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Acute Side Effects and Complications After Short-Term Preoperative Radiotherapy Combined With Total Mesorectal Excision in Primary Rectal Cancer: Report of a Multicenter Randomized Trial

From the Departments of Clinical Oncology and Surgery, Leiden University Medical Center, Leiden; Department of Radiotherapy, Catharina Hospital, Eindhoven; Department of Surgery, Leijenburg Hospital, the Hague; Department of Surgery, Groningen University Hospital, Groningen; and Department of Radiotherapy, Academical Hospital Nijmegen, Nijmegen, the Netherlands.

Address reprint requests to C.A.M. Marijnen, MD, Department of Clinical Oncology, Leiden University Medical Center, K1-P, PO Box 9600, 2300 RC Leiden, the Netherlands; email: marijnen{at}lumc.nl

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Total mesorectal excision (TME) surgery in the treatment of rectal cancer has been shown to result in a reduction in the number of local recurrences in retrospective studies. Reports on improved local control after preoperative, hypofractionated radiotherapy (RT) have led to the introduction of a prospective randomized multicenter trial, in which the effect of TME surgery with or without preoperative RT were evaluated. Any benefit in regard to a reduced local recurrence rate and possible improved survival must be weighed against potential adverse effects in both the short-term and the long-term. The present study was undertaken to assess the acute side effects of short-term, preoperative RT in rectal cancer patients and to study the influence of five doses of 5 Gy on surgical parameters, postoperative morbidity and mortality in patients randomized in the Dutch TME trial.

PATIENTS AND METHODS: We analyzed 1,530 Dutch patients entered onto a prospective randomized trial, comparing preoperative RT with five doses of 5 Gy followed by TME surgery with TME surgery alone, of which 1,414 patients were assessable. Toxicity from RT, surgery characteristics, and postoperative complications and mortality were compared.

RESULTS: Toxicity during RT hardly occurred. Irradiated patients had 100 mL more blood loss during the operation (P < .001) and showed more perineal complications (P = .008) in cases of abdominoperineal resection. The total number of complications was slightly increased in the irradiated group (P = .008). No difference was observed in postoperative mortality (4.0% v 3.3%) or in the number of reinterventions.

CONCLUSION: Preoperative hypofractionated RT is a safe procedure in patients treated with TME surgery, despite a slight increase in complications when compared with TME surgery only.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
IN THE TREATMENT of rectal cancer, local recurrences are a major problem, occurring in 15% to 45% of rectal cancer patients.^1-4 Local recurrences cause severe disabling symptoms and are difficult to treat. To reduce local recurrence rates after curative surgery, additional radiotherapy (RT) has been administered to patients either preoperatively^5-14 or postoperatively.^4,15-18 In a large Swedish trial, short-term preoperative RT resulted in better local control than postoperative RT (local recurrences, 13% v 22%).⁵ All trials with short-term preoperative RT showed lower local recurrence rates in the RT arm.^7,12,13,19 Results of the Swedish Rectal Cancer Trial (SRCT) even showed an improved overall survival with the short-term regimen of five doses of 5 Gy compared with surgery alone, with 58% 5-year survival in the irradiated (RT+) group versus 48% in the nonirradiated (RT-) group.¹⁴ However, this beneficial effect of preoperative RT was observed in combination with conventional surgery. This conventional procedure includes partially blunt dissection of the rectum along the presacral fascia, which results in the incomplete removal of mesorectal tissue. This possible residue of tumor cells was a logical rationale behind the application of RT. The acknowledgment of the important role of circumferential margin involvement in the appearance of local recurrences in rectal cancer has led to the general introduction of total mesorectal excision (TME) surgery, as advocated by Heald²⁰ and Enker.²¹ The main principle of this technique is to achieve a radical resection by sharp dissection within the true pelvis around the intact mesorectum under direct vision, thus enveloping the entire midrectum, including the tumor. This technique has shown to significantly reduce the number of local recurrences in retrospective series.²² A second beneficial effect of TME surgery is the possibility of preserving the autonomic pelvic nerve plexus, resulting in less bladder dysfunction and less sexual morbidity.^23,24

To answer the question of whether preoperative RT is still beneficial in TME-treated patients, a randomized prospective international multicenter trial was conducted under the auspices of the Dutch Colorectal Cancer Group (DCRCG) to compare the effect of preoperative, hypofractionated RT combined with TME surgery with TME surgery alone.²⁵ Any benefit in regard to a reduced local recurrence rate and possible improved survival had to be weighed against potential adverse effects in both the short-term and the long-term. Several trials with preoperative, short-term RT have shown that five preoperative doses of 5 Gy followed by surgery within 1 week is a safe procedure.^12,26-28 In these studies, however, the preoperative RT was combined with conventional surgery.

