Laparoscopic Nephroureterectomy for Upper Urinary Tract Transitional Cell Carcinoma: Results of a Belgian Retrospective Multicentre Survey

european urology 51 (2007) 1633–1638

available at www.sciencedirect.com journal homepage: www.europeanurology.com

Laparoscopy

Laparoscopic Nephroureterectomy for Upper Urinary Tract Transitional Cell Carcinoma: Results of a Belgian Retrospective Multicentre Survey Peter Schatteman a,*, Charles Chatzopoulos b, Christophe Assenmacher c, Luc De Visscher d, Jean-Luc Jorion e, Ve´ronique Blaze f, Ben Van Cleynenbreugel g, Ignace Billiet h, Hans Van der Eecken i, Renaud Bollens j, Alexandre Mottrie a a

Onze-Lieve-Vrouwziekenhuis, Aalst, Belgium Clinique St-Anne St-Remi St-Etienne, Brussels, Belgium c Clinique St-Elisabeth, Ukkel, Belgium d Clinique St-Luc, Namur, Belgium e Clinique St-Pierre, Ottignies, Belgium f Clinique Ve´sale, Charleroi, Belgium g Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium h AZ Groeninge, Kortrijk, Belgium i H-Hart-Ziekenhuis, Roeselare, Belgium j Hoˆpital Erasme, Brussels, Belgium b

Article info

Abstract

Article history: Accepted September 25, 2006 Published online ahead of print on October 10, 2006

Objectives: To evaluate the technical and oncologic feasibility of laparoscopic nephroureterectomy for upper urinary tract transitional cell carcinoma. Methods: A retrospective survey of 100 patients, treated with laparoscopic nephroureterectomy in 10 Belgian centres, was performed. Most procedures were performed transperitoneally. The distal ureter was managed by open surgery in 55 patients and laparoscopically in 45 patients. The mean follow-up was 20 mo. Results: Mean operation time was 192 min and mean blood loss 234 ml. The conversion rate was 7%. Important postoperative complications were seen in 9%. Pathologic staging was pTa in 31 patients, pT1 in 23, pT2 in 12, pT3 in 33, and pT4 in 1, concomittant pTis in 3. Pathologic grade was G1 in 24 patients, G2 in 28, and G3 in 48. Negative surgical margins were obtained in all but one patient. Twenty-five patients developed progressive disease (24%) at a mean postoperative time of 9 mo (local recurrence in 8%, metastases in 11%, both in 5%). Progression was 0% for pTa, 17% for pT1, 17% for pT2, 51% for pT3, and 100% for pT4. Cancer-specific survival was 100% for pTa, 86% for pT1, 100% for pT2, 77% for pT3, and 0% for pT4. Conclusion: Laparoscopic nephroureterectomy appears to be a technically and oncologically feasible operation. To prevent tumour seeding, one should avoid opening the urinary tract and should extract the specimen with an intact organ bag. The high local recurrence rate in this study probably reflects the high percentage of high-grade and high-stage tumours in this study.

Keywords: Laparoscopic nephroureterectomy Trocar recurrence Upper tract transitional cell carcinoma

# 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Onze-Lieve-Vrouwziekenhuis, Moorselbaan 164, 9300 Aalst, Belgium. Tel. +32 53 724378; Fax: +32 53 216557. E-mail address: [email protected] (P. Schatteman). 0302-2838/$ – see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.eururo.2006.09.016

1634

1.

european urology 51 (2007) 1633–1638

Introduction

Table 1 – Patient characteristics Patients

Upper urinary tract transitional cell cancer (TCC) represents a highly aggressive disease; any diagnostic or therapeutic procedure should avoid urinary spillage and thus possible tumour contamination by all means. Standard treatment is open radical nephroureterectomy with excision of bladder cuff. This intervention requires either two incisions (lumbotomy–lower abdominal incision) or one large (‘‘ventral’’ lumbotomy or midline incision). This results in considerable postoperative morbidity (pain, herniation, slow convalescence). Since publication of the first laparoscopic radical nephrectomy for renal cell cancer in 1991 [1], it has been proven that excellent oncologic results can be achieved with laparoscopic radical nephrectomy for renal cell cancer [2]. Encouraged by these results, TCC of the upper urinary tract seems a good candidate for laparoscopic treatment, omitting the troublesome lumbotomy incision. In recent years, the first reports with intermediate-term follow-up have been published, showing acceptable oncologic outcomes. This study evaluated the technical and oncologic feasibility of laparoscopic nephroureterectomy for upper urinary tract TCC in a retrospective multicentre survey. 2.

