seedlings are mostly seeded to customer order, but also produced to forecast or sourced to order (especially for specific variety mixtures). Cuttings are mostly produced by the firm, but are also sourced from third parties. Production of cuttings starts with propagation and growing of parent plants, which is done in southern countries for reasons of climate and labour costs. After almost two years, cuttings can be harvested. They are shipped directly to customers, or transported to Holland for rooting. Unrooted cuttings can be stored for 10 days at the most, including 3 days for transportation. The company strives for order-driven harvesting and rooting of cuttings, but production to stock also occurs. Furthermore, logistics are complex, due to the global distribution of both production locations and customers, combined with high requirements concerning delivery leadtimes and flexibility.

Need for combined product and process configuration

The interviews indicated that the case company is characterised by high uncertainty of both demand and supply. Demand requirements (about product features, quality and service levels) are diverse and difficult to predict. Also predictability of the demand amount and time is low, although basic seasonable patterns can be determined. Moreover, the lead-times, yields and qualities of production very much depend on the growth of living materials.

The company deals with this high uncertainty by providing variety in their product assortment and flexibility in meeting customer demands with respect to product specifications and delivery schedules. To date, it has relied heavily on improvisation by experienced employees. However, since the company is growing, they face problems in keeping this manageable, which set limits to further growth. As a consequence, the interviewees in particular stressed the lack of tools for customer requirement definition based on real-time information of the supply capabilities, as well as flexible back-office systems for (re)planning, (re)scheduling and monitoring of order fulfilment. The addressed most urgent bottlenecks are:

• Knowledge of production processes and options to reconfigure these processes is only implicitly available in the minds of some experienced staff members. This problem is manageable with the firm's current scale, but inhibits further growth. • Information systems are fragmented and poorly integrated. They require a lot of manual data re-entry. Information inconsistency leads to larger safety buffers than strictly required, and many redundant data checks and duplicate registrations are performed. • Mid-term planning is not coordinated with operational data, due to a lack of system integration. The company's management assessed existing ERP systems for solving these problems, but evaluated them to lack the required flexibility. Therefore, the firm decided to consider implementation of configuration software for products and processes, in combination with an ERP system, as possible option to master uncertainty.

Role of configurators in supply chain management

This section provides some conceptual background about the use of configurators and defines the dependence between product and process configuration in a typology of interdependencies.

Product configurators in responsive supply chains

Configurators have emerged from the development of rule-based product design in the field of Artificial Intelligence. A well-known early application was R1, a product configurator for VAX computers [START_REF] Mcdermott | R1: The Formative Years[END_REF]. A product configurator is a tool that guides users interactively through specification of customer-specific products [START_REF] Sabin | Product configuration frameworks -a survey[END_REF][START_REF] Forza | Product configuration and inter-firm co-ordination: an innovative solution from a small manufacturing enterprise[END_REF][START_REF] Tseng | Coordinating product configuration in the order fulfilment processing: an approach based on the binary tree algorithm[END_REF][START_REF] Reinhart | An approach for the offer specification process for customised products[END_REF]. Configurators generate specific product variants by combining sets of predefined components and specifying features according to permitted values. Next, they check the completeness and consistency of configured products based on rules that define the interdependencies between components or features. Product configurators are based on generic product models, which define the class of objects that can be configured [START_REF] Hegge | Generic bill-of-material: a new product model[END_REF].

Currently, configurators play an important role in responsive supply chains, which are characterised by high demand uncertainty and low supply uncertainty [START_REF] Lee | Aligning supply chain strategies with product uncertainties[END_REF]. They are widely used for product configuration to enable rapid response to customer demands. In interaction with the user, the software generates consistent and complete specifications of customised products, taking into account both customer's requirements (e.g. functional specifications and delivery conditions) and feasibility of production, sourcing and delivery. Along with the product specification, current configurators can produce commercial offers and draft contracts, and schedules and contracts for support and maintenance of the product. The software can be designed for use either by a sales representative of the supplier, or by a customer, e.g. through the internet. In both cases the configuration process results in a quick and effective Formatted: Font: Italic Deleted: [START_REF] Sabin | Product configuration frameworks -a survey[END_REF][START_REF] Forza | Product configuration and inter-firm co-ordination: an innovative solution from a small manufacturing enterprise[END_REF], Stormer, 2009) Deleted: [START_REF] Hegge | Generic bill-of-material: a new product model[END_REF] Deleted: z Deleted: e.g.

