World J. Surg. 16, 106--112, 1992
World Journal of Surgery © 1992by the Soci~t~ Internationale de Chirm'gi¢
Pre-Operative Radiotherapy as Adjuvant Treatment in Rectal Cancer F. Izar, M.D., G. Fourtanier, M.D., B. Pradere, M.D., P. Chiotasso, M.D., E. Bloom, M.D., I. Fontes-Dislaire, M.D., R. Bugat, M.D., and N. Daly, M.D. Departments of Radiotherapy and Medical Oncology, Centre Claudius Regaud, Department of Digestive Surgery, Centre Hospitalier Universitaire Rangueil, and Department of Digestive Surgery, Centre Hospitalier Universitaire Purpan, Toulouse, France From January, 1975 to December, 1987, 241 patients with rectal cancer underwent pre-operative irradiation and surgical resection. The radiation was delivered with 25 MeV photons, 5 days per week by 2.4 grays fractions up to a total dose of 36 grays. Surgery was curative in 195 patients; 57% had abdomino-perinal resection. Irradiation had to he discontinued in 3 patients and 4 patients subsequently developed severe acute ileitis. Postoperative mortality rate was 2.9%. The most frequent postoperative complications were delayed healing of abdominal wounds (18%) and perineal wounds (14%). Severe late complications occurred in 27 (13%) patients. The incidence of intestinal obstruction was 5%. Follow-up survivors ranged from 18 months to 13 years. Local failure occurred in 24 (12%) of the 195 patients. Local failure rates were 10% for Dukes' A tumors, 11.6% for Dukes' B, and 22.7% for Dukes' C tumors. Five and 10 year actuarial survival rates after curative surgery were 70 % and 52%. The Dukes' classification was the only factor that influenced survival.
Surgical resection is the basic treatment for rectal adenocarcinoma. However, local recurrence rates are quite high following surgery alone, 25% to 30% of patients with stage B2 rectal tumors and almost 50% of patients with stage C disease [1, 2]. Patterns of loco-regional failure have been studied by Gunderson and Sosin [3]. Most of these recurrences were located in the pelvis and the sites could have been included in a radiation field. The predominant reason for such failures is the inability to obtain an adequate radical excision margin at sites where the tumor extends into the peri-rectal soft tissue. Therefore, pelvic irradiation has been proposed in an attempt to eradicate those microscopic deposits of tumor cells which may have invaded lymphatic or soft tissues near the pelvic side walls. Controversy still remains regarding the timing of radiotherapy (either before or after the initial surgical procedure) to create optimal tumorcidal effects. Moreover, the optimal dose of irradiation has not yet been well defined. In pre-operative irradiation trials, the doses varied from 20 grays over 2 weeks to 50 grays over 6.5 weeks [4, 5]. The purpose of this paper is to report the morbidity, local recurrence, and overall survival of 241 patients with rectal cancer who underwent surgical resection and preoperative irradiation (36 grays). Reprint requests: F. Izar, M.D., Department of Radiotherapy, Centre Claudius Regaud, 20-24, rue du Pont Saint-Pierre, 31052 Toulouse, France.
Material and Methods
This retrospective series included 241 patients, treated in our Department of Radiotherapy from January, 1975 to December, 1987. All patients had a histologically proven and potentially resectable adenocarcinoma of the rectum located within 15 cm of the anal margin. Patients found to have metastatic disease on the initial workup were excluded. All 241 patients were treated with curative intent. There were 163 men (67.6%) and 78 (32.3%) women. The median age was 63 years with a range of 24 years to 84 years. In all cases, the pretreatment workup included clinical examination and liver function tests. The majority of the patients (89.6%) had a serum CEA assay. Liver morphology was studied in 95% of the patients by an isotopic scan and, since 1975, by ultrasonography or computed tomography. Before treatment, tumors were classified according to the 1968 T.N.M. staging system. The results of clinical staging and the topography of the lesion are shown in Table 1. Stage T2 and T3 tumors were found in 226 (93.8%) patients. When this protocol was established in 1975, it was believed that the main factor of local recurrence was a sub-peritoneal implantation of the tumor. For that reason, in our study, 81% of the tumors were located in the middle or lower third of the rectum. All patients were treated with high energy photon beams (25 Mev). We used a AP-PA technique. Both fields were treated daily with a rhythm of 5 sessions per week. The volume of irradiation encompassed the true pelvis, the upper limit being located at the L4-L5 intervertebral disk. The total tumor dose was 36 grays delivered in 15 daily fractions of 2.4 grays over a period of I9 days. This dose equates to 1360 rets in the N.S.D. formulation. Two hundred and forty patients underwent operation by 3 surgical teams including 7 senior surgeons. One patient did not undergo planned surgery because of complication from preoperative radiotherapy. The mean delay after the end of the irradiation to surgery was 16 days (range 1-80 days). Forty-five patients had palliative surgery (Table 2). The intra-operative diagnosis of liver metastases was made in 23 (9.6%) patients. Radical resection with curative intent was performed in 195 (81.2%) patients. This operation includes primary high ligation of the inferior mesenteric vessels, section of the rectum at least
