Postoperative pelvic radiotherapy with or without elective irradiation of para-aortic nodes and liver in rectal cancer patients. A controlled clinical trial of the EORTC Radiotherapy Group

Radiotherapy and Oncology 61 (2001) 7–13 www.elsevier.com/locate/radonline

Postoperative pelvic radiotherapy with or without elective irradiation of para-aortic nodes and liver in rectal cancer patients. A controlled clinical trial of the EORTC Radiotherapy Group Jean-Francois Bosset a,*, J.C. Horiot b, H.P. Hamers c, L. Cionini d, H. Bartelink e, R. Caspers f, M. Untereiner g, E. Ciambelloti h, M. Pierart i, M. Van Glabbeke i a

Radiotherapy-Oncology Department, Besanc¸on University Hospital, Besanc¸on, France b Department of Radiotherapy, Centre G.F. Leclerc, Dijon, France c Department of Radiotherapy, Dr Bernard Verbeeten lnstituut, Tilburg, The Netherlands d Division di Radiotherapia, Opedale S. Chiara, Pisa, Italy e Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands f Department of Radiotherapy, Leiden University Medical Centre, Leiden, The Netherlands g Radiotherapy Department, Esch/Alzette, Luxembourg h Ospedale degli Infermi, Biella, Italy i EORTC Data Center, Brussels, Belgium Received 18 December 2000; received in revised form 19 June 2001; accepted 17 July 2001

Abstract Objective: The purpose of this randomized multicenter study was to assess the impact on disease free and overall survival of low dose irradiation to para-aortic nodes and liver in patients with a locally advanced resected rectal cancer receiving a 50 Gy postoperative pelvic radiotherapy. Patients and methods: Main inclusion criteria were: a curative resection for a histologically proved carcinoma of the rectum, Gunderson– Sosin stages B2–B3, C1–C3, age ,70 years. The patients were randomized between pelvic irradiation (Lim-XRT): 50 Gy in 25 fractions over 5 weeks and extended irradiation (Ext-XRT): same scheme/doses in the pelvis and extended fields on para-aortic nodes and liver, delivering 25 Gy in 19 fractions over 25 days. From 1983 to 1992, 484 patients were enrolled by 18 EORTC institutions and 29 patients were ineligible. The end-points were local and distant relapses, toxicity and survival. Results: Compliance to treatment: 87.2% in Lim-XRT arm and 71.8% in Ext-XRT arm. Moderate acute hematological and hepatic toxicities were significantly increased in Ext-XRT arm. Among 325 patients at risk, 44 suffered a severe intestinal complication requiring surgery in 29. The 5- and 10-year estimates of disease free survival were respectively 42 and 31% in Lim-XRT arm and 47 and 31% in ExtXRT arm (ns). The corresponding figures for overall survival were respectively 45 and 40% in Lim-XRT arm and 48 and 37% in Ext-arm (ns). The 10 years estimate of intra-pelvic failures was ~30% in both arms. Patients in Ext-arm appeared to have a slight shorter interval free of liver metastases (P ¼ 0:047). Conclusion: Low dose irradiation to the para-aortic nodes and liver did not improve survival for patients with resected adenocarcinoma of the rectum. q 2001 Published by Elsevier Science Ireland Ltd. Keywords: Rectal cancer; Radiotherapy; Prophylactic hepatic irradiation

1. Introduction The outcome of patients with locally advanced rectal cancer is associated with a high risk of local failure (LF), distant metastasis (DM) and dismal survival despite curative resection. The 5-year survival drops from 80% in Dukes A patients, to 44–76% in Dukes B and 10–40% in Dukes C [1– 3]. LFs range from 5% in a few selected surgical series, to * Corresponding author.

