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Preoperative radiotherapy is better than postoperative radiotherapy in patients with rectal cancer
September
SELECTED SUMMARIES
1990
THE EFFECT OF PROTEIN ON RENAL FUNCTION IN CIRRHOSIS Badalamenti S, Gines P, Arroyo V, et al. (Liver Unit and Hormonal and Nuclear Medicine Laboratories, Hospital Clinic i Provincial, University of Barcelona, 08036-Barcelona, Spain). Effects of intravenous amino acid infusion and dietary proteins on kidney function in cirrhosis. Hepatology 1990:11:379-386. Protein loads, whether given as IV infusions of amino acids (AA] (Am J Physiol1986;25l:Fl31-Fl40) or following a high-protein oral diet (Am J Med 1983;75:943-950) can increase glomerular filtration rate (GFR) and renal plasma flow [RPF) in healthy humans. Low-protein diets have been associated with a decrease in GFR and RPF in normal patients. Brenner (N Engl J Med 1982;307:652-659) has suggested that the hyperfiltration induced by a high-protein diet accelerates the progression of chronic renal failure, whereas a low-protein diet retards it. Patients with cirrhosis are often on a low-protein diet because of anorexia, iatrogenie restriction of protein, or a reliance on alcohol for a substantial portion of caloric intake. Decreased renal function, especially as measured by inadequate sodium excretion and elevated blood urea nitrogen and creatinine levels, is common in cirrhosis. Therefore, there is a possibility that an increased protein load to the kidneys might increase GFR and RPF and perhaps enhance the response to diuretics or other therapeutic maneuvers. The present study investigated the effects of an IV load of AA and of an oral high-protein diet on groups of cirrhotic patients in various stages of hepatic and renal failure. In the first protocol, eight patients without ascites, nine with ascites and normal blood urea nitrogen and creatinine levels, and seven with functional renal failure were studied. After 5 days on a diet of 50 mEq sodium/day, they received a lo%-AA infusion for 3 hours. After catheterization via the antecubital vein, GFR and RPF were determined using standard clearance techniques. All three groups showed a significant increase in GFR and RPF, but there were no significant differences among the three groups in the percentage increase of these parameters. Free water clearance and urinary sodium levels, however, did not increase. As was expected, there was a twofold-to-threefold increase in serum glucagon levels during the infusion period. The second protocol involved nine nonazotemic, cirrhotic patients with ascites. The patients were randomly assigned in a crossover pattern to two II-day periods of either a high-protein diet (1.5 g/kg body wt per day] or a low-protein diet (0.5 g/kg body wt per day]. Both diets contained 50 mEq/day of sodium, 80 mEq/day of potassium, and 30 kcal/kg per day. Up to day 6 of the test periods the patients received diuretics, but these were discontinued on day 7. On day 11, renal function was studied using methods similar to those used in the first protocol. Values of GFR and RPF were significantly higher after the high-protein diet than the low-protein diet: GFR increased 13% (range, 0%-32%). and As with the AA infusion RPF, 12% (range, -12%-30%). protocol, there was no change in free water clearance or serum or urine sodium levels. Serum glucagon concentra-
895
tions were significantly higher after the high-protein diet but were not correlated with changes in GFR or RPF. The authors state that no subject in either protocol developed encephalopathy. Comment.
increased
These studies indicate that the renal response to an protein load, whether IV or from a high-protein diet, is
similar in cirrhotics and normal patients. The mechanism for the increased GFR and RPF in these situations is unclear. It does not seem to be a result of plasma volume expansion secondary to an increased osmotic load because hypertonic mannitol or isotonic saline solutions do not have this effect (Nephron 1985;41:193-199). Even without an increased osmotic load, AA infusion can increase GFR and RPF. Glucagon seems to play an essential role in these reactions. Infusions of AA have been previously shown to increase serum glucagon levels, and when glucagon release is blocked by somotostatin AA, infusions do not change renal hemodynamics. There are problems with accepting the central role of glucagon in these reactions; there is a decreased renal sensitivity to glucagon in cirrhosis and there is no correlation between glucagon serum levels and changes in GFR and RPF. Castellino [Am J Physiol 1988;255: F444-F449) has presented several lines of evidence indicating that both IV AA infusions and glucagon, either endogenous or exogenous, are required to produce the increased GFR and RPF. Levels of
other hormones such as renin and norepinepbrine, although they tend to increase in the presence of ascites and renal failure, did not increase during the AA infusions; therefore, it is unlikely that they are important factors in these hemodynamic changes. Prostaglandins have also been suggested as playing a role because it is known that nonsteroidal antiinflammatory drugs can blunt the renal hemodynamic response to acute protein loading, presumably by blocking prostaglandin effects. Overall, the changes observed in this study were not large, although there was a wide splay to the data, a few results showing a 40%-50% change. There was no demonstrable alteration in sodium clearance. It is not immediately apparent, therefore, whether such increases in GFR and RPF have any particular therapeutic implications. The studies were of short term, however, and it is possible that a lo%-20% increase in GFR and RPF that was sustained over a longer period of time cirrhosis. Perhaps the recognition that the functioning normally capable of responding
might lead to an improved management of most encouraging finding of the study is the kidney in cirrhosis, which clearly is not even before the development of ascites, is to protein loads in a manner comparable with
normal kidneys. This at least raises the possibility of manipulating renal function therapeutically in cirrhosis. It also raises the question of whether protein restriction, which has become so fixed a part of out treatment of cirrhosis, is appropriate for all patients. i. SWEETING,
M.D.