Deleted: e.g. order specification that can directly be entered into the production planning and scheduling systems.

Configuration in agile supply chains

Next to demand uncertainty, agile supply chains are also characterised by high uncertainties at the supply-side [START_REF] Lee | Aligning supply chain strategies with product uncertainties[END_REF]. High supply uncertainty makes great demands on the flexibility of supporting information systems. The development of modular software approaches especially has been advocated for realizing this flexibility (for example [START_REF] Verwijmeren | Software component architecture in supply chain management[END_REF]. Service-Oriented Architecture (SOA) is the latest development in software modularity [START_REF] Wolfert | Organizing information integration in agri-food: A method based on a service-oriented architecture and living lab approach[END_REF]. In a SOA approach, business process models are leading in routing event data amongst multiple application components that are packaged as autonomous, platform-independent services [START_REF] Erl | Service-Oriented Architecture: Concepts, Technology, and Design[END_REF][START_REF] Papazoglou | Service-Oriented Computing: State of the Art and Research Challenges[END_REF]. Consequently, new or adapted business processes can be supported without changing the underlying software. Induced by the emergence of Service-Oriented Architecture, also ERP vendors have commenced to modularise their software [START_REF] Møller | ERP II: a conceptual framework for next-generation enterprise systems[END_REF][START_REF] Loh | An investigation of the value of becoming an extended enterprise[END_REF].

The leading role of business processes in modular software approaches puts emphasis on rapid configuration of processes in achieving flexibility. The concept of process configuration is introduced by Schierholt ( 2001), who applied the principles of product configuration to support process planning. [START_REF] Rupprecht | Project-specific Process Configuration in Virtual Enterprises[END_REF] and [START_REF] Zhou | Project-oriented resource assignment: from business process modelling to business process instantiation with operational performance consideration[END_REF] described approaches for automatic configuration of business process models for specific projects. [START_REF] Jiao | Process Variety Modeling for Process Configuration in Mass Customization: An Approach Based on Object-Oriented Petri Nets with Changeable Structures[END_REF] formalised the modelling of process configurations for given product configurations. [START_REF] Verdouw | Towards dynamic reference information models: Readiness for ICT mass customization[END_REF] argue that reference process models should be set-up as dynamic configurable models to enable ICT mass customisation and they assess the readiness of existing models. Furthermore, the ERP vendor SAP has addressed process configuration to manage the complexity of their reference process models that are used as a basis for system implementation. They conducted extensive research to make these models configurable [START_REF] Dreiling | Model-based software configuration: patterns and languages[END_REF][START_REF] Rosemann | A configurable reference modelling language[END_REF]. Building upon this, [START_REF] Rosa | Questionnaire-driven Configuration of Reference Process Models[END_REF] proposed a questionnaire-driven approach to guide users interactively through process model configuration.

Nevertheless, the majority of existing literature focuses either on product or on process configuration. The mutual dependence between product and process configuration is relatively under-researched (c.f. Jiao et al., 2007, Chandra and[START_REF] Chandra | Role of flexibility in supply chain design and modeling--Introduction to the special issue[END_REF]. The papers, found in our literature review, all focus on the definition domain, i.e. translation of customer requirements to an integrated design of products and manufacturing processes. [START_REF] Jiao | Generic Bill-of-Materials-and-Operations for High-Variety Production Management[END_REF] put forward an integrated product and process model that unifies Bill-of-Materials and routings, called generic Bill-of-Materials-and-Operations. [START_REF] Jiao | Coordinating product and process variety for mass customized order fulfilment[END_REF] proposed a product-process variety grid to unify product data and routing information. De [START_REF] De Lit | An integrated approach for product family and assembly system design[END_REF] introduced an integrated approach for product family and assembly system design. [START_REF] Bley | Variant-oriented Assembly Planning[END_REF] developed an approach to integrate product design and assembly planning.

As argued before, the presence of supply uncertainty results in a high mutual dependence also after the definition phase. During configuration and execution, the effects of unforeseen backend events on the defined product and fulfilment processes must continuously be evaluated based on the actual state of the required resources. However, no research is found that explicitly considers the interdependences during definition, configuration and execution, and that develops the corresponding information architecture for coordination of this interdependence using configurators. Therefore, in next section we first develop a typology of product and process interdependences based on organisational literature.