107
F. lzar et al,: Pre-Operative Radiotherapy for Rectal Cancer Table 5. Postoperative mortality and morbidity.
Table 1. Staging and location of rectal cancers. Characteristic
No. of patients (%)
TNM classification TI T2 T3 T4 Location Upper third Middle third Lower third
9 (3.7) 119 (49.4) 107 (44.4) 6 (2.5) 45 (18.7) 119 (49.4) 77 (31.9)
Table 2. Surgical findings in patients treated with palliative surgery.
No. of patients Mortality Cardiac failure Pulmonary embolism Sepsis Gastro-intestinal hemorrhage Total Morbidity Abdominal wound sepsis Perineal wound sepsis Intra-abdominal abscess or septicemia Fistulas Total
1 3 2 1 7 (2.9%) 36 (18%) 28 (14%) 8 5 82 (34%)
Surgical finding
No. of patients (%)
LOcal residual tumor Liver metastases Liver metastasese + local residua! tumor Patients with suspected residual tumor Total
12 (26.7) 15 (33.3) 9 (20.0)
the Cox proportional hazards model. After univariate analysis, significant prognostic factors were reanalyzed with a multivariate model.
9 (20.0) 45
Results
Mortality and Morbidity
Table 3. Surgical techniques. S~urgical technique
All patients (%)
Patients with curative resection (%)
Abdomino-perineal resection Anterior resection Synchronous abdominotranssphincteric resection I'lartmann procedure No resection Total
130 (54.2)
111 (56.9)
48 (20.0) 45 (18.8)
39 (20.0) 41 (21.0)
8 (3.3) 9 (3.7) 240
4 (2.1) 0 195
Table 4. Dukes classification.
EXtent of tumor I)uke~' A I)ukes" B bUkes' C No residual tumor nknown Total
All patients (%) 43 (17.9) 113 (47. I) 63 (26.2) 10 (4.2) 11 (4.6) 240
Patients with curative resection (%) 43 (22.1) 96 (49.2) 44 (22.6) 10 (5.1) 2 (1.0) 195
3 crn beneath the lower pole of the tumor, and excision of the Perirectal cellulo-lymphatic tissues as near as possible to the Pelvic wall. In our series, curative resection was defined as no macroscopic residual tumor. The various surgical procedures employed are presented in Table 3. Among the patients who had Curative surgery, 57% had an abdomino-perineal resection. ]'he operative specimens were classified according to the DUkes' staging system (Table 4) [6]. Histopathologic examination revealed complete tumor sterilization in 10 (5%) patients. Most of the patients had well differentiated (71%) or moderately differentiated (12%) tumors. Survival and tumor progression rates were determined from the date of surgery. No patient was lost to follow-up. Survival rates were calculated according to the method of Kaplan-Meier. A two step analysis of prognostic factors was performed using
Irradiation had to be discontinued in only 3 patients and definitively abandoned in 1 patient. In 2 patients, the reason was diarrhea, the third patient had an intercurrent illness. During week 3 of radiotherapy, most patients suffered with diarrhea, but responded to Symptomatic treatment. Four patients completed their radiotherapy, but subsequently developed severe acute ileitis with denutrition a few days later. Two patients died of peritonitis due to intestinal perforation. This complication occurred 10 days after the end of the irradiation and 3 months after the resection of the primary tumor. Three patients had leucopenia (grade 3 of the W.H.O. Scale) at the end of the radiotherapy that resolved without delaying surgical treatment. Thus, only l patient did not undergo planned surgery because of a side effect from radiotherapy. Two hundred and forty patients underwent surgery. The 30 day postoperative mortality rate was 2.9% (7 of 240 patients). Most of the deaths were due to nondigestive causes (Table 5). The mean in-hospital postoperative stay was 26 days (range, 7 to 96 days). Postoperative complications were shown in Table 5. The most frequent complications included delayed healing due to sepsis of the abdominal wound (18%) and the perineal wound (14%). The long term morbidity rate of the combined treatment regimen in 195 patients with curative resection was 13.8% (Table 6). Of these 27 patients with complications, 12 patients underwent repeat operation. Two patients died from posttherapeutic complications. The incidence of intestinal obstruction was 6% (12 of !95 patients). Two of these patients were treated conservatively but in I0 patients surgery was required. In 2 patients the intestinal damage was secondary to the radiotherapy, in 6 patients postoperative adhesions were responsible, and in 2 patients no mechanism was apparent. The total mortality rate attributed to the combined treatment Was 4.5% (11 of 241 patients).