The present study was undertaken to assess the side effects of short-term, preoperative RT in rectal cancer patients who underwent the TME surgical technique and to study the influence of five doses of 5 Gy on surgical parameters, postoperative morbidity, and mortality in patients randomized in the TME trial.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Study Population
From January 1996 until December 1999, 1,861 patients were randomized to preoperative RT followed by standardized TME surgery or to TME surgery only in a large international multicenter trial. Patients entering onto the trial were required to have biopsy confirmation of a rectal adenocarcinoma, resectable tumors as judged by clinical examination, tumors with the inferior margin within 15 cm of the anal verge, and no hereditary colorectal cancer syndrome. Distant metastases had to be excluded by chest x-ray and ultrasound or computed tomography scan of the liver. Patients in whom a malignancy had been previously diagnosed were not included in the study. The World Health Organization performance score had to be two. The patient had to provide written or oral informed consent, depending on local hospital regulations.

Stratification took place for institute of surgery and expected type of resection, ie, abdominoperineal resection (APR) or low anterior resection (LAR). Balanced randomization lists with a block size of six were used for central randomization at the data center in Leiden.

The majority of the included patients (n = 1,530) were from the Netherlands. The other 331 patients were included by Swedish, other European, and Canadian coinvestigators. For the final analysis of the trial, all patients will be analyzed. Because the Dutch follow-up has been extremely thorough, data about the Dutch patients in regard to treatment characteristics, toxicity, complications, and mortality are complete and checked by the study coordinators. We, therefore, only included the Dutch patients in the current analysis.

Preoperative RT
Patients assigned to preoperative RT received a total dose of 25 Gy in five fractions during 5 to 7 days. The prescribed dose was specified according to International Commission on Radiation Units and Measurements 50 guidelines.²⁹ The clinical target volume included the primary tumor and the mesentery with vascular supply, containing the perirectal, presacral, and the internal iliac nodes (up to the S1/S2 junction).

The recommended upper border was at the level of the promontory. The perineum was included if an APR was planned, whereas the lower border was 3 cm above the anal verge if the planned operation was an LAR. The treatment was delivered with three portals or with a four-portal box technique, depending on the institutes’ preference.

Shielding of the lordotic area at the dorsum of the sacrum was recommended. The protocol recommended a treatment time from Monday to Friday, with surgery on the following Monday, Tuesday, or Wednesday. In case treatment started on other days and was interrupted during the weekend, the time between the first RT fraction and the day of surgery was not to exceed 10 days.

In case of resection margins smaller than 1 mm or tumor spill during operation, postoperative RT was mandatory for the TME-only patients. Treatment details were reported on a RT form and checked by a radiation oncologist for inconsistencies.

Surgery
All patients underwent surgery according to the TME principle, as advocated by Heald.²⁰ An extensive structure of workshops, symposia, and instruction videos ensured the instruction of this novel technique. In addition, a committee of instructor surgeons was formed to optimize quality. In each participating hospital, the first five TME procedures had to be supervised by an instructor surgeon.

A surgery form and a postsurgery form, on which all operation characteristics, and operative and postoperative complications were recorded, was completed by the operating surgeon. These forms were compared with the operation report and discharge letters by the surgical trial coordinator and checked for inconsistencies. Additional information was requested when data were not clear or incomplete.

Pathology Procedures
Standardized routine pathology examination was performed as described by Quirke et al³⁰ Pathologic information on the resected tumor was recorded by pathologists from the referral hospital on a pathology case record form for all patients. A pathology quality manager and a pathology review committee were installed to ensure constant quality of all pathology data and procedures.³¹ Tumor staging was performed using the tumor-node-metastasis system classification.³²

Side Effects and Complications
Radiation oncologists were asked to score acute side effects within 3 months from start of RT according to the Radiation Therapy Oncology Group scoring system.³³ In general, grade 0 represented no complaints, whereas grade 5 was any toxicity leading to death. The Radiation Therapy Oncology Group system has no scoring system for acute neurologic symptoms. Because acute plexopathy was observed in the SRCT,³⁴ we introduced a scoring system for neurologic complaints, with the following categories for painful buttocks or legs: 0, no complaints; 1, mild or intermittent pain not requiring intervention; 2, moderate constant pain requiring narcotics or adjustment of the treatment; 3, intractable severe pain or treatment interruption. This scoring system was introduced in 1997, a year after the start of the trial, explaining the missing data for patients randomized in 1996.