Methods

In 2004, a survey concerning laparoscopic nephroureterectomy for upper urinary tract TCC was sent to all Belgian urologists, members of the Belgian Laparoscopic Urology Group (BLUG). They were asked to retrospectively collect the following: demographic and diagnostic data, perioperative data, and follow-up data. Data of cases with non–organ-confined disease on preoperative imaging were excluded from this survey as well as all data from centres with fewer than four reported cases. Cases from 10 Belgian hospitals were included, accounting for 100 patients, operated on from March 1998 to December 2004. Diagnosis was made by radiologic imaging (intravenous urography [IVU] or abdominal computed tomography [CT] or both). Preoperative biopsies of the lesion were not routinely performed. Staging examinations (bone scan, chest CT) were performed only on indication. Patient characteristics are shown in Table 1. The median number of cases in each hospital was eight (range: 4–21). The transperitoneal approach was used in all but five cases. A lymphadenectomy was performed in 20% of patients (grossly enlarged lymph nodes in 4%, staging lymphadenectomy in 16%). The indication for lymphadenectomy was at the discretion of the treating physicians. The management of distal ureter is shown in Table 2. The surgical specimen was extracted with an impermeable organ retrieval bag in all but two patients.

n = 100

No. of hospitals Median no. of cases/hospital (range) Gender, male/female Mean age, yr (range) Side, right/left

10 8 (4–21) 67/33 71 (41–96) 60/40

Tumour location Pelvicaliceal Proximal ureter Mid ureter Distal ureter Multifocal

63 3 14 19 1

Enlarged lymph nodes

4 (4%)

Follow-up was at discretion of the individual centre but, in general, comprised cystoscopy every 3–6 mo, 6-mo chest x-ray and abdominal sonography, and abdominopelvic CT scanning at 6 mo postoperatively. The mean follow-up was 20 mo (range: 1–74 mo). A minimum follow-up of 1 yr was available in 74 patients. Progressive disease was defined as distant metastasis or as local recurrent disease in the retroperitoneum.

3.

Results

Operative data are shown in Table 2. Perioperative complications were encountered in four patients (4%): urinary tract perforation in two and splenic bleeding in two. One urinary tract perforation of pyelum occurred in a patient with a pTaG1 tumour in the proximal ureter. The second case was a perforation of distal ureter in a pT3G3 pelvicaliceal tumour. To date, both patients have had an uneventful follow-up. The two patients with splenic bleeding were managed with Floseal1 (a high-viscosity gel for

Table 2 – Operative data Patients Transperitoneal/retroperitoneal Mean operation time, min (range) Mean blood loss, ml (range) Management of distal ureter Open surgery (bladder cuff) Laparoscopic With transurethral preparation Without transurethral preparation

n = 100 95/5 192 (75–359) 234 (20–1200)

55 45 15 30

Perioperative complications

4 (4%)

Postoperative complications Major complications Minor complications

15 (15%) 9 (9%) 6 (6%)

Postoperative mortality

2 (2%)

Conversions

7 (7%)