Typology of interdependences between product and process configuration

Dependence is a central notion of the General Systems Theory. This theory argues that the whole of a system is more than its parts, because of the existence of dependencies between their elements [START_REF] Bertalanffy | An Outline of General System Theory[END_REF]. [START_REF] Thompson | Organization in Action: Social Science Bases of Administrative Theory[END_REF] was one of the first to apply this idea to organisational theory. He distinguished three basic types of dependency: pooled, sequential and reciprocal interdependence, which require different coordination modes: coordination by standardisation, by plan and by mutual adjustment. His work is refined by many others, all focusing on coordination of generic dependencies between organisational subunits. [START_REF] Malone | The Interdisciplinary Study of Coordination[END_REF] have introduced different types of dependencies between activities and resources. They distinguish between flow, sharing and fit dependencies (see also [START_REF] Malone | Tools for inventing organizations: Toward a handbook of organizational processes[END_REF]. Flow dependencies arise whenever one activity produces a resource that is used by another activity (precedence relation). Sharing dependencies occur whenever multiple activities all use the same resource. Fit dependencies arise when multiple activities collectively produce a single resource.

If we apply these interdependencies to product and process configuration, distinction should be made between different decision levels, i.e. definition, configuration and execution. First, in the definition phase designers predefine reference product and process models. These are generic models, or family models, which define the possible product and process components, and that include rules that define the possible combinations of components. A product reference model is constrained by the available business processes as defined in process reference models. Vice versa, a process reference model must contain the business processes that produce the variety of products as defined in product reference models. Second, the configuration phase starts when a customer order request comes in. A customised product is configured in interaction with the customer, and taking into account whether the enabling business process can be configured. Therefore, the required input products and capacity must be available to promise. The result is an accepted order, which triggers configuration of the business processes that fulfil the order. These might include distribution activities (Make to Stock), and production activities (Assemble / Make to Order), and engineering activities (Engineering to Order). Last, the execution phase comprises planning, scheduling and completion of the configured business processes. The progress is monitored continuously and if necessary the product and process configurations are updated.

Figure 1 more precisely defines the interdependence among product and process configuration in a typology of dependencies. This typology is an application of the categorisation of [START_REF] Malone | The Interdisciplinary Study of Coordination[END_REF] and [START_REF] Malone | Tools for inventing organizations: Toward a handbook of organizational processes[END_REF] as discussed above. <insert figure 1> Product configurators are primarily means for coordination of fit dependencies: assembling consistent product variants that meet specific customer requirements from available components and options. Analogously, process configuration coordinates the assembly of consistent process variants from available activities or services. The alignment of product and process configuration requires coordination of precedence (flow) dependencies: process configuration is conditional for product configuration and vice versa. Furthermore, process configuration depends on operational execution because fulfilment of the configured process needs capacity and input products. More specific, the defined interdependencies are:

(1) Product Assembling: multiple product modules are required to produce a single product (fit dependency). Product configurators are primarily means for coordination of this dependency. They specify components, options, interfaces and interdependency rules in reference product models and guide customerspecific configuration of product variants. (2) Process Rules Precedence: process properties set constraints to possible product configurations. Consequently, process reference models are a precondition for product reference models (flow dependency). This dependency is mostly coordinated by mutual adjustment of product and process models by designers, ideally supported by tools that ensure consistency of both model types.