PREOPERATIVE RADIOTHERAPY IS BETTER THAN POSTOPERATIVE RADIOTHERAPY IN PATIENTS WITH RECTAL CANCER Pahlman L, Glimelius B (Departments of Surgery and Oncology, Uppsala University, Uppsala, Sweden). Pre- or postoperative radiotherapy in rectal and rectosigmoid carcinoma: report from a randomized multicenter trial. Ann Surg 1990;211:187-195.
Between 1980 and 1985,471 patients with resectable rectal carcinomas were entered into a randomized multicenter
898 SELECTED SUMMARIES
trial for comparison of preoperative and postoperative adjuvant irradiation. Patients with metastatic disease, locally unresectable tumors, or large fixed tumors were excluded. Patients randomized to preoperative radiotherapy (n = 236) received a total dose of 25.5 Gy in five fractions of 5.1 Gy daily over a period of 5-7 days, which corresponds to 47-49 Gy given with fractions of 2 Gy daily (10 Gy/wk). The patients underwent surgery within 1 week of radiotherapy. Two hundred thirty-five patients were randomized to the postoperative group. Radiation was administered in a dose of 2 Gy daily, five days per week for 4 weeks. After an interval of lo-14 days, further radiation was given for a period of 2 weeks for a total dose of 60 Gy. The patients were followed up clinically every third month during the first year, every fourth month in the second year, and twice yearly up to a least 5 years. Pelvic computed tomographic scans were performed at least once 6-9 months after surgery. Fine-needle or Tru-cut (Travenol Lab., Deerfield, IL) biopsies of any clinically or roentgenologically suspicious areas were performed, and only patients with morphologically proven recurrent cancers within the pelvic cavity were recorded as having local recurrences. In the group undergoing preoperative radiotherapy, all patients but one received the intended radiation. Preoperative radiotherapy was very well tolerated. The operations were locally curative in 209 (89%) patients. In the postoperative radiotherapy group, 204 (87%) patients underwent resections that were locally curative. Of these, 137 were potential candidates for radiotherapy (i.e., Dukes stages B2, Cl, or C2). Radiotherapy was started, however, in only 115 patients (84%). The reasons for patients not receiving radiotherapy were postoperative deaths (n = 91, prolonged recovery (n = 8), distant metastasis (n = 4), and treatment refusal (n = 1). The length of time from operation to initiation of radiation was ~6 weeks in 62 patients (54%), between 7 and 8 weeks in 26 patients (23%), and >8 weeks in 27 patients (23%). In most patients, the reason for delay was prolonged postoperative recovery. Many patients did not tolerate the postoperative radiotherapy. Only nine patients completed the treatment without adverse effects. Nine patients did not complete treatment. The postoperative mortality rates were 3% in the preoperative group and 5% in the postoperative group. Perineal wound infections occurred more frequently in the preoperative radiotherapy group (33% vs. 18%). The local recurrence rates in the preoperative and postoperative radiotherapy groups were 12% and 21%, respectively (P = 0.02). There was no difference in overall rates of survival between groups (all patients or patients who underwent surgery for cure). The report did not stratify data by any other patient groups (e.g., tumor stage, patient age, protocol violations, etc.]. Comment. Most patients with carcinomas of the rectum should receive adjuvant radiotherapy to decrease the chance of local recurrence. Patients with minimally invasive tumors (Dukes stages A and Bl) are usually cured by surgery alone. However, the local recurrence rate in patients with Dukes stage B2 or C cancers who do not receive adjuvant radiotherapy is 30%-50%. Preoperative or postoperative adjuvant radiotherapy decreases the incidence of local recurrences in these patients to x0%-30% depending on the size and/or stage of the tumor. This study is the first randomized
GASTROENTEROLOGY
comparison
of preoperative
and postoperative
Vol. 99, No. 3
radiotherapies
in
Why should preoperative radiotherapy be better than postoperative? First, radiotherapy may shrink large, fixed tumors, making complete resection feasible. Second, postoperative radiotherapy may damage the small bowel because the bowel usually descends into the pelvis after proctectomy, placing it in the radiation field. Third, wound complications are frequent after abdominoperineal resections (APR), frequently postponing radiotherapy for weeks. There are also theoretical or unproven advantages of preoperative radiotherapy. For example, it has been suggested that residual pelvic tumor cells after APR are disrupted or hypoxic, making them less susceptible to postoperative radiation damage. It is also possible that preoperative radiation, short of tumoricidal doses, may render tumor cells unable to metastasize. thus decreasing the chance of distant metastasis at the time of surgery (Am J Roentgen01 1968;102: 176-192). Preoperative irradiation, therefore, could potentially improve