european urology 51 (2007) 1633–1638

haemostasis, a combination of gelatin granules and topical thrombin). All but seven cases were successfully completed laparoscopically (93%). The seven conversions were due to bleeding from renal vessels in three patients, abdominal adhesions in two, and anaesthetic problems (hypercapnia/hypertension) in another two. In the immediate postoperative course, minor complications developed in six patients (abdominal haematoma in 3, paralytic ileus in 2, lymphatic leak in 1) and major complications in nine (bowel injury in 2, pulmonary infection/embolism in 5, acute renal failure in 1, and transient ischaemic attack in 1). A diagnostic laparoscopic revision was performed in three patients with persistent abdominal complaints, demonstrating a bowel injury in two of them. They were treated with open intestinal repair. Postoperative mortality was 2%; one patient died on the third postoperative day due to pulmonary embolism. The other patient developed a severe pulmonary infection after open bowel injury repair and died on postoperative day 12. Mean hospital stay was 10 d (range: 4–39 d). Table 3 shows the histopathologic staging and grading. Lymphadenectomy revealed pN0 in 17 patients and pN1 in 3 patients. Only one of these 3 patients had enlarged lymph nodes detected preoperatively. This patient was treated with adjuvant gemcitabine-cisplatinum and to date is without evidence of disease. The two other pN+ patients were treated conservatively; one died after 2 yr with liver metastasis and the other is alive without evidence of disease. Negative surgical margins were obtained in all but one patient. He was operated on for a nonsuspicious afunctional (hydronephrotic) kidney. The specimen was extracted in pieces without an organ bag. Histopathology showed a pT4 tumour. This patient developed a port-site recurrence with distant metastasis at 5 mo and died at 8 mo. Twenty-four patients developed progressive disease (24%) at a mean postoperative time of 9 mo (range: 1–25 mo). Progression was related to stage: 0% for pTa, 17% for pT1, 17% for pT2, 51% for

Table 3 – Histopathologic data Tumour stage

n = 100

Tumour grade

n = 100

pTa pT1 pT2 pT3 pT4 Associated pTis

31 23 12 33 1 3

G1 G2 G3

24 28 48

1635

pT3, and 100% for pT4; and to grade: 0% for G1, 4% for G2, and 50% for G3. Distant metastases occurred in 11 patients, local recurrence in 8, and combined local and distal disease in 5. Location of the 13 cases with local recurrence was retroperitoneum in 10 (all pT3G3) and port site in 3 (pT1G3, pT3G3, and pT4G3). The distal ureter in these 13 patients was managed by open surgery in 6 and laparoscopically in 7. The three port-site recurrences were diagnosed after 5, 8, and 11 mo. In all three patients, distant metastatic disease was also found. The first patient suffered from a unsuspected pelvicaliceal pT4G3R1 tumour; the specimen was extracted without organ bag. This patient died at 8 mo. The second patient was diagnosed with a unsuspected pelvicaliceal pT3G3R0 tumour, and again extraction was done without organ bag. He developed a port-site recurrence at 8 mo and died at 15 mo. The third patient, with a pelvicaliceal pT1G3 tumour, developed a portsite recurrence at 11 mo and died at 14 mo. Distant metastases occurred in 16 patients (5 of them with local recurrent disease as well). Cancer-specific survival was 88% overall, 100% for pTa, 86% for pT1, 100% for pT2, 77% for pT3, and 0% for pT4.

4.

Discussion

Over the last decade, laparoscopy has become standard treatment for a variety of benign urologic disorders (nephrectomy for benign disease, colpopromonto-fixation, pyeloplasty, etc); it has proven its technical feasibility and its superior postoperative outcome (less postoperative pain, shorter hospital stay, more rapid convalescence) [3]. Several publications show that these advantages also are present for laparoscopic nephroureterectomy [4–8]. The operative and postoperative data of this study are comparable to previously published data (Table 4). The somewhat longer hospital stay in this survey is due to Belgian sociomedical factors. However, the application of laparoscopy in oncologic situations has always raised concerns about the possible risk of tumour spillage with local recurrence and port-site recurrence. Possible risk factors are the high-pressure environment with so-called chimney effect and the lack of tactile feedback. For organs where tumour is surrounded by an anatomic capsule (prostate cancer, renal cell cancer), the risk is probably small. But for TCC with its known aggressive nature and absence of anatomic capsule, this risk could be significant. In a survey of tumour seeding in urologic laparoscopy, the incidence of tumour seeding was low at

1636

european urology 51 (2007) 1633–1638

Table 4 – Technical feasibility Author

n

Kawauchi et al. [4] Shalhav et al. [5] Gill et al. [6] Tsujihata et al. [7] Klinger et al. [8] Current survey