Recurrent Disease Local recurrence developed in 24 (12%) of the 195 patients who underwent curative surgery. The 5 year actuarial local failure
108
World J. Surg. Vol. 16, No. 1, Jan./Feb. 1992
Table 6. Severe late side effects of the combined treatment in patients treated with curative intent,
Complication
No. of patients
Perineal complication Fistulas Pelvic sepsis Cecal perforation Proctitis Intestinal obstruction Total
8 Y' 2 1 I 12° 27 (13.8%)
~s~ to~.
~
~.
Survival The overall 5 and 10 year Kaplan-Meier survival rates were 60.5% and 45%. For the 45 patients who underwent palliative surgery, the median survival was 13 months (mean: 21 months). Among these 45 patients, 3 patients were long-term survivors, but all had "suspected" residual tumor, and received up to 70 grays irradiation. For the 195 patients who underwent curative resection, the mean follow up was 64 months (18-157 months). Overall actuarial 5 and 10 year survival rates were 69.6% and 52%, respectively (Fig. 1). The actuarial 5 and 10 year survival rates, corrected to take into account deaths due to intercurrent disease, were 80.6% and 70%, respectively. Among these 195 patients, 123 are still alive, 14 with evolutive disease. Among the 72 patients who died, the cause of death in patients was related to tumor progression, 5 deaths were due to iatrogenic complications, and 18 deaths were due to intercurrent disease. In a monovariate statistical analysis, we found that age >60 years had a negative influence on survival (p < 0.05). Contrarily, patients with stage TI (p < 0.05) or those treated with synchronous abdomino-trans-sphincteric resection had a better survival (p < 0.05). In a multivariate analysis, age was the only
Cen~ed
....
"! patient died due to post-treatment complications. rate was 13%. The median and mean delay of local recurrence were 35 months and 31 months (+-- 25.5 months). In 2 patients recurrence occurred 80 months and 86 months following surgery. In 13 (54%) patients, this local evolution was further complicated by metastatic disease. Most of those recurrences occurred in the posterior pelvis. In a monovariate statistical analysis, the following clinical and pathological parameters were studied: age, sex, T.N.M. classification, location of the tumor, tumor differentiation, Dukes' classification, and type of surgery. The single most significant parameter of local recurrence was found to be the Dukes' classification. Patients with Dukes' C tumor had a local recurrence rate of 22.7% versus 10% with Dukes' A and 11.6% with Dukes' B tumors (p < 0.01). Following curative surgery, 52 (26.6%) of the 195 patients developed metastases. The 5 year actuarial rate for distant failure was 30%. Eighteen (9.2%) patients had liver metastases alone. Eleven (5.6%) patients displayed liver involvement associated with other visceral metastases. In 23 (11.8%) patients, we observed extra-hepatic metastases exclusively (lung, bone, brain). The median delay of onset of the metastatic disease was 29 months (mean delay: 32.6 +-- 21.8 months). The monovariate analysis of various factors (age, T.N.M. classification, tumor differentiation and Dukes' classification) determined that only Dukes' classification was statistically correlated. The metastatic disease rate was 43.2% for Dukes' C versus 15% for Dukes' A and 26% for Dukes's B (p < 0.001).
....
",~13
II0
"1'20
sm~
Mmtlw 'If~l
F~g.1
Fig. 1. Kaplan-Meier survival curves after curative surgery.
|o0
75
. . . . .