For the postoperative complications, all complications during the first admission were taken into account, and the following definitions were used. Anastomotic leaks include those clinically apparent or after suspicion determined on a contrast enema. An abscess around the anastomosis was recorded as leakage. Because it is difficult to discriminate between perineal dehiscence or perineal wound infection, these complications were recorded as perineal wound complication. Rare complications were classified as other. Two categories were used: moderate, consisting of complications that needed noninvasive treatment, or serious, defined as complications that required reintervention or caused a prolonged hospital stay. Hospital death was defined as any death that occurred during first admission, whereas postoperative mortality was defined as any death that occurred during the first 30 days after the operation.

A reintervention was defined as any surgical procedure that took place in the operating room after the initial operation during the first admission. Only the first reintervention was taken into analysis. Elective procedures like the removal of gauzes left behind during the initial operation for bleeding or opening/closure of stoma were not considered reinterventions. Reresections for positive margins were not considered reinterventions.

Data Collection and Statistics
All case record forms were sent to the central data office in Leiden. After several checking rounds, the data were entered in a database and analyzed with the SPSS package (SPSS, Inc, Chicago, IL).

Mann-Whitney tests were used to compare quantitative and ordered variables, and Student’s t tests were used to analyze differences in normally distributed data between the two groups. ² tests were used to compare proportions. A P value of .05 or less was considered statistically significant.

	RESULTS

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Patients
Of the 1,530 Dutch patients included in the trial, 116 turned out to be ineligible. Reasons for ineligibility are recorded in Table 1. In some institutes, a computed tomography scan was performed for treatment planning of the RT, leading to detection of metastasis or irresectability. Consequently, more TME-only patients turned out to be irresectable or metastasized during the operation. Thus, 1,414 patients remained assessable: 695 in the RT group and 719 in the surgery-alone group. Table 2 shows well balanced clinical and tumor characteristics on both treatment arms. There was also no difference in the distribution in TNM stages or in the percentage of patients with a positive circumferential margin.

RT was administered with three portal fields in 75% of the patients and with four portal fields in 25% of the patients. Fifty-three percent of the patients were treated in supine position. Of the 322 patients treated in prone position, 92 (29%) were treated on a belly board. The dorsal sacrum and lordotic curve were shielded in 90% of all patients.

The median interval between randomization and surgery was 21 days in the RT group and 14 days in the surgery group, indicating that postponement of surgery did not occur more often in the RT group. It had been anticipated that RT would increase the treatment time by a maximum of 10 days.

Toxicity. During RT, any side effects were reported in 26% of all RT+ patients (Table 3). Nineteen percent experienced grade 1 toxicity, representing only minor complaints. In 7% of the patients, there was a grade 2 or 3 complication.

In four patients (< 1%), other grade 3 toxicities were reported, leading to the postponement of the operation in two patients with thromboembolic complications. One patient required a catheter because of urinary retention after the RT. The fourth patient had experienced blood loss 2 months after RT, and proctoscopy confirmed a proctitis.

Surgery
Surgical characteristics. To evaluate whether preoperative RT influences operation procedures, surgery characteristics are compared in Table 4. There was no significant difference in median operation time or median hospital stay between both treatment arms. Total blood loss was slightly increased (100 mL) in the RT+ group (P < .001). Subset analysis revealed that the difference in median blood loss was mainly present in the LAR patients: 1,025 mL in the RT+ group versus 800 mL in the RT- group (P < .001), whereas median blood loss in the APR patients was not significantly different across the treatment arms.

More RT+ patients received a temporary diverting stoma at the time of TME surgery than RT- patients did (60% v 53%; P = .05). Postoperatively, slightly more RT- patients required a stoma as a result of complications, resulting in a not significantly different overall number of temporary stomas in both groups (68% v 63%; P = .2), as is shown in Figure 1.

View larger version (10K): [in this window] [in a new window]   Fig 1. Percentage of LAR patients with a diverting stoma.

All reported postoperative complications are listed in Table 5. For most complications, there was no difference between the two treatment arms. The overall postoperative complication rate was 48% in the RT+ group versus 41% in the RT- group (P = .008). This difference was mainly attributable to the difference in perineal wound healing.