about 20–30% in most reports [4–6]. For the period 1976– 1984, results from the Burgundy Tumor Registry in France depicted a 5-years actuarial estimate of LF being 24 and 53% in Dukes B and C, respectively for surgery only [7]. LFs are seldom curable and responsible for extreme disability and painful symptoms [8,9]. Therefore, improving the local control remains a major end-point for treatment strategies in rectal cancer. DM account for 50–70% of relapses, the main site being the liver and lungs [10]. In the early eighties, postoperative radiotherapy was

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admitted valuable to decrease LFs [11–15]. However, at that moment, survival remained roughly unchanged, due to the inefficacy of systemic treatment to reduce the metastatic process [16]. Radiotherapy directed to the liver appeared attractive on biological as well as on clinical arguments: doses in the 20–30 Gy range result in some tumor cell killing effect controlling at least 30% of 10 6 tumor cell microaggregates [17]; low dose pre-operative pelvic radiotherapy were acknowledged to reduce nodal involvement in patients with rectal cancer [18,19], and whole abdominal low dose irradiation to increase survival in some subgroups of patients with ovarian cancer [20]. In 1983, the European Organization for Research and Treatment on Cancer (EORTC) Radiotherapy Group initiated a prospective multicenter randomized trial comparing in high-risk selected patients a postoperative pelvic radiotherapy (Lim-XRT arm) to the same radiotherapy scheme with extended fields to the para-aortic nodes and the whole liver (Ext-XRT arm). 2. Methods 2.1. Eligible criteria

plus para-aortic nodes and liver. The target encompassed the transverse process of the lumbar vertebras. For the liver it included on the right the lateral thoraco-abdominal side wall and on the left it followed a vertical line drawn from the mid part of the diaphragmatic dome. The upper limit was defined as the diaphragm, the lower was defined using clinical or better ultrasonographic delineation of the liver. The limits of the treatment fields were outlined 1.5–2 cm beyond the anatomical definition of the targets. The width of AP/PA pelvic fields should cover the pelvic inlet with a 1.5– 2 cm margin; the width of lateral fields should extend beyond the widest point of the bony pelvis. The pelvis was treated using a four-field box technique. The para-aortic and liver were treated using two parallel opposed fields. These extended fields were drawn in continuity with the AP-PA pelvic fields up to the diaphragm (Fig. 1). An IVP was mandatory during simulation. The complete left kidney had to be shielded while it was permitted to include the upper part of the right kidney in the radiation portals. Treatment in prone position was requested. Small bowel series using full and empty bladder were recommended. Patients were asked to have full bladder at each radiotherapy session. Weekly portal films were recommended.

Patients eligibility criteria were: rectal adenocarcinoma; a tumor located below the promontory on the lateral pelvic view of the preoperative barium enema; a potentially curative resection has been performed without no gross evidence of residual disease left as assessed by the surgeon, by either abdomino-perineal resection (APR) or anterior resection (AR); a tumor pathologically staged as B2, B3, Cl, C2 or C3 using the Gunderson–Sosin classification (GSC) [21]; recovery from surgery; normal oral nutrition; age less than 70 years; WHO performance status #2; serum creatinine level less than 130 pmol/l; bilirubine level less than 130 mmol/l; leucocyte count above 3.10 9/l and platelet count above 130.10 9/l. Exclusion criteria were: distant metastases clinically documented or found at the time of surgery; previous history of malignant disease (except basal cell carcinoma of the skin or in situ carcinoma of the cervix); previous history of bowel obstruction, previous multiple abdominopelvic surgery; chronic inflammatory disease of the ileum or colon; delay to start radiation over 12 weeks from surgery. 2.2. Treatment Lim-XRT arm: the clinical target volume included the posterior pelvis; the posterior half of the bladder; the prostate and seminal vesicles or the posterior vaginal wall; the peri-rectal, hypogastric and low common iliac nodes up to the promontory; the external iliac nodes if tumor extended to the uterus, vagina, bladder or to the prostate. The entire perineum was included after an APR; the distal half part of the anal canal was excluded after an AR. Ext-XRT arm: the target was the pelvis as described above

Fig. 1. Diagram of an AP pelvic field with extension to the para-aortic nodes and the liver.