Dukes B
t,
50
D~esA
~ --i - nlil~is c
25
MonU~ "*,t~
.......... "8o
"12o
"~6o
Fig. 2. Kaplan-Meier survival curves after curative surgery according
to Dukes' classification. significant parameter (p < 0.05). The Dukes' classification was the only factor selected when we analyzed parameters that could influence corrected survival. Patients with Dukes' C had the worse survival (p < 0.01) (Fig. 2). The 10 patients with no residual tumor had a 90% 5 year survival without recurrence. Discussion
Many rancIomized and non-randomized studies have assessed the value of adjuvant irradiation in adenocarcinoma of the rectum administered either pre-operatively [7-9], postoperatively [10, 11], or both [12]. A review of the literature dealing with pre-operative irradiation reveals that the general characteristics of our patients were similar to other series (Table 7). In our series, curative resection was performed in 195 (81.2%) patients only. This high rate of residual tumor found at the time of surgery is probably due to the high rate of large tumors .(47% of T3-T4). Thereafter, complete resection of tumor could not be performed whatsoever the distal or tangential margins. Compared to treatment with surgery only, pre-operative irradiation did not significantly increase postoperative mortality [7, 8, 13, 14]. The mean stay in the surgery department was 26 days. In the randomized E.O.R.T.C. study [7], the mean stay was 27 days in the group of patients treated by pre-operative irradiation and 2I days for patients treated by surgery alone. The most frequently reported postoperative complication related to the radiotherapy was delayed perineal wound healing. Comparing delayed wound healing in patients receiving irradiation and surgery to those receiving surgery alone, the differences were statistically significant in the studies of Gerard and
F. Izar et al.: Pre-Operative Radiotherapy for Rectal Cancer
109
Table 7. General characteristics of the patients undergoing preoperative irradiation. Stage (%) Author, year (reference)
Age (yrs.)
T.N.M.
A.P. resection
Curative surgery
Stevens" 1976 (4) Higgins, V.A. Study 1986 (7) Gerard, EORTC Study 1989 (6) Present study"
64 NR
NR NR
78 94
86 85
58
T2 (47) T3 (46) T2 (49) T3 (44)
85.5
77
54
81.2
-.-.._.
63
"Non-randomized studies. A.P.: abdomino-perineal resection; NR: not reported.
COWorkers [7] (48% versus 29%) and Palhman and Glimelius [13] (28% versus 19%). This complication was not serious in most cases, however. In our study, irradiation was definitively interrupted in 1 patient only, but 2 patients died of acute ileal complications. This morbidity was probably due to the high daily dose of 2.4 grays which apparently caused severe acute ileal damage leading to intestinal necrosis and perforation. In the literature, two trials have been conducted in which the daily close was >2 grays [7, 13], In both studies, pre-operative !rradiation was well tolerated and no death related to acute intestinal toxicity was reported. Stevens and colleagues [4] described 1 of 57 patients undergoing irradiation who after a total dose of 50 grays died from bowel perforation. After curative surgery, the most frequent complication obServed was small bowel obstruction (5%). In exclusive surgical series reported by Stevens and associates [15], the incidence of Small bowel adhesions ranged from 2% to 7%. It is not apparent that pre-operative irradiation increases the rate of ileal obstruction. In our study, the rate of local recurrence was 12%. A number of studies have been done which clearly show that local recurrence is the major cause of failure following curative SUrgery and that significant morbidity results from recurrence. Adjuvant pre-operative radiotherapy has been shown to deCrease the local failure rate (Table 8). In a series of 57 patients treated with high dose pre-operative irradiation (50-60 grays) and curative resections, Stevens and coworkers [4] observed no Pelvic recurrence. In randomized studies with pre-operative radiation ->40 grays in 20 fractions, results are contradictory. The recurrence rate is significantly reduced in the series of Gerard and associates, 15% Versus 30% [7] but not in the Veteran's Administration trial [8]. In OUr series, the recurrence rate was 12%, similar to that of the E-O.R.T.C. trial or Swedish study [16]. In Our statistical analysis, we tried to determine factors that COuld predict local recurrence. The results should be interPreted with caution because of the retrospective character of the analysis and the difficulty in maintaining a homogenous Series over a long period of time (12 years) due to evolving SUrgical techniques. The review of the literature is quite controversial concerning factors that could be predictive of local ecurrence. In a monofactorial analysis, Moosa and colleagues 17] found that tumors low within the rectum, local spread into Peri-rectal fat or serosa, lymph node involvement, and age
World Journal of Surgery © 1992by the Soci~t~ Internationale de Chirm'gi¢