(3) Order Precedence: specific product configurations (order information) are input for configuration of specific fulfilment processes (flow dependency). Therefore, order information must be interpretable by back-office systems for production and distribution. This dependency can be coordinated by standardisation of order data in an executable form, including Bill-of-Materials. (4) Process Assembling: multiple activities, i.e. process modules, are required to compose a single process (fit dependency). Process configuration is primarily a mechanism to coordinate this dependency. It specifies the activities, interfaces and interdependency rules in reference process models and guides configuration of order-specific processes. (5) Process Precedence: the output of the process configuration task is conditional for the planning and scheduling of the fulfilment (flow dependency). Execution of a configured process consumes input products (raw material or semi-finished products) and uses capacity. This dependency can be coordinated by standardisation of configured processes in a model format that is interpretable by planning and scheduling systems. (6) Product Precedence: for execution of a fulfilment process, the required input products must be available (flow dependency). This dependency can be coordinated by integration with planning and scheduling mechanisms. (7) Capacity Precedence: for order-driven processes, the required capacity must be available (flow dependency). This can be coordinated by integration with planning and scheduling mechanisms. (8) Capacity Rules Precedence: the characteristics of used capacity (e.g. machine setup, other facility layouts, and human resource competences) set constraints for the possibilities for process configuration (flow dependency). This can be coordinated similarly to Process Rules Dependencies: mutual adjustment of capacity layouts and process models by designers ideally supported by tools that ensure model consistency. The last dependencies to be mentioned are related to operational execution of configured processes: (9) Product Consumption: multiple configured processes all use the same input products (sharing dependency). ( 10) Capacity Usage: configured processes for multiple orders all use the same capacity (sharing dependency). ( 11) Capacity Assembling: multiple capacity units are required to set up specific layouts (fit dependency).

Deleted: i.e.

Deleted: z

Deleted: e.g. These last three dependencies are coordinated by planning and scheduling systems. They do not directly impact product and process configuration (only via product, capacity and process precedence's) and are thus beyond the scope of this paper.

Information architecture for combined product and process configuration

This section describes a conceptual information architecture for combined support of both product and process configuration, including a Proof of Feasibility implementation in a configurator.

Basic design requirements

The uncertainty of both demand and supply of the case company is high, as section 2 demonstrates. Demand requirements (about product features, quality and service levels) are diverse and difficult to predict. Also predictability of the amount and time is low, although basic seasonable patterns can be determined. Moreover, the leadtimes, yields and qualities of production very much depend on uncontrollable factors.

In order to make this variability manageable, the solution to be designed must support coordination of the high interdependence between the company's products and processes during:

• Definition: it must be possible to define integrated reference models, which cover the variety of the firm's products and enabling processes, and that take into account the constraints arising from its specific process characteristics; • Configuration: it must be possible to configure customised products and the accompanying processes, in interaction with the customer and taking into account whether the required input products and capacity are available to promise; • Execution: it must be possible to implement the configured business processes in the company's backend systems, to monitor its progress and update product and process configurations if necessary. More specifically, these basis requirements imply that the design must support coordination of the dependences as developed in previous section. Table 1 identified these dependencies for the case company by matching the investigation results with the defined typology. The remainder of this section develops a corresponding information architecture, including a Proof of Feasibility implementation in the configurator Sofon.

Information architecture for product configuration

Sofon Guided Selling is a model-based product configurator. It provides functionality for the definition of questionnaires that guide users interactively through requirements specification and translate this information to product configurations in the form of Bills-of-Materials, quotation calculations, visualisations and document generation. Most users utilise Sofon as a front-office system, in combination with an ERP system for the back-office. Figure 2 illustrates the underlying information architecture. <insert figure 2> The focus is on coordination of Product Assembling dependencies. Therefore, functionality is provided to specify the product range, possible features, and rules that define permitted selections in reference product models. Additionally, other order specifications such as delivery dates can be defined here. Product experts can enter configuration rules into the configurator's repository. Product data (Bill-of-Materials, part numbers, prices) and process data (routing, lead times, production cost) can be copied from ERP master data, to ensure that production orders will be in terms that can be interpreted by ERP systems (Process and Capacity Rules Precedence).

Questionnaires are then generated that guide configuration, either directly by the customer or through a sales representative. The configured product and other customer specifications (orders, Bill of Material) are generated in a format that can be executed by ERP systems (Order Precedence). Also, basic order-specific routings can be generated that serve as a basis for planning and scheduling (Process Precedence).

For the case firm, the reference product model includes product categories (including Begonia and Cyclamen), specific varieties and product features, such as budded seeds or grown up, cutting size, rooted or unrooted, possible tray types, delivery conditions and royalty types. Figure 3 presents a simplified example in Sofon. <insert figure 3> The figure shows that the generic model is defined in two ways. The main part is the definition of wizard-like questionnaires in the language of customers. The generic questionnaire is defined to the left of the screen and possible answers are shown to the top-right of the screen. At the bottom, the product model is specified as a generic Billof-Materials (BOM) that is executable by ERP systems. During configuration, selections made in the questions are specified automatically into this BOM. For example: based on the selection of the colour red, the variety 'Begonia Elatior Baladin' is defined (see figure 3: article code BE72).