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According to the ICRU guidelines available at the time of the trial [22], the radiotherapy doses were specified at the intersection of the central axis of the beams in the pelvis; at 1 cm in front of the L3 body for the para-aortic nodes, and at mid diameter as measured 3 cm below the right nipple for the liver. The dose delivered to the pelvis was 50 Gy in 25 fractions over 5 weeks. The 2 Gy daily dose was given at 1.32 Gy through the AP-PA fields, and 0.68 Gy through the laterals. The dose to the para-aortic area and liver was 25 Gy in 19 fractions and 25 days. During irradiation, patients had weekly examination and investigations including hemogram, renal and liver function tests. 2.3. Follow-up Follow-up examination was performed at least every 6 months after the end of treatment until disease progression, death, or the end of the study period. Each evaluation included clinical examination, body weight, WHO performance status, chest X-ray, ultrasonography of the liver, and the determination of creatinine value, liver function tests and CEA level. Failures were defined as indicated by any morphologic proof of tumor regrowth. Only first failures were reported. After a disease relapse occurred, patients could be treated following local standards of the participating institutes. 2.4. Randomization and statistical analysis Patients were centrally randomized at the EORTC Data Center in Brussels before the start of radiotherapy. The Pocock minisation technique was used for random treatment allocation [24]. Randomization was stratified by center and by GSC stage. The principal end-point of this study was disease free survival, computed from the date of randomization to the date of progression or death. A total of 225 patients were intended to be recruited in each arm, to provide a 80% power against a 30% increase in the median disease free survival (hazard ratio ¼ 0:77, a ¼ 0:05, b ¼ 0:2, two-sided test). Overall survival and time to the development of liver metastases, and of local failures were secondary end-points. For these two last parameters, patients who first progressed in other sites than the target site, and patients who died without evidence of recurrence in the target site were censored at the date of first progression or death. Disease free survival, overall survival and time to the development of recurrences were evaluated by the Kaplan–Meier method [25]; comparison between therapeutic arms used the log rank test [26]. Acute toxicities were reported according to the WHO toxicity scale [27]; treatment arms were compared using the Mantel–Haenszel chisquare test for trend [28]. Patients considered as ineligible were excluded in the analysis. Severe late intestinal complications were defined as obstruction, fistula or perforation of the small intestine or colon. Patients who progressed within

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6 months of randomization were excluded from this analysis. Patients who progressed later were excluded at their date of progression. Other small bowel complications have been previously published [23] and are not analyzed in this paper.

3. Results 3.1. Patients A total of 484 patients have been included in the trial. Twenty nine patients (11 in the Lim-XRT arm and 18 in the Ext-arm) were found to be ineligible. The reasons for ineligibility were inappropriate stage (ten patients), poor performance status (five patients), prior irradiation (one patient), other various reasons (13 patients). For 4 additional patients, no data at all were obtained. Thus, a total of 451 patients (229 in the Lim-XRT arm and 222 in the Ext-XRT arm) remained in the analysis. The two treatment groups were comparable (Table 1). 3.2. Compliance to treatment The median delay between surgery and radiotherapy was 52 days (20–108 days) and 50.5 days (22–116 days) for Lim-XRT and Ext-XRT respectively (ns). Among the 229 patients assigned to Lim-XRT, three refused radiotherapy; 197 (87.2%) completed the treatment as planned; 25 (11.1%) had a temporarily interruption and four stopped treatment. The median delivered pelvic dose was 50 Gy (range, 18–55 Gy). Among the 222 patients assigned to Ext-XRT, two refused radiotherapy; two never started treatment; two received pelvic XRT only; 155 (71.8%) completed the treatment as planned; 33 (15.5%) had a temporarily interruption; 28 (13.0%) stopped treatment. The median delivered pelvic dose was 50 Gy (range, 32–56 Gy) and the median dose to para-aortic nodes and liver was 25 Gy (range, 4–34 Gy). The compliance to treatment was better in Lim-XRT arm (P ¼ 0:09). 3.3. Toxicity During treatment, patients in the Ext-XRT arm suffered significantly more moderate acute liver and hematological toxicity, while diarrhoea did not increase (Table 2). Among 167 patients at risk in the Lim-XRT arm, 26 developed severe late intestinal complications requiring surgery in 18. Among 158 patients at risk in the Ext-XRT arm, those figures were 18 and 11, respectively. The 10 years severe complication rate was 26 and 16%, respectively in the LimXRT and Ext-XRT arms (P ¼ 0:26) (Fig. 2). Two patients died from intestinal complication in the Lim-XRT arm, one from intestinal complication and one from veino-occlusive liver disease in the Ext-XRT arm. Secondary malignancies were observed in 14 patients and