Pre-Operative Radiotherapy as Adjuvant Treatment in Rectal Cancer F. Izar, M.D., G. Fourtanier, M.D., B. Pradere, M.D., P. Chiotasso, M.D., E. Bloom, M.D., I. Fontes-Dislaire, M.D., R. Bugat, M.D., and N. Daly, M.D. Departments of Radiotherapy and Medical Oncology, Centre Claudius Regaud, Department of Digestive Surgery, Centre Hospitalier Universitaire Rangueil, and Department of Digestive Surgery, Centre Hospitalier Universitaire Purpan, Toulouse, France From January, 1975 to December, 1987, 241 patients with rectal cancer underwent pre-operative irradiation and surgical resection. The radiation was delivered with 25 MeV photons, 5 days per week by 2.4 grays fractions up to a total dose of 36 grays. Surgery was curative in 195 patients; 57% had abdomino-perinal resection. Irradiation had to he discontinued in 3 patients and 4 patients subsequently developed severe acute ileitis. Postoperative mortality rate was 2.9%. The most frequent postoperative complications were delayed healing of abdominal wounds (18%) and perineal wounds (14%). Severe late complications occurred in 27 (13%) patients. The incidence of intestinal obstruction was 5%. Follow-up survivors ranged from 18 months to 13 years. Local failure occurred in 24 (12%) of the 195 patients. Local failure rates were 10% for Dukes' A tumors, 11.6% for Dukes' B, and 22.7% for Dukes' C tumors. Five and 10 year actuarial survival rates after curative surgery were 70 % and 52%. The Dukes' classification was the only factor that influenced survival.
Surgical resection is the basic treatment for rectal adenocarcinoma. However, local recurrence rates are quite high following surgery alone, 25% to 30% of patients with stage B2 rectal tumors and almost 50% of patients with stage C disease [1, 2]. Patterns of loco-regional failure have been studied by Gunderson and Sosin [3]. Most of these recurrences were located in the pelvis and the sites could have been included in a radiation field. The predominant reason for such failures is the inability to obtain an adequate radical excision margin at sites where the tumor extends into the peri-rectal soft tissue. Therefore, pelvic irradiation has been proposed in an attempt to eradicate those microscopic deposits of tumor cells which may have invaded lymphatic or soft tissues near the pelvic side walls. Controversy still remains regarding the timing of radiotherapy (either before or after the initial surgical procedure) to create optimal tumorcidal effects. Moreover, the optimal dose of irradiation has not yet been well defined. In pre-operative irradiation trials, the doses varied from 20 grays over 2 weeks to 50 grays over 6.5 weeks [4, 5]. The purpose of this paper is to report the morbidity, local recurrence, and overall survival of 241 patients with rectal cancer who underwent surgical resection and preoperative irradiation (36 grays). Reprint requests: F. Izar, M.D., Department of Radiotherapy, Centre Claudius Regaud, 20-24, rue du Pont Saint-Pierre, 31052 Toulouse, France.
Material and Methods
This retrospective series included 241 patients, treated in our Department of Radiotherapy from January, 1975 to December, 1987. All patients had a histologically proven and potentially resectable adenocarcinoma of the rectum located within 15 cm of the anal margin. Patients found to have metastatic disease on the initial workup were excluded. All 241 patients were treated with curative intent. There were 163 men (67.6%) and 78 (32.3%) women. The median age was 63 years with a range of 24 years to 84 years. In all cases, the pretreatment workup included clinical examination and liver function tests. The majority of the patients (89.6%) had a serum CEA assay. Liver morphology was studied in 95% of the patients by an isotopic scan and, since 1975, by ultrasonography or computed tomography. Before treatment, tumors were classified according to the 1968 T.N.M. staging system. The results of clinical staging and the topography of the lesion are shown in Table 1. Stage T2 and T3 tumors were found in 226 (93.8%) patients. When this protocol was established in 1975, it was believed that the main factor of local recurrence was a sub-peritoneal implantation of the tumor. For that reason, in our study, 81% of the tumors were located in the middle or lower third of the rectum. All patients were treated with high energy photon beams (25 Mev). We used a AP-PA technique. Both fields were treated daily with a rhythm of 5 sessions per week. The volume of irradiation encompassed the true pelvis, the upper limit being located at the L4-L5 intervertebral disk. The total tumor dose was 36 grays delivered in 15 daily fractions of 2.4 grays over a period of I9 days. This dose equates to 1360 rets in the N.S.D. formulation. Two hundred and forty patients underwent operation by 3 surgical teams including 7 senior surgeons. One patient did not undergo planned surgery because of complication from preoperative radiotherapy. The mean delay after the end of the irradiation to surgery was 16 days (range 1-80 days). Forty-five patients had palliative surgery (Table 2). The intra-operative diagnosis of liver metastases was made in 23 (9.6%) patients. Radical resection with curative intent was performed in 195 (81.2%) patients. This operation includes primary high ligation of the inferior mesenteric vessels, section of the rectum at least