The percentage of LAR patients who showed clinical leakage postoperatively was 11% (n = 105) and was not statistically different for RT+ and RT- patients (11% v 12%). Leakage was less common in patients with a diverting stoma (8% v 16%, P = .001). In patients with an end-to-end anastomosis, leakage occurred in 16% of the LAR patients, whereas only 9% of the patients with a pouch reconstruction experienced anastomotic failure. In patients with a side-to-end anastomosis, 12% experienced anastomotic failure. There was no influence of the distance of the tumor from the anal verge or age on the occurrence of leakage. Twenty percent of the patients with leakage were treated conservatively, whereas 80% required a surgical reintervention.

In total, 201 patients (14%) underwent one or more reinterventions, with 103 patients in the RT+ group and 98 in the RT- group. Indications for reinterventions are listed in Table 6. No difference between the number of reinterventions in the LAR or APR patients was observed.

View larger version (25K): [in this window] [in a new window]   Fig 2. Percentage of hospital deaths per age category.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Lumbosacral plexopathy was a major cause of concern in the SRCT because six patients developed long-standing pain and/or neurologic symptoms at the level of the lower lumbar plexus.³⁴ These six patients all complained about pain during the RT. An extensive study on dose distribution showed that these patients might have received a higher dose (112%) at the level of the lumbar vertebrae, when the dorsal shields were inappropriately placed.

In our study, 53 patients had pain or a feeling of discomfort in the legs or gluteal region, 18 of whom needed medication or treatment interruption. In these patients, a careful evaluation of the treatment fields and the dorsal shielding was performed, and adjustments were made in five patients. As a precaution, treatment was interrupted in 14 patients. So far, with a median follow-up of 25.4 months, there are no reports of longstanding pain or neurologic symptoms. This might be attributed to the fact that the upper border of the radiation field was defined as L5/S1, as opposed to mid-L4 as it was defined in the Swedish trials. This prevents the irradiation of the lower dorsal lumbar roots.

Although there was initial concern that irradiation would hamper the operation, this was not reflected in the parameters of the surgical procedure. There was no increase in the duration of the operation, and although the difference in blood loss was significant, an increase of 100 mL is not a serious clinical problem. Irradiation did not influence the choice of the surgeon to perform a LAR or an APR procedure.

The relatively high incidence of postoperative complications in our trial (45%) might be explained by the great effort taken to meticulously register all possible complications. Apart from data from the case record forms as recorded by the surgeon, data from operation notes and discharge letters were taken into account as well. Similar complication rates were reported in a prospective comparison of conventional and TME surgery.³⁵

The mortality rate in the Stockholm I trial with five doses of 5 Gy was 2% in the RT+; group versus 8% in the RT+ group.²⁷ In the Imperial Cancer Research Fund trial, in which patients were treated with three doses of 5 Gy, these percentages were 7% versus 12% respectively.⁷ The difference was mainly due to an increase in cardiovascular deaths, particularly in patients older than 75 years. Therefore, patients older than 80 years were excluded from the Stockholm II trial and SRCT. The explanation for the increased mortality rates in the Stockholm I trial and the Imperial Cancer Research Fund trial is possibly the suboptimal treatment technique. In these trials, the treatment was administered by two opposed fields, which increased the volume treated with 25 Gy considerably. Later trials, therefore, requested a three-portal or four-portal technique to reduce the treated volume. In the SRCT, 48 patients were treated with a two-portal technique, and those patients showed a higher mortality rate than the patients treated with three or four portals.²⁶ In the Stockholm II trial, there was not a difference in mortality within 30 days between the two treatment arms: 2% in the RT+ group versus 1% in the RT- group. In-hospital mortality rates in the SRC trial were 4% in the RT+ versus 3% in the RT- group. The in-hospital mortality rate in our trial showed no difference between the treatment arms and was 4% in the RT+ group versus 3.3% in the RT- group. This can be considered a satisfying result, taking into account that patients above the age of 80 were included in our trial. Our results demonstrate that the introduction of TME surgery after preoperative RT does not lead to an increase in the postoperative mortality rate, as long as at least three portals are used for the RT. The two major causes of postoperative mortality in our trial were cardiovascular problems and complications caused by anastomotic failure in LAR patients.