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Table 1 Characteristics of the 451 patients according to treatment groups Characteristics

Sex-no (%) Male Female Mean age ^ 2 SD WHO performance status no (%) 0 1 2 CEA level ng/ml no (%) ,2 2—10 . 10 Unknown Distance from AM a cm # 11 . 11 Unknown Type of surgery no (%) APR AR Unknown Gunderson—Sosin classification B2 63 Cl C2 C3 Unknown No (%) involved nodes None 1—2 $3 Unknown Tumor differentiation Well differentiated Moderate Poor Unknown a

Lim-XRT arm N ¼ 229

Ext-XRT arm N ¼ 222

141 (61.6) 88 (38.4) 57.62 ^ 9.45

143 (64.4) 79 (35.6) 57.98 ^ 8.47

168 (73.4) 56 (24.5) 5 (2.2)

169 (76.1) 45 (20.3) 8 (3.6)

30 (13.1) 74 (32.3) 25 (10.9) 100 (43.6)

39 (17.6) 75 (33.8) 36 (16.2) 72 (32.4)

180 (78.6) 47 (20.5) 2 (0.9)

163 (73.4) 53 (23.9) 6 (2.7)

100 (43.7) 126 (55) 3 (1.3)

105 (47.3) 115 (51.8) 2 (0.9)

79 (34.5) 3 (1.3) 31 (13.5) 106 (46.3) 7 (3.1) 3 (1.3)

76 (34.2) 7 (3.2) 14 (6.3) 115 (51.8) 8 (3.6) 2 (0.9)

82 (35.8) 72 (31.4) 66 (28.8) 9 (3.9)

83 (37.4) 61 (27.5) 71 (32) 7 (3.2)

62 (27.1) 122 (53.3) 9 (3.9) 3 (1.3)

48 (21.6) 132 (59.5) 10 (4.6) 2 (0.9)

Distance of the tumor from anal margin.

in 12 patients in Lim-XRT and Ext-XRT arms respectively (ns).

Fig. 2. Freedom from severe late intestinal complications.

compared with arm 2, 1.032; 95% confidence interval, 0.81–1.31; P ¼ 0:80). The 5- and 10-year estimates of the DES rates were 42 and 31%, respectively in Lim-XRT arm and 47 and 31% in Ext-XRT arm (Fig. 3). 3.5. Overall survival Overall, 243 patients died. The survival curves of the two groups did not significantly differ (relative risk of death in arm I as compared with arm 2, 1.093; 95% confidence interval, 0.85–1.41; P ¼ 0:49). The 5- and 10-year estimates of the survival rates were 45 and 40%, respectively in LimXRT arm and 48 and 37% in Ext-XRT arm (Fig. 4). The causes of death are reported in Table 3. 3.6. Time to relapse The 10 years estimate of the rate of liver metastases was 21% in the Lim-XRT arm and 27% in the Ext-XRT arm (relative risk of liver metastases in arm 1 as compared with arm 2, 1.53; 95% confidence interval, 1.005–2.32; P ¼ 0:047) (Fig. 5). The 10 years estimate of the rate of local failure was 33 and 28%, respectively in Lim-XRT arm and Ext-XRT arm (P ¼ 0:96). Among the 105 patients with local failure, 92 had the recurrence within the pelvic irradiated fields, one