the rate of survival in patients with cancer of the rectum. Several retrospective studies have suggested that preoperative radiotherapy does improve the survival rates of patients with rectal cancers (Surgery 1988;103:161-167; Ann Surg 1989;209:194-199). For example, one study compared 65 patients who received radiotherapy before curative operations with 135 historical controls treated with surgery alone (Dis Colon Rectum 1988;31:287-290). The 5-year local-regional failure rates were 7.7% for the preoperative radiotherapy group and 29% in the historical controls (P < 0.001). The B-year determinate disease-free survival rates were 66% and 38% for patients with and without radiotherapy, respectively (P < O.OOl]. The results of prospective studies are conflicting. A recently published trial from Brazil involved patients with rectal cancers (n = 68) randomized to groups undergoing preoperative radiotherapy or surgery alone (Dis Colon Rectum 1989;32:702-710). Local recurrence rates in the preoperative-radiotherapy group and the operation-only group were 2.9% and 23.5%) respectively. Corrected survival rates were 80% and 34.4%. respectively. A much larger study performed by the European Organization for Research and Treatment of Cancer (EORTC) found little or no survival benefit with preoperative radiotherapy compared with surgery alone (Ann Surg 1988;208:606-614). Four hundred sixty-six patients with rectal cancer were randomized. The local recurrence rates at 5 years were 30% and 15% in the control and adjuvant-radiotherapy groups, respectively (P = 0.003). Considering only the 341 patients resected for potential cure, the 5-year survival rates were 59.1% and 69.1% in the control group and the combined modality group, respectively (P = 0.08). One subgroup analysis did show a significant treatment difference in patients t55 years of age (n = 103). The 5-year survival rates were 48% and 80% for the control group and the combined modality group, respectively (P = 0.004). Because it is unclear whether adjuvant preoperative radiotherapy improves survival rates over surgery alone in patients with carcinoma of the rectum, it is not surprising that the present study did not show an overall survival benefit of preoperative vs. postoperative radiotherapy. Nevertheless, the present study is important for several reasons. First, it showed a significantly decreased local recurrence rate in patients treated preoperatively (12% vs. 21%; P = 0.02). This improved “disease-free” survival rate may eventually translate into improved overall survival rates with longer periods of follow-up. Regardless, local recurrence is a devastating outcome. Second, the preoperative treatment was tolerated very well. Radiotherapy was administered at high doses (5.1 Gy) in only five fractions, and surgery was performed within 1 week of radiotherapy. Typical protocols in this country require at least 25 fractions over 5-6 weeks and cause considerable local morbidity (e.g., perianal excoriation]. Surgery is usually performed 6 weeks after completion of radiotherapy; therefore, the entire process takes 11-12 weeks. The protocol in this study took lo-14 days and achieved local control rates as good as or better than previously
September
1996
reported protocols. This important study establishes preoperative radiotherapy as the superior technique of adjuvant radiotherapy. Other controversies still exist in the care of patients with rectal cancer [a] what is the role of chemoradiotherapy? (b] what is the role of “sandwich’ therapy? and (c] what is the role of intraoperative radiotherapy? The data suggest that radiosensitizing agents [e.g., 5FU) should be added to all radiotherapy protocols. The Gastrointestinal Tumor Study Group reported a prospective, four-arm, randomized trial comparing surgery alone, surgery plus postoperative radiotherapy (XRT), surgery plus chemotherapy, and surgery plus XRT plus chemotherapy (N Engl J Med 1985;312:1465-1472). The recurrence rate at 5 years in the control group was 55% compared with a rate of 33 % in patients receiving adjuvant treatment (P < 0.94). Chemotherapy seemed to enhance the effect of radiation on local control. Cancer recurred in 48% of patients in the irradiation arm and in 33% of patients in the chemoradiotherapy arm. In a retrospective analysis of patients with advanced rectal cancer treated at the Mayo Clinic with preoperative external-beam radiotherapy, the risk of local failure was lower in patients who received 5FU during external-beam radiotherapy (9% vs. 19%) (Ann Surg 1988;207:52-66). The “sandwich’ technique of radiotherapy was popularized by a report from the Thomas Jefferson University Hospital (Cancer 1985;55359-353). This technique involves radiation (566-1969 rads) within 24 hours of surgery followed by full-dose postoperative radiotherapy for Dukes stage B2 or C lesions. Irradiation on the day of surgery is held to render tumor cells nonviable and thus incapable of distant metastasis at the time of surgery (Am J Roentgen01 1968;102:176-192). At the Thomas