Information architecture for combined product and process configuration

Currently, configurators such as Sofon focus on product configuration in the responsive segment. Agile supply chains require combined product and process configuration. Two essential differences can be distinguished: i) introduction of process configuration between product configurators and planning and scheduling systems, and ii) dynamic alignment of resulting interdependencies. In the case study, Sofon was used to develop an information architecture for this and to evaluate the feasibility of configurators. Figure 4 shows the resulting conceptual model. <insert figure 4> Analogous to product configuration, the focus of process configuration is on the coordination of Process Assembling dependencies, i.e. to assemble specific order fulfilment processes from multiple activities (process modules). Therefore, standard process models can be specified and the composition of customer-specific processes can be guided by configurator tools. However, the important difference with product configuration is that most information required for process configuration is available in the system. Two important information sources can be distinguished for process configuration: customer orders (output of product configuration) and availability of required input products and capacity (output of ERP back-office system). Neither of these types of information needs to be specified manually during process configuration.

Although Sofon focuses on companies in the responsive segment that do not face high supply uncertainties, the tool can be applied to configure processes in the same way that it is used to configure products. Figure 5 presents an example for the case company using Sofon's existing functionality. <insert figure 5> It shows that there are three additional questions for the configuration of the young plant order fulfilment processes, all of which are answered automatically. The questions concerning capacity and product availability are queries to ERP back-office systems. The question "How far order-driven?" is answered by an automatic calculation using the retrieved data about product and capacity availability and information about the required versus possible lead-time. The required delivery leadtime is as specified during product configuration. The possible lead-time is the sum of all order-driven fulfilment processes. The calculation result is input for activity specification in the generic routing (i.e. Bill of Activities) that is executable by ERP systems (see right-bottom at figure 5).

Consider, for example, an illustrative order for Cyclamen. The customer specification, resulting from product configuration, shows that this is an order for 2000 budded 'Cyclamen Miniwella Twinkle blanc' to be delivered within 4 days in 66-66-44 trays to Hamburg, Germany. Operational ERP data shows that these are in stock and that distribution will take two days. Thus, only distribution activities are on customer order and these activities are selected for this order (see figure 5: D2.5 and further).

Consider another simplified example: an order for Begonia cuttings. The configured order shows that this is an order for 5000 rooted 'Begonia Eliator Baladin' to be delivered in 7 weeks in 72-72-44 trays to Latina, Italy. Operational ERP data shows that the required cuttings are available at parent plants in Brazil and that the required air freight and greenhouse capacity is also available. The lead-time of rooting cuttings from these parent plants is 5 weeks. The total lead-time from harvesting until delivery at the customer site is 6 weeks and 3 days. This is less than 7 weeks, so all activities from harvesting onwards can be on customer order. Consequently, all activities for production of cuttings and for distribution are selected in the generic routing (see right-bottom at figure 5).