Mean operation time, min

34 25 42 25 19 100

Mean blood loss, ml

233 462 234 305 198 192

236 199 242 321 282 234

0.1% of all 10,912 oncologic procedures. However, more than half of all cases were due to TCC of the upper urinary tract, accounting for tumour seeding in 1.2% (7 of 559) of all nephroureterectomies [9]. In another report, the local recurrence rate for oncologic laparoscopic procedures was 1.4%. However, this rate was higher at 4.5% (1 of 22) in laparoscopic procedures for TCC of the upper urinary tract [10]. Large series of laparoscopic nephroureterectomy with short- and intermediate-term follow-up show a disease-free survival rate of 72–95%. Local recurrence and distant metastatic rates are, respectively, 0–15% and 0–28% (Table 5). In a literature review of 377 laparoscopic and 969 open nephroureterectomy cases, Rassweiler et al. described disease-free 2-yr survival rates of 75.2% and 76.2%, respectively. The local recurrence rates were 4.4% versus 6.3%, respectively and distant metastases, 15.5% versus 15.2% [14]. Hall et al. published their experience in 252 open nephroureterectomies and found a disease-free survival rate of 73% at a median follow-up of 12 mo with local recurrence in 9% and distant metastases in 22% [20].

Postoperative complications Major

Minor

6% 8%

6% 40%

Mean hospital stay, d

13 6 2.3 2.2 8.1 10

12% – 0% 9%

6%

The current study shows a 2-yr cancer-specific survival rate of 88% and a 2-yr disease-free survival rate of 76%, comparable to literature data (Table 5). However, the local recurrence rate of 13% in this study is high. A possible explanation for this problematic local tumour control could be the high percentage of pT3–T4 tumours (34%) and G3 (48%) tumours compared to other studies (Table 5). Obviously, it is advisable to manage cT3–T4 tumours by open surgery [14]. However, this implies accurate staging in urothelial upper tract tumours, which in our experience is not always possible. Taking biopsies of upper tract urothelium may give you tumour grade but seldom will tell you the tumour stage. Another explanation for the local tumour control could be the fact that this study includes the initial results from 10 different urologic departments. This means that technical reasons due to initial experience could be a factor. However, one should keep in mind that prognosis in open surgery of T3–T4 tumours is also often problematic [19]. Concerning distal ureter management, local recurrence was seen in 6 of 55 cases (11%) with

Table 5 – Oncologic outcomes Author

n

Follow-up, mo

Positive margins

Local recurrence

Metastatic disease

>pT2

Disease-free survival

Cancerspecific survival

Laparoscopic

Kawauchi et al. [4] Shalhav et al. [5] Klinger et al. [8] Jarrett et al. [11] El Fettouh et al. [12] Bariol et al. [13] Rassweiler et al. [14] Matsui et al. [15] Hattori et al. [16] Wolf et al. [17] Matin et al. [18] McNeill et al. [19] Current survey

34 20 19 25 116 25 23 17 44 54 60 25 100

13 >24 22 >12 25 101 – 9 – 25 23 35 20

– – 0% 4% – – – – – 8% 8% – 1%

0% 15% 0% 8% 2% 4% 0% 6% – 8% 12% – 13%

6% 15% 5% 16% 9% 28% 17% 0% 25% 16% 12% – 16%

35% – 26% – 18% – 17% 35% – 28% 45% 48% 34%

94% 75% 95% 75% 89% 72% 83% 94% – 75% – – 76%

– 85% 95% 92% 87% 72% 89% – 85% 80% – 84% 88%

Open

Hall et al. [20]

252

12

–

9%

22%

–

73%

–

european urology 51 (2007) 1633–1638

open distal ureter management and in 7 of 45 (16%) with laparoscopic handling of the distal ureter. To date, three case reports of port metastasis after purely laparoscopic handling of TCC of the upper urinary tract have being published [21–23]. In all three cases, extraction of the specimen was performed without an organ bag or with a defective (torn) organ bag. In one of these patients, port-site metastasis occurred after a procedure on a tuberculous atrophic kidney with an unsuspected TCC within it [23]. Also in the present survey, two of three port-site recurrences occurred in patients with ‘‘unsecured organ retrieval’’ due to unsuspected TCC. Hence, the use of an organ bag for organ retrieval seems imperative. Another interesting point is the timing of port-site recurrence. In a review of laparoscopic oncologic procedures in gastrointestinal, gynaecologic, and urologic procedures, Schaeff et al. described that the majority of port-site recurrences occurred in the first postoperative year (88% in the first year and up to 96% in the first 2 yr) [24]. The three cases in this survey, as well as the three previously described cases [21–23], follow this timing. The indication for regional lymphadenectomy in urothelial cancer of the upper urinary tract is not yet well defined. Also the anatomic boundaries of lymphadenectomy related to location of tumour are unclear. Klinger et al. advised to perform it routinely for staging purpose and adequate adjuvant treatment in pN+ patients. They found micrometastasis in 14.3% (2 of 14) of cN0 patients [8]. In the current report, staging lymphadenectomy was performed in 16 cN0 patients. Two of these 16 had positive lymph nodes (12.5%). Obviously, staging is more accurate if one performs a lymphadenectomy, but the survival benefit for the patient is unclear. There are no strong data supporting that patients with regional lymphatic micrometastasis should be treated with adjuvant chemotherapy.