107
F. lzar et al,: Pre-Operative Radiotherapy for Rectal Cancer Table 5. Postoperative mortality and morbidity.
Table 1. Staging and location of rectal cancers. Characteristic
No. of patients (%)
TNM classification TI T2 T3 T4 Location Upper third Middle third Lower third
9 (3.7) 119 (49.4) 107 (44.4) 6 (2.5) 45 (18.7) 119 (49.4) 77 (31.9)
Table 2. Surgical findings in patients treated with palliative surgery.
No. of patients Mortality Cardiac failure Pulmonary embolism Sepsis Gastro-intestinal hemorrhage Total Morbidity Abdominal wound sepsis Perineal wound sepsis Intra-abdominal abscess or septicemia Fistulas Total
1 3 2 1 7 (2.9%) 36 (18%) 28 (14%) 8 5 82 (34%)
Surgical finding
No. of patients (%)
LOcal residual tumor Liver metastases Liver metastasese + local residua! tumor Patients with suspected residual tumor Total
12 (26.7) 15 (33.3) 9 (20.0)
the Cox proportional hazards model. After univariate analysis, significant prognostic factors were reanalyzed with a multivariate model.
9 (20.0) 45
Results
Mortality and Morbidity
Table 3. Surgical techniques. S~urgical technique
All patients (%)
Patients with curative resection (%)
Abdomino-perineal resection Anterior resection Synchronous abdominotranssphincteric resection I'lartmann procedure No resection Total
130 (54.2)
111 (56.9)
48 (20.0) 45 (18.8)
39 (20.0) 41 (21.0)
8 (3.3) 9 (3.7) 240
4 (2.1) 0 195
Table 4. Dukes classification.
EXtent of tumor I)uke~' A I)ukes" B bUkes' C No residual tumor nknown Total
All patients (%) 43 (17.9) 113 (47. I) 63 (26.2) 10 (4.2) 11 (4.6) 240
Patients with curative resection (%) 43 (22.1) 96 (49.2) 44 (22.6) 10 (5.1) 2 (1.0) 195
3 crn beneath the lower pole of the tumor, and excision of the Perirectal cellulo-lymphatic tissues as near as possible to the Pelvic wall. In our series, curative resection was defined as no macroscopic residual tumor. The various surgical procedures employed are presented in Table 3. Among the patients who had Curative surgery, 57% had an abdomino-perineal resection. ]'he operative specimens were classified according to the DUkes' staging system (Table 4) [6]. Histopathologic examination revealed complete tumor sterilization in 10 (5%) patients. Most of the patients had well differentiated (71%) or moderately differentiated (12%) tumors. Survival and tumor progression rates were determined from the date of surgery. No patient was lost to follow-up. Survival rates were calculated according to the method of Kaplan-Meier. A two step analysis of prognostic factors was performed using
Irradiation had to be discontinued in only 3 patients and definitively abandoned in 1 patient. In 2 patients, the reason was diarrhea, the third patient had an intercurrent illness. During week 3 of radiotherapy, most patients suffered with diarrhea, but responded to Symptomatic treatment. Four patients completed their radiotherapy, but subsequently developed severe acute ileitis with denutrition a few days later. Two patients died of peritonitis due to intestinal perforation. This complication occurred 10 days after the end of the irradiation and 3 months after the resection of the primary tumor. Three patients had leucopenia (grade 3 of the W.H.O. Scale) at the end of the radiotherapy that resolved without delaying surgical treatment. Thus, only l patient did not undergo planned surgery because of a side effect from radiotherapy. Two hundred and forty patients underwent surgery. The 30 day postoperative mortality rate was 2.9% (7 of 240 patients). Most of the deaths were due to nondigestive causes (Table 5). The mean in-hospital postoperative stay was 26 days (range, 7 to 96 days). Postoperative complications were shown in Table 5. The most frequent complications included delayed healing due to sepsis of the abdominal wound (18%) and the perineal wound (14%). The long term morbidity rate of the combined treatment regimen in 195 patients with curative resection was 13.8% (Table 6). Of these 27 patients with complications, 12 patients underwent repeat operation. Two patients died from posttherapeutic complications. The incidence of intestinal obstruction was 6% (12 of !95 patients). Two of these patients were treated conservatively but in I0 patients surgery was required. In 2 patients the intestinal damage was secondary to the radiotherapy, in 6 patients postoperative adhesions were responsible, and in 2 patients no mechanism was apparent. The total mortality rate attributed to the combined treatment Was 4.5% (11 of 241 patients).