Anastomotic leakage is a major clinical problem in rectal or anal anastomoses. The reported clinical leakage rate after anterior resection varies from 3% to 11%.^36-39 Karanjia et al³⁷ showed that a diverting colostomy is an important measure in reducing the complications of anastomotic leakage. After TME surgery, more serious anastomotic leakage has been reported as compared with conventional surgery^35,40 This increase can be partly explained by the removal of the pain-sensitive peritoneum, which prevents early detection of anastomotic failure.³⁷ In our study, the number of patients with clinical anastomotic leakage was 105 (11%). This is consistent with other reports in which TME surgery was applied. It is particularly reassuring because this trial was a large multicenter study, whereas most other reports concern single-institution experiences. No difference in clinical leakage rate between the RT+ and RT+; patients was observed, which is in agreement with previous reports about preoperative RT.^11,12,27,28 Because patients with a diverting colostomy developed fewer leaks, we recommend a diversion in case there is any doubt about the quality of the anastomosis. Increase in perineal dehiscence after preoperative RT has been observed by several authors, both after short-term as well as after long-term preoperative RT. Although results are difficult to compare, because of various definitions of perineal dehiscence, a two-fold increase is generally reported after RT.^11,12,26-28

In our study, 100 patients suffered from perineal complications, with 18% in the RT- group versus 29% in the RT+ patients. When the perineum was not included in the target volume, there was no increase of perineal complications as compared with the RT- patients. However, avoidance of irradiation of the perineum is not desirable in APR patients because this might lead to an increase in local recurrences.

In conclusion, our results show that, although application of short-term preoperative RT in combination with TME surgery leads to an increase in the overall postoperative complication rate when compared with TME surgery alone, the number of complications that lead to reintervention or even mortality are similar in both treatment arms. Although follow-up is too short to comment on the occurrence of late side effects, long-term results from the SRCT give no reasons for concern so far. Therefore, preoperative hypofractionated RT is to be considered a safe procedure in patients treated with TME surgery, despite a slight increase in complications when compared with patients who only received TME surgery.

APPENDIX
The appendix is available online at www.jco.org.