5.

Conclusions

Laparoscopic nephroureterectomy is a technical feasible operation. Tumour control, in general, is comparable to results of open series. Local recurrence is mainly related to tumour stage/grade and is equally high in laparoscopic and open series. To prevent tumour seeding, one should avoid opening the urinary tract and should extract the specimen with an intact organ bag. In this survey, the local recurrence rate was somewhat higher, possibly

1637

reflecting the high percentage of high-grade and high-stage tumours.

Conflicts of interest The authors have nothing to disclose.

References [1] Clayman RV, Kavoussi LR, Soper NJ, et al. Laparoscopic nephrectomy: initial case report. J Urol 1991;146:278–82. [2] Permpongkosol S, Chan DY, Link RE, et al. Long-term survival analysis after laparoscopic radical nephrectomy. J Urol 2005;174:1222–5. [3] Rassweiler J, Frede T, Guillonneau B. Advanced laparoscopy. Eur Urol 2002;42:I–XII. [4] Kawauchi A, Fujito A, Ukimura O, Yoneda K, Mizutani Y, Miki T. Hand assisted retroperitoneoscopic nephroureterectomy: comparison with the open procedure. J Urol 2003;169:890–4. [5] Shalhav AL, Dunn MD, Portis AJ, Elbahnasy AM, McDougall EM, Clayman RV. Laparoscopic nephroureterectomy for upper tract transitional cell cancer: the Washington University experience. J Urol 2000;163:1100–4. [6] Gill IS, Sung GT, Hobart MG, et al. Laparoscopic radical nephroureterectomy for upper tract transitional cell carcinoma: the Cleveland Clinic experience. J Urol 2000;164: 1513–22. [7] Tsujihata M, Nonomura N, Tsujimura A, Yoshimura K, Miyagawa Y, Okuyama A. Laparoscopic nephroureterectomy for upper tract transitional cell carcinoma: comparison of laparoscopic and open surgery. Eur Urol 2006;49:332–6. [8] Klinger HC, Lodde M, Pycha A, Remzi M, Janetschek G, Marberger M. Modified laparoscopic nephroureterectomy for treatment of upper urinary tract transitional cell cancer is not associated with an increased risk of tumour recurrence. Eur Urol 2003;44:442–7. [9] Micali S, Celia A, Bove P, et al. Tumor seeding in urological laparoscopy: an international survey. J Urol 2004;171: 2151–4. [10] Rassweiler J, Tsivian A, Kumar AV, et al. Oncological safety of laparoscopic surgery for urological malignancy: experience with more than 1000 operations. J Urol 2003;169:2072–5. [11] Jarrett TW, Chan DY, Cadeddu JA, Kavoussi LR. Laparoscopic nephroureterectomy for the treatment of transitional cell carcinoma of the upper urinary tract. Urology 2001;57:448–53. [12] El Fettouh HA, Rassweiler JJ, Schulze M, et al. Laparoscopic radical nephroureterectomy: results of an international multicenter study. Eur Urol 2002;42:447–52. [13] Bariol SV, Stewart GD, McNeill SA, Tolley DA. Oncological control following laparoscopic nephroureterectomy: 7-year outcome. J Urol 2004;172:1805–8. [14] Rassweiler JJ, Schulze M, Marrero R, Frede T, Palou Redorta J, Bassi P. Laparoscopic nephroureterectomy for

1638

[15]

[16]

[17]

[18]