Configurator development strategies

The previous analysis shows that product configurators also can be used to support process configuration. Below, it is evaluated more precisely to what extent the identified basic requirements can be met by existing configurators. This by discussing how coordination of the defined interdependencies is supported (see figure 1): (1) Product Assembling: is well supported, since this is the traditional focus of configurators. For example: Sofon provides rich functionality for defining generic product models in wizard-like questionnaires and accompanying rules, and generic Bill-of-Materials. (2) Process Rules Precedence: requires solid integrations with back-office systems and mechanisms to prevent redundant process logic or to ensure consistency. For example: Sofon provides functionality to copy master data from ERP, CAD, and PDM packages, but alignment has to be done manually by product experts; consistency checks are not supported. (3) Order Precedence: configurators and ERP systems must be technically integrated and order-related data must be defined in a format that is executable by backoffice systems. Especially in agile supply chains, functionality is required for reconfiguration of order-related data if changes in the back-office occur. For example, Sofon contains rich functionality for defining standard orders and accompanying Bill-of-Materials and it provides standard application connectors for ERP packages. However, reconfiguration of adjusted requirements after contract conclusion is not supported. (4) Process Assembling: this could be supported by applying available product configuration functionality to processes. However, adequate process configuration requires rich functionality to specify reference process models and to configure Business Process Models based on configured orders and operational back-office data. In existing questionnaire-based product configurators, this functionality might be rather basic. For example, in Sofon, generic routings for customerspecific processes can be configured, but this functionality just lists activities, possibly including fixed lead-times. It does not specify possible interactions and sequences among activities, and it is not possible to derive activity lead-times from operational data. ( 5) Process Precedence: configured processes should be executable in back-office systems to orchestrate order-specific fulfilment, including product reconfigurations. For compatibility with different software environments, process models should be configured in XML-standard notations (i.e. BPMN and BPEL) that are executable in any SOA-compliant back-office system or integration platform. For example, in Sofon order-specific routings can be configured and executed by planning and scheduling systems. However, as argued at the previous dependency, this is rather basic decomposition information. Sofon does not yet support the configuration of BPMN and BPEL process models. ( 6) Product Precedence: in product configurators, product availability data can be incorporated into configuration, e.g. to determine the Availability to Promise (ATP). This functionality could also be used for process configuration. For example, in Sofon it is possible to define questions that retrieve data automatically from back-office systems. ( 7) Capacity Precedence: particularly in the case of order-driven production, capacity availability data is also needed. This can be retrieved in the same way as product availability data. ( 8) Capacity Rules Precedence: in this case, required functionality is similar to Process Rules Precedence: solid integration with back-office and mechanisms to prevent redundant capacity logic or to ensure consistency. ( 9) Product Consumption, (10) Capacity Usage and ( 11) Capacity Assembling: these dependencies are supported by back-office systems for planning and scheduling and are beyond the scope of configurators. All together, it is found that product configurators do not yet provide sufficient functionality for combined product and process configuration. Especially, intensive interaction among product configuration, process configuration and execution in back-office systems is poorly supported. Based on the analysis, three basic configurator development strategies are distinguished. The strategies involve different implementations of the developed information architecture (see figure 4), in particular different divisions of product configuration, process configuration and management of the order fulfilment among dedicated configurator software and the ERP system.

First, existing product configurators can be made appropriate for reconfiguration and intensive interaction with back-office systems. At this option, functionality for product and process configuration is provided by different applications. Process configuration is done outside product configurators, either within ERP systems or in service-oriented middleware. In addition to existing functionality, the product configurator includes functionality for synchronisation of order-related data (Order Precedence) and process logic (Process Rules Precedence).

The second alternative is to extend configurators with functionality for process configuration and for coordination of the different interdependences that have been defined. For this option, both product and process configuration are incorporated within one configurator and this tool is integrated with external planning & scheduling systems, either directly or via service-oriented middleware. The external Last option is to include both product and process configuration into the ERP system and thus integrate all features (product configuration, process configuration and planning and scheduling) within one system. In this case, the ERP system is also the front office for customer interaction. All identified dependencies are supported by integrations within the system.

Summary and Outlook

The objective of this paper was to asses how configuration software can be used for combined product and process configuration to support mastering high uncertainty of both supply and demand. In order to answer this question, first the role of configurators in Supply Chain Management has been discussed. The traditional domain of configurators is in responsive supply chains, i.e. high demand uncertainty with reliable and stable supply. The additional presence of supply uncertainty in agile supply chains results in a high mutual dependence between product and processes, not only in the definition phase, but also during configuration and execution. First, in the definition phase, designers predefine integrated reference product and process models. A product reference model is constrained by the available business processes as defined in process reference models. Vice versa, a process reference model must contain the business processes that produce the variety of products as defined in product reference models. Second, in the configuration phase customised products are configured in interaction with the customer and taking into account whether the enabling business processes can be configured. Therefore, the required input products and capacity must be available to promise. The result is an accepted order, which triggers configuration of the business processes that fulfil the order. Last, the execution phase comprises planning, scheduling and completion of the configured business processes. The progress is monitored continuously and if necessary the product and process configurations are updated. The interdependence of products and processes during definition, configuration and execution has been defined more precisely in a typology of interdependencies.

In order to support coordination of the defined interdependencies, configurators must provide additional functionality for process configuration that links product configurators and planning and scheduling systems. Based on a case study in the Dutch flower industry, a conceptual information architecture has been proposed for this and tested in a Proof of Feasibility implementation. It has been found that currently flexible process configuration and back-office/frontoffice/customer communication are not sufficiently supported. Based on the developed information architecture, three basic development strategies have been identified, each including a different division of product configuration, process configuration and management of the order fulfilment among dedicated configurator software, ERP systems and service-oriented middleware. On the other hand, the case study has shown that the investigated firm heavily relied on improvisation by experienced staff having in-depth product and process knowledge. This type of tacit knowledge is to be captured in the system for successful application of combined product and process configuration.