The following clinical investigators participated in this trial:Surgeons:A.B. Bijnen, P. de Ruiter, Medisch Centrum Alkmaar, Alkmaar; B. van Ooijen, Algemeen Christelijk Ziekenhuis Eemland Locatie de Lichtenberg, Amersfoort; D. van Geldere, R.P.A. Boom, Ziekenhuis Amstelveen, Amstelveen; R.P. Bleichrodt, S. Meyer, Academisch Ziekenhuis Vrije Universiteit; F.A.N. Zoetmulder, F. van Coevorden, Antonie van Leeuwenhoek Ziekenhuis; R.M.J.M. Butzelaar, E.P. Steller, Sint Lucas Andreas Ziekenhuis, Locatie Lucas; W.F. van Tets, A.C.H. Boissevain, Sint Lucas Andreas Ziekenhuis, Locatie Andreas; F.J. Sjardin, BovenIJ Ziekenhuis; J.F.M. Slors, Academisch Medisch Centrum, Amsterdam; W.H. Bouma, J.G.J. Roussel, Gelre Ziekenhuizen, Locatie Lukas Ziekenhuiscentrum Apeldoorn, Apeldoorn; J.H.G. Klinkenbijl, E.J. Spillenaar Bilgen, Ziekenhuis Rijnstate, Arnhem; Ph.M. Kruyt, W.K. de Roos, Stichting Ziekenhuisvoorzieningen Gelderse Vallei Locatie Ziekenhuis Gelderse Vallei Bennekom, Bennekom; E.J.R. Slingenberg, P.D. de Rooij, Sint Ziekenhuis Lievensberg, Bergen Op Zoom; M.A.J.M. Hunfeld, Rode Kruis Ziekenhuis, Beverwijk; A.L.A. Meersman, Maasziekenhuis Boxmeer, Boxmeer; J.K.S. Nuytinck, Ignatius Ziekenhuis Breda; R.M.P.H. Crolla, Ziekenhuis de Baronie, Breda; J. van der Bijl, Atrium Brunssum, Atrium Heerlen, Brunssum, Heerlen; G.W.M. Tetteroo, IJsselland Ziekenhuis, Capelle A/D Ijssel; L.P.S. Stassen, P.W. de Graaf, Reinier de Graaf Groep Loc Reinier de Graaf Gasthuis, Delft; W.A.H. Gelderman, F.G.J. Willekens, Bosch Medicentrum Locatie Groot Ziekengasthuis; I.P.T. van Bebber, E.J. Carol, Stichting Carolus-Liduina-Lindelust Ziekenhuis Locatie Carolus Ziekenhuis, Den Bosch; G.W. Kastelein, H. Boutkan, Stichting Juliana Kinderziekenhuis/Rode Kruis Ziekenhuis Locatie Rode Kruis Ziekenhuis; C. Ulrich, B.C. de Vries, Medisch Centrum Haaglanden Locatie Westeinde; H.J. Smeets, J.M. Heslinga, Stichting Bronovo-Nebo, Ziekenhuis Bronovo; P.V.M. Pahlplatz, Ziekenhuis Leyenburg, Den Haag; P. Heres, J.A. van Oijen, Stichting het van Weel-Bethesda Ziekenhuis, Dirksland; M. van Hillo, Stichting Talma Sionsberg, Dokkum; R.J Oostenbroek, K.G. Tan, Albert Schweitzer Ziekenhuis Locatie Dordwijk, Dordrecht; H.C.J. van der Mijle, Christelijk Ziekenhuis Nij Smellinghe; R. Looijen, Christelijk Ziekenhuis Nij Smellinghe, Drachten; H.J.T. Rutten, J.J. Jakimowicz, Catharina Ziekenhuis; O.J. Repelaer van Driel, P.H.M. Reemst, Diaconessenhuis Eindhoven, Eindhoven; E.J.T. Luiten, R.F.T.A. Assmann, Sint Annaziekenhuis, Geldrop; C.M. Dijkhuis, Oosterscheldeziekenhuis, Goes; R.T. Ottow, Het Groene Hart Ziekenhuis Locatie Bleuland, Gouda; J.T.M. Plukker, Academisch Ziekenhuis Groningen, Groningen; E.J. Boerma, R. Silvis, Kennemer Gasthuis Locatie Deo, Haarlem; J.H. Tomee, Stichting Streekziekenhuis Coevorden-Hardenberg Locatie Röpcke Zweers, Hardenberg; G.J.M. Akkersdijk, Spaarne Ziekenhuis, Heemstede; C.G.B.M. Rupert, de Tjongerschans, Ziekenhuis Heerenveen, Heerenveen; G.J.C.M. Niessen, G. Verspui, Elkerliek Ziekenhuis Locatie Helmond, Helmond; J.H. Kroesen, J.W. Juttmann, Ziekenhuis