[19]

european urology 51 (2007) 1633–1638

upper urinary tract transitional cell cancer: is it better than open surgery? Eur Urol 2004;46:690–7. Matsui Y, Ohara H, Ichioka K, et al. Retroperitoneoscopyassisted total nephroureterectomy for upper urinary tract transitional cell carcinoma. Urology 2002;60: 1010–5. Hattori R, Ono Y, Gotoh M, Yoshino Y, Ohshima S. Retroperitoneoscopic nephroureterectomy for transitional cell carcinoma of the renal pelvis and ureter: Nagoya experience. J Urol 2003;169(Suppl):77, abstract no. 299. Wolf JS, Dash A, Hollenbeck BK, Johnston WK, Madii R, Montgomery JS. Intermediate followup of hand-assisted laparoscopic nephroureterectomy for urothelial carcinoma: factors associated with outcomes. J Urol 2005; 173:1102–7. Matin SF, Gill IS. Recurrence and survival following laparoscopic radical nephroureterectomy with various forms of bladder cuff control. J Urol 2005;173:395–400. McNeill SA, Chrisofos M, Tolley DA. The long-term outcome after laparoscopic nephroureterectomy: a compar-

Editorial Comment Rajiv Puri, Bradford Teaching Hospitals, United Kingdom [email protected] This paper reflects, among other things, the rapid dissemination and adoption of laparoscopic techniques by urologists. Clayman reported the first laparoscopic nephroureterectomy in 1991 [1]. The current paper reports results of a survey of 10 centres in Belgium that have performed at least four procedures since 1998. The procedure is inherently attractive to patients and surgeons, recognising that demand and consumer choice are rapidly embracing it, often before studies showing equivalence with the ‘‘gold standard’’ procedures are available. This is unlikely to be reversed because the momentum is so enormous. This paper addresses a few important issues that should make us pause and reflect for a moment.  How many laparoscopic radical nephectomies should a surgeon perform before attempting to undertake laparoscopic nephroureterectomy, a procedure for a tumour with well-known propensity for implantation unlike the more indolent renal cell carcinoma. These tumours disseminate readily and it has been feared that tumour dissemination in a high-pressure environment, as in laparoscopic nephroureterectomy, might be associated with a higher risk of recurrence [2,3].

[20]

[21]

[22]

[23]

[24]

ison with open nephroureterectomy. BJU Int 2000;86: 619–23. Hall MC, Womack S, Sagalowsky AI, Carmody T, Erickstad MD, Roehrborn CG. Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. Urology 1998;52:594–601. Ong AM, Bhayani SB, Pavlovich CP. Trocar site recurrence after laparoscopic nephroureterectomy. J Urol 2003; 170:1301. Ahmed I, Shaikh NA, Kapadia CR. Track recurrence of renal pelvic transitional cell carcinoma after laparoscopic nephrectomy. Br J Urol 1998;81:319. Otani M, Irie S, Tsuji Y. Port site metastasis after laparoscopic nephrectomy: unsuspected transitional cell carcinoma within a tuberculous atrophic kidney. J Urol 1999; 162:486–7. Schaeff B, Paolucci V, Thomopoulos J. Port site recurrences after laparoscopic surgery. A review. Dig Surg 1998;15:124–34.

 With ureteroscopy and cytology often providing fair warning about the presence of a poorly differentiated (G3) transitional cell carcinoma, should a unit starting nephroureterectomy or dealing with a small number of tumours, attempt to tackle such tumours laparoscopically during the early days? With increasing experience all good units decrease the complication rates and problems such as inadvertent opening of the collecting system or removal of specimen without using a collecting bag become rare. A number of units in Europe and rest of the world are attempting to join the laparoscopic bandwagon and they would be well advised to consider the lessons from this honest retrospective survey.

References [1] Clayman RV, Kavoussi LR, Figenshau RS, Chandhoke PS, Albala DM. Laparoscopic nephroureterectomy: initial clinical case report. J Laparoendosc Surg 1991; 1:343–9. [2] Reymond MA, Schneider C, Hohenberger W, Ko¨ckerling F. The pneumoperitoneum and its role in tumor seeding. Dig Surg 1998;15:105–9. [3] Jacobi CA, Wenger F, Sabat R, Volk T, Ordemann J, Mu¨ller JM. The impact of laparoscopy with carbon dioxide vs. helium on immunological function and tumour growth in a rat model. Dig Surg 1998;15:110–6.