3.4. Disease free survival At the time of analysis, 270 patients had disease relapse. The disease free survival curves of the two arms did not differ significantly (relative risk of relapse in arm I as Table 2 $ WHO grade 1 liver and hematological acute toxicity during treatment

Bilirubin SGOT White blood Platelets

Lim-XRT N ¼ 229 no (%)

Ext-XRT N ¼ 222 no (%)

P value

0 (0) 2 (0.8) 28 (12.2) 4 (1.7)

6 (2.7) 14 (6.3) 106 (47.7) 50 (22.5)

0.03 0.004 0.001 0.001

Fig. 3. Disease free survival.

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Fig. 4. Overall survival.

outside and five were at the borderline. For the remaining seven patients this information was not reported. A summary of failure sites is reported in Table 4.

4. Discussion This study failed to demonstrate that low dose elective irradiation to para-aortic nodes and liver could improve the disease free survival in GSC B2–C3 rectal cancer patients who received a postoperative pelvic irradiation. The value of adjuvant hepatic irradiation has been tested in colon cancer by the US Gastrointestinal Tumor Study Group [29]. Three hundred patients with a Dukes B or C cancer were allocated to surgery alone or to postoperative hepatic irradiation combined with Fluorouracil (5-FU). The radiotherapy dose was 21 Gy in 14 fractions over 18 days. The 5FU was delivered during the first 3 days of irradiation. Two additional 5-FU courses were delivered post radiotherapy. After a 72 month median follow-up, the survival curves of the two groups did not differ. The EORTC and GITSG trials definitively exclude therapeutic gain from liver irradiation and 5-FU as adjuvant treatment in colorectal cancer. Patients who received extended fields irradiation had significantly more moderate acute toxicity, mainly hematological and hepatic, resulting in decreased compliance to treatment. Myelosuppression has also been reported in whole abdominal irradiation for ovarian cancer and is due to the presence of bone marrow in extended fields [20]. Table 3 Causes of death Causes

Lim-XRT N ¼ 229 no (%)

Ext-XRT N ¼ 222 no (%)

Metastases Local failure Both Toxicity Myocardial infarction Others Unknown

42 24 30 2 4 10 7

56 24 26 2 4 7 5

(18.3) (10.4) (13.5) (0.8) (1.7) (4.4) (3.1)

(25.2) (10.8) (11.7) (0.9) (0.1) (0.3) (0.2)

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Fig. 5. Freedom from liver metastases.

Elevation of the liver function tests (alkaline phosphatase, SGOT and SGPT) has also been reported after prophylactic hepatic irradiation for ovarian and pancreatic cancers [20,30,31]. A slight increase in liver metastasis rate was observed in patients receiving irradiation, especially during the first 3 years after treatment. This phenomenon was also observed in the group of patients who received hepatic irradiation and 5-FU in the GITSG trial [29]. Therefore, despite possible bias, low dose irradiation to the liver as adjuvant treatment should be suspected to facilitate the development of the metastatic process within this organ. This observation has not been reported in whole abdomen irradiation nor in hepatic irradiation as adjuvant treatment in ovarian and pancreatic cancers [20,31]. One may assume either a facilitating process of the development of cancer cells due to a killing-effect of radiotherapy on immunological competent cells or an acceleration of the cancer cell growth in relation Table 4 Summary of initial failure sites Sites a

Lim XRT N ¼ 229 no (%)

Ext-XRT N ¼ 222 no(%)

Local failure LF subsite b Pelvis Perineum Others Extrapelvic intra-abdominal Ext-pelvic subsite b Liver Para-aortic LN Others Extra-abdominal Ext-abdominal subsite b Lung Bone Brain Others

54 (23.5)

51(22.9)

48 (20.9) 7 (3.0) 11 (4.8) 59 (25.7)

44 (19.8) 12 (5.4) 6 (2.7) 60 (27.0)

36 (15.7) 13 (5.6) 28 (12.2) 41(17.9)

52 (23.4) 9 (4.0) 16 (7.2) 41 (18.4)

41 (17.9) 8 (3.4) 4 (1.7) 6 (2.6)

41 (18.4) 3 (1.3) 4 (1.8) 6 (2.7)

a b

One patient may have $1 failure site at time of initial relapse. One patient may have $1 subsite of failure.