Hilversum, Hilversum; J.W.D. de Waard, M.W.C. de Jonge, Westfries Gasthuis Locatie Sint Jan, Hoorn; D.B.W. de Roy van Zuidewijn, W. Dahmen, Medisch Centrum Leeuwarden Locatie Zuid, Leeuwarden; R. Vree, J.A. Zonnevylle, Diaconessenhuis Leiden; R.A.E.M. Tollenaar, Leids Universitair Medisch Centrum, Leiden; P.A. Neijenhuis, S.A. da Costa, S.K. Adhin, Rijnland Ziekenhuis Locatie Sint Elisabeth, Leiderdorp; F.J. Idenburg, Medisch Centrum Haaglanden Locatie Antoniushove, Leidschendam; H. van der Veen, IJsselmeerziekenhuizen Loc Zuiderzeeziekenhuis; C.E.A.M. Hoynck van Papendrecht, Ijsselmeerziekenhuizen Locatie Zuiderzeeziekenhuis, Lelystad; C.G.M.I. Baeten, M.F. von Meyenfeldt, G.L. Beets, Academisch Ziekenhuis Maastricht, Maastricht; T. Wobbes, Academisch Ziekenhuis Nijmegen Sint Radboud; E.D.M. Bruggink, L.J.A. Strobbe, Canisius-Wilhelmina Ziekenhuis Nijmegen, Nijmegen; O.J. van West, R.A.J. Dörr, Pasteurziekenhuis, Oosterhout; C.D. van Duyn, Ziekenhuis Bernhoven Locatie Oss, Oss; J.W.M. Bol, T.A.A. van den Broek, Waterlandziekenhuis, Purmerend; J.M.H. Debets, R.J.A. Estourgie, Laurentius Ziekenhuis, Roermond; H.W.P.M. Kemperman, Ziekenhuis Franciscus, Roosendaal; H.F. Veen, W.F. Weidema, C.J. van Steensel, Ikazia Ziekenhuis; F. Logeman, A.A.E.A. de Smet, Sint Clara Ziekenhuis; A.W.K.S. Marinelli, Academisch Ziekenhuis Rotterdam, Daniel den Hoed Kliniek; J.H. Driebeek-van Dam, Havenziekenhuis; W.R. Schouten, P.P.L.O. Coene, Academisch Ziekenhuis Rotterdam, Dijkzigt; M.A. Paul, Zuiderziekenhuis, Rotterdam; J.J. van Bruggen, Schieland Ziekenhuis, Schiedam; E.J. Mulder, Antonius Ziekenhuis, Sneek; R. den Toom, A.J van Beek, Ruwaard van Putten Ziekenhuis, Spijkenisse; S.J. Brenninkmeyer, G.P. Gerritsen, TweeSteden ziekenhuis; H.J.M. Oostvogel, J.A. Roukema, Sint Elisabeth Ziekenhuis, Tilburg; E.B.M. Theunissen, Mesos, Medisch Centrum Locatie Overvecht; L.W.M. Janssen, A. Hennipman, Universitair Medisch Centrum Utrecht; A.J.M. van Wieringen, Mesos, Medisch Centrum Locatie Oudenrijn; A. Pronk, P. Leguit, Diakonessenhuis, Utrecht; F.A.A.M. Croiset van Uchelen, R.M.H. Roumen, Sint Joseph Ziekenhuis, Veldhoven; C.L.H. van Berlo, J.F.M. Reinders, Sint Maartens Gasthuis, Venlo; C.D.G.W. Verheij, Sint Elisabeth Ziekenhuis, Venray; J.H. ten Thije, Ziekenhuis Walcheren, Vlissingen; W. van Overhagen, I.H. Oei, Reinier de Graaf Groep Locatie Diaconessenhuis Voorburg, Voorburg; E.M.G. Leerkotte, J.W.A. van Luijt, TweeSteden ziekenhuis, Waalwijk; H.C.M. Verkooyen, J.A.L. Jansen, Sint Jans-Gasthuis, Weert; J. Merkx, J.P. Vente, Hofpoort Ziekenhuis, Woerden; H. de Morree, Stichting Oosterscheldeziekenhuizen, Zierikzee; P.J.J. van Rijn, ’t Lange Land Ziekenhuis, Zoetermeer; W.F. Blom, Albert Schweitzer Ziekenhuis Locatie Zwijndrecht, Zwijndrecht; Pathologists:J.P.A Baak, Medisch Centrum Alkmaar, Alkmaar; H. Barrowclough, Algemeen Christelijk Ziekenhuis Eemland Locatie de Lichtenberg, Amersfoort; G.J.A. Offerhaus, Academisch Medisch Centrum; G: Brutel de la Riviere, Sint Lucas Andreas Ziekenhuis Locatie Sint Lucas; M.L.F. van Velthuysen, Antoni van