The main contribution of this paper to existing literature is that it provides an integrated typology of product and process interdependences and it develops a

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The first option is to make product configuration functionality appropriate for reconfiguration and intensive interaction with back-office systems. At this, process configuration is done outside product configurators, either within ERP systems or in service-oriented middleware. The second strategy is to add functionality for process configuration. For this option, product and process configuration are incorporated within one configurator and this tool is integrated with external planning & scheduling systems, either directly or via serviceoriented middleware. Last alternative is to include product and process configuration into the ERP system and thus integrate all features within one system. ¶ corresponding information architecture for its coordination. Contrary to related work, the addressed dependences go beyond the definition phase and do also include the effects of unforeseen backend events during configuration and execution. As a result, the developed architecture supports the mastering of both demand and supply uncertainty, which exceeds the traditional application domain of configurators.

The research encompasses an explorative analysis that is based on a single case study. Advantage of this approach is that it puts the different related topic areas of the studied complex phenomena into context. This is in line with [START_REF] Jiao | Product family design and platform-based product development: a state-of-the-art review[END_REF] who stresses the need for a holistic view and system-wide solutions. However, an important weakness of single case study research in general is the little basis for scientific generalisation. In the paper we used the typology of dependencies based on literature as core vehicle to abstract general development strategies from the case study. Nevertheless, future research is needed to further develop, test and implement the designed architecture. Important remaining issues include: i) development of configurable reference process models that bridge between product configuration and back-office systems, ii) broad feasibility survey of existing configurators, iii) implementation of the designed architecture in combination with ERP and SOA platforms, and iv) case studies that test the applicability in other sectors. • Required delivery time must be equal to or more than the summed leadtimes of order-driven processes (about 14 weeks for seedlings, 5-6 weeks for rooted cuttings, 10 days for unrooted cuttings) • Several varieties can only be delivered during a specific season • Price depends on delivery week because of seasonable production • Import regulations, including phytosanitary requirements, differ per country 3) Order Precedence

• Configured order for cuttings triggers configuration of the propagation process • Configured order for seedlings determines mixture of seeds to be sourced 4) Process Assembling

• Scope of activities for order fulfilment depend on the extent to which processes are order-driven • Type of production activities to be configured differs for seedlings and cuttings • Type of distribution activities to be configured depends on country of destination (for example: road, rail or air freight, and different requirement to shipping documentation).

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  Deleted: , while leaving process configuration to back-office systems either through inclusion in ERP software, or in service-oriented middleware. exchange of process flows (Process Precedence), product & capacity data (Product & Capacity Precedence), and capacity layouts (Capacity Rules Precedence).

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  These are generic models, or family models, which define the possible product and process components, and include rules that define the possible combinations of components.

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  ., 2001. The Limits of Mass Customization.MIT Sloan Management Review, 42 (3),[81][82][83][84][85][86]

FontFigure 5 .

 5 Figure 3. Illustrative case-firm implementation of product configuration

Table 1 .

 1 Important configuration-related dependencies of the case company that should be supported

	Tables
	Type (see	Dependencies
	figure 1)
	1) Product	• Possible size of cuttings depends on variety
	Assembling	• Colour and growing characteristics differ per variety
			• Possible tray type depends on variety and maturity
			• Applicable category of the royalties depends on variety and customer
			country
			• Product information differs per variety (e.g. growing characteristics) and
			customer (e.g. barcode)
	2)	Process
	Rules
	Precedence

URL: http://mc.manuscriptcentral.com/tandf/tcim Email:ijcim@bath.ac.ukInternational Journal of Computer Integrated Manufacturing

Appendix -Questionnaire

Structure of the questionnaire and main questions: A. Introduction

• Please, could you introduce your organisation and your current function? • To what extent are your processes order-driven?

• How do you make your future (production) planning?

• What are your most important control challenges? E. Information Management

• What are your main information systems?

• How far are you satisfied with your information systems?

• What is your vision about the possibilities of ICT for better performance? F. To conclude

• How does your organisation look like 5 years hence?

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