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with protraction of hepatic irradiation [32] and or an insufficient daily or total radiotherapy dose [33]. However it is well-known that the delivery of whole-liver dose of greater 25–30 Gy would produce an increasing risk of radiation induced liver disease [33]. In a detailed analysis previously published, the 5 years estimate of small bowel obstruction (sbo) requiring surgery and chronic diarrhoea/malabsorption was 11 and 41%, respectively. The study found no correlation between the volume of small bowel within the pelvic fields and the risk of sbo, while the risk of chronic diarrhoea/malabsorption was significantly dependant on the volume of small bowel irradiated [23]. The actuarial 5-year estimate of chronic diarrhoea and malabsorption varied from 31% for small bowel volumes below 77 cm 3 to 42% in patients with volume over 328 cm 3 (P ¼ 0:025). After postoperative pelvic radiotherapy for rectal cancer, sbo may increase to 25–37% with extended pelvic fields, inappropriate radiotherapy techniques, non standard fractionated schemes, and doses over 50 Gy [34]. Using surgical methods to exclude small intestine and optimal radiotherapy techniques, allow to decrease the sbo rates to what is observed after surgery alone [35–37]. Despite a 50 Gy pelvic dose, the observed LF rate was close to 30% after 5 and 10 years follow-up and was in the same range as there reported with surgery alone in this patient group during the same period [3,7]. Postoperative radiotherapy with doses ranging from 40 to 50 Gy demonstrated a slight LF reduction but no effect on survival in comparison to surgery alone in randomized trials [38–44]. This figure has widely been considered insufficient and our trial indirectly confirms that postoperative pelvic irradiation alone should be abandoned. For the past 15 years, US randomized trials brought evidence that postoperative pelvic irradiation plus concurrent 5-FU based chemotherapy and maintenance chemotherapy should be considered standard approach in resected stage II and III rectal cancer patients [45]. The trimodality postoperative approach has decreased the incidence of both local (pelvic) and distant relapse and improved both disease free and overall survival [46]. Conversely moderate dose preoperative radiotherapy showed benefit on LF and overall survival in comparison with upfront surgery [6,45]. The EORTC Radiotherapy trial 22921 is currently testing preop XRT versus preop XRT-CT and postop CT versus no further CT in a four-arm randomized trial [47].

5. Conclusion Elective radiotherapy to para-aortic nodes and liver was unable to change the outcome of patients with resected B2– C3 rectal cancer who received a 50 Gy dose pelvic irradiation. Our results should definitively discourage this approach in rectal cancer.

Appendix A. Other participating centers Dr Van Den Weyngaert, Antwerpen, Algemeen Ziekenhuis Middelheim, Belgium. Professor Gonzalez, Amsterdam, Academisch Medisch Centrum, The Netherlands Dr Arcangeli, Roma, Instituto Medico e di Ricerca Scientifica, Italy Professor Le Floch, Tours, Hoˆ pital Bretonneau, France Dr Milla, Barcelona, Instituto Policlinico, Spain Dr Svoboda, Portsmouth, St. Mary’s Hospital, England Dr Montpetit, Vannes, Centre Saint-Yves, France Professor Vilhena, Lisboa, I.P.O. Francisco Gentil, Portugal Professor Kutten, Haifa, Rambam Medical Center, Israel Professor Chenal, Rennes, Centre Eugene Marquis, France

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