APPENDIX (Cont’d)
Leeuwenhoek Ziekenhuis; B.A. van de Wiel, Sint Lucas Andreas Ziekenhuis Locatie Andreas; H.H. Oushoorn, BovenIJ Ziekenhuis, Amsterdam; T.A.J.M. Manschot, Gelre Ziekenhuizen Locatie Lukas Ziekenhuiscentrum Apeldoorn, Apeldoorn; J.M. Wiersma-van Tilburg, Ziekenhuis Rijnstate, Arnhem; V. Potters, Stichting Ziekenhuis Lievensberg, Bergen Op Zoom; H.V. Stel, Ziekenhuis Gooi-Noord, Blaricum; J. Los, Ignatius Ziekenhuis Breda, Breda; G.W. Verdonk, Atrium Brunssum, Brunssum; C. van Krimpen, S.H. Sastrowijoto, E.M. van der Loo, Stichting Diagnostisch Centrum Stichting Samenwerkende Delftse Ziekenhuizen, Delft; H.A. Meijer, Bosch Medicentrum Locatie Groot Ziekengasthuis, Den Bosch; P. Blok, Ziekenhuis Leyenburg; C.J. Tinga, Stichting Bronovo-Nebo, Ziekenhuis Bronovo; E.C.M. Ooms, Medisch Centrum Haaglanden Locatie Westeinde; C.M. Bruijn-van Duinen, Ziekenhuis Leyenburg; J.W. Steffelaar, Stichting Juliana Kinderziekenhuis/Rode Kruis Ziekenhuis Locatie Rode Kruis Ziekenhuis, Den Haag; P.J. Westenend, Pathologisch Laboratorium voor: Dordrecht en omstreken, Dordrecht; I.W.N. Tan-Go, H.M. Peters, Stichting Pathologische Anatomie en Medische Microbiologie, Eindhoven; E.J.M. Ahsmann, Stichting LaboratoriaGoudse Ziekenhuizen, Gouda; J.F. Keuning, Stichting Pathologisch Anatomisch Laboratorium Kennemerland, Haarlem; K. van Groningen, Spaarne Ziekenhuis, Heemstede; P.H.M.H. Theunissen, Atrium Heerlen, Heerlen; F.J.J.M. van Merrienboer, Elkerliek Ziekenhuis Locatie Helmond, Helmond; G. Freling, Ziekenhuis Bethesda, Hoogeveen; A.J.K. Grond, Laboratorium voor de Volksgezondheid in Friesland, Leeuwarden; M.C.B. Gorsira, Diaconessenhuis Leiden; I.D. Nagtegaal, Leids Universitair Medisch Centrum, Leiden; J.J Calame, Rijnland Ziekenhuis Locatie Sint Elisabeth, Leiderdorp; E.A. Neefjes-Borst, IJsselmeerziekenhuizen Locatie Zuiderzeeziekenhuis, Lelystad; J.W. Arends, academisch ziekenhuis Maastricht, Maastricht; A.P. Runsink, Streeklaboratorium: Zeeland, Middelburg; C.A. Seldenrijk, Stichting Sint Antonius Ziekenhuis, Nieuwegein; J.H.J.M. van Krieken, Academisch Ziekenhuis Nijmegen St Radboud; M. Mravunac, Canisius-Wilhelmina Ziekenhuis Nijmegen, Nijmegen; W.S. Kwee, Laurentius Ziekenhuis, Roermond; H. van Dekken, Academisch Ziekenhuis Rotterdam, Daniel den Hoed Kliniek; J.C. Verhaar, Stichting Pathan; N.A.L. van Kaam, Stichting Pathan; H. van Dekken, Academisch Ziekenhuis Rotterdam, Dijkzigt; R.W.M. Giard, Sint Clara Ziekenhuis; H. Beerman, Zuiderziekenhuis, Rotterdam; A.A.M. van der Wurff, Sint Elisabeth Ziekenhuis, Tilburg; M.E.I. Schipper, Universitair Medisch Centrum Utrecht Locatie Academisch Ziekenhuis Utrecht; H.M. Ruitenberg, Diakonessenhuis, Utrecht; R.F.M. Schapers, Stichting Pathologisch Laboratorium, Venlo; A.P. Willig, Sint Jans-Gasthuis, Weert; A.G. Balk, Stichting Ziekenhuis De Heel, Zaandam; Radiation oncologists:E.H.J.M. Rutten, Medisch Centrum Alkmaar, Alkmaar; D. Gonzalez Gonzalez, G. van Tienhoven, Academisch Medisch Centrum; B.J Slotman, J.A. Langendijk, Academisch Ziekenhuis Vrije Universiteit; G.M.M. Bartelink, B.M.P. Aleman, Antoni van Leeuwenhoek Ziekenhuis, Amsterdam; A.H. Westenberg, Arnhems Radiotherapeutisch Instituur, Arnhem; J. Pomp, Reinier de Graaf Gasthuis, Delft; C.C.E. Koning, R.G.J. Wiggenraad, Medisch Centrum Haaglanden Locatie Westeinde; F.M. Gescher, Ziekenhuis Leyenburg, Den Haag; J.J.F.M. Immerzeel, A.C.A. Mak, Radiotherapeutisch Instituut Stedendriehoek en Omstreken, Deventer; J.G. Ribot, Catharina Ziekenhuis, Eindhoven; D.F.M. de Haas-Kock, Stichting Radiotherapeutisch Instituut Limburg, Heerlen; G. Botke, A. Slot, Radiotherapeutisch Instituut Friesland, Leeuwarden; E.M. Noordijk, Leids Universitair Medisch Centrum, Leiden; Ph. Lambin, Academisch Ziekenhuis Maastricht, Maastricht; J.W.H. Leer, J Hoogenhout, Academisch Ziekenhuis Nijmegen Sint Radboud; Academisch Ziekenhuis Nijmegen Sint Radboud, Nijmegen; P.C. Levendag, P.E.J Hanssens, Academisch Ziekenhuis Rotterdam, Daniel den Hoed Kliniek, Rotterdam; G.S.J Bunnik, K.A.J. de Winter, Dokter Bernard Verbeeten Instituut, Tilburg; J.J. Batterman, H.K. Wijrdeman, Universitair Medisch Centrum Utrecht, Utrecht; J.M. Tabak, M.F.H. Dielwart, Zeeuws Radiotherapeutisch Instituut, Vlissingen.

	ACKNOWLEDGMENTS

 
Supported by the Dutch Cancer Society (grant no. CKVO 95-04) and the Dutch National Health Council (grant no. OWG 97/026).

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted January 18, 2001; accepted September 17, 2001.

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