Recurrent Disease Local recurrence developed in 24 (12%) of the 195 patients who underwent curative surgery. The 5 year actuarial local failure
108
World J. Surg. Vol. 16, No. 1, Jan./Feb. 1992
Table 6. Severe late side effects of the combined treatment in patients treated with curative intent,
Complication
No. of patients
Perineal complication Fistulas Pelvic sepsis Cecal perforation Proctitis Intestinal obstruction Total
8 Y' 2 1 I 12° 27 (13.8%)
~s~ to~.
~
~.
Survival The overall 5 and 10 year Kaplan-Meier survival rates were 60.5% and 45%. For the 45 patients who underwent palliative surgery, the median survival was 13 months (mean: 21 months). Among these 45 patients, 3 patients were long-term survivors, but all had "suspected" residual tumor, and received up to 70 grays irradiation. For the 195 patients who underwent curative resection, the mean follow up was 64 months (18-157 months). Overall actuarial 5 and 10 year survival rates were 69.6% and 52%, respectively (Fig. 1). The actuarial 5 and 10 year survival rates, corrected to take into account deaths due to intercurrent disease, were 80.6% and 70%, respectively. Among these 195 patients, 123 are still alive, 14 with evolutive disease. Among the 72 patients who died, the cause of death in patients was related to tumor progression, 5 deaths were due to iatrogenic complications, and 18 deaths were due to intercurrent disease. In a monovariate statistical analysis, we found that age >60 years had a negative influence on survival (p < 0.05). Contrarily, patients with stage TI (p < 0.05) or those treated with synchronous abdomino-trans-sphincteric resection had a better survival (p < 0.05). In a multivariate analysis, age was the only
Cen~ed
....
"! patient died due to post-treatment complications. rate was 13%. The median and mean delay of local recurrence were 35 months and 31 months (+-- 25.5 months). In 2 patients recurrence occurred 80 months and 86 months following surgery. In 13 (54%) patients, this local evolution was further complicated by metastatic disease. Most of those recurrences occurred in the posterior pelvis. In a monovariate statistical analysis, the following clinical and pathological parameters were studied: age, sex, T.N.M. classification, location of the tumor, tumor differentiation, Dukes' classification, and type of surgery. The single most significant parameter of local recurrence was found to be the Dukes' classification. Patients with Dukes' C tumor had a local recurrence rate of 22.7% versus 10% with Dukes' A and 11.6% with Dukes' B tumors (p < 0.01). Following curative surgery, 52 (26.6%) of the 195 patients developed metastases. The 5 year actuarial rate for distant failure was 30%. Eighteen (9.2%) patients had liver metastases alone. Eleven (5.6%) patients displayed liver involvement associated with other visceral metastases. In 23 (11.8%) patients, we observed extra-hepatic metastases exclusively (lung, bone, brain). The median delay of onset of the metastatic disease was 29 months (mean delay: 32.6 +-- 21.8 months). The monovariate analysis of various factors (age, T.N.M. classification, tumor differentiation and Dukes' classification) determined that only Dukes' classification was statistically correlated. The metastatic disease rate was 43.2% for Dukes' C versus 15% for Dukes' A and 26% for Dukes's B (p < 0.001).
....
",~13
II0
"1'20
sm~
Mmtlw 'If~l
F~g.1
Fig. 1. Kaplan-Meier survival curves after curative surgery.
|o0
75
. . . . .
Dukes B
t,
50
D~esA
~ --i - nlil~is c
25
MonU~ "*,t~
.......... "8o
"12o
"~6o
Fig. 2. Kaplan-Meier survival curves after curative surgery according
to Dukes' classification. significant parameter (p < 0.05). The Dukes' classification was the only factor selected when we analyzed parameters that could influence corrected survival. Patients with Dukes' C had the worse survival (p < 0.01) (Fig. 2). The 10 patients with no residual tumor had a 90% 5 year survival without recurrence. Discussion
Many rancIomized and non-randomized studies have assessed the value of adjuvant irradiation in adenocarcinoma of the rectum administered either pre-operatively [7-9], postoperatively [10, 11], or both [12]. A review of the literature dealing with pre-operative irradiation reveals that the general characteristics of our patients were similar to other series (Table 7). In our series, curative resection was performed in 195 (81.2%) patients only. This high rate of residual tumor found at the time of surgery is probably due to the high rate of large tumors .(47% of T3-T4). Thereafter, complete resection of tumor could not be performed whatsoever the distal or tangential margins. Compared to treatment with surgery only, pre-operative irradiation did not significantly increase postoperative mortality [7, 8, 13, 14]. The mean stay in the surgery department was 26 days. In the randomized E.O.R.T.C. study [7], the mean stay was 27 days in the group of patients treated by pre-operative irradiation and 2I days for patients treated by surgery alone. The most frequently reported postoperative complication related to the radiotherapy was delayed perineal wound healing. Comparing delayed wound healing in patients receiving irradiation and surgery to those receiving surgery alone, the differences were statistically significant in the studies of Gerard and
F. Izar et al.: Pre-Operative Radiotherapy for Rectal Cancer
109
Table 7. General characteristics of the patients undergoing preoperative irradiation. Stage (%) Author, year (reference)
Age (yrs.)
T.N.M.
A.P. resection
Curative surgery
Stevens" 1976 (4) Higgins, V.A. Study 1986 (7) Gerard, EORTC Study 1989 (6) Present study"
64 NR
NR NR
78 94
86 85
58
T2 (47) T3 (46) T2 (49) T3 (44)
85.5
77
54
81.2
-.-.._.
63
"Non-randomized studies. A.P.: abdomino-perineal resection; NR: not reported.
COWorkers [7] (48% versus 29%) and Palhman and Glimelius [13] (28% versus 19%). This complication was not serious in most cases, however. In our study, irradiation was definitively interrupted in 1 patient only, but 2 patients died of acute ileal complications. This morbidity was probably due to the high daily dose of 2.4 grays which apparently caused severe acute ileal damage leading to intestinal necrosis and perforation. In the literature, two trials have been conducted in which the daily close was >2 grays [7, 13], In both studies, pre-operative !rradiation was well tolerated and no death related to acute intestinal toxicity was reported. Stevens and colleagues [4] described 1 of 57 patients undergoing irradiation who after a total dose of 50 grays died from bowel perforation. After curative surgery, the most frequent complication obServed was small bowel obstruction (5%). In exclusive surgical series reported by Stevens and associates [15], the incidence of Small bowel adhesions ranged from 2% to 7%. It is not apparent that pre-operative irradiation increases the rate of ileal obstruction. In our study, the rate of local recurrence was 12%. A number of studies have been done which clearly show that local recurrence is the major cause of failure following curative SUrgery and that significant morbidity results from recurrence. Adjuvant pre-operative radiotherapy has been shown to deCrease the local failure rate (Table 8). In a series of 57 patients treated with high dose pre-operative irradiation (50-60 grays) and curative resections, Stevens and coworkers [4] observed no Pelvic recurrence. In randomized studies with pre-operative radiation ->40 grays in 20 fractions, results are contradictory. The recurrence rate is significantly reduced in the series of Gerard and associates, 15% Versus 30% [7] but not in the Veteran's Administration trial [8]. In OUr series, the recurrence rate was 12%, similar to that of the E-O.R.T.C. trial or Swedish study [16]. In Our statistical analysis, we tried to determine factors that COuld predict local recurrence. The results should be interPreted with caution because of the retrospective character of the analysis and the difficulty in maintaining a homogenous Series over a long period of time (12 years) due to evolving SUrgical techniques. The review of the literature is quite controversial concerning factors that could be predictive of local ecurrence. In a monofactorial analysis, Moosa and colleagues 17] found that tumors low within the rectum, local spread into Peri-rectal fat or serosa, lymph node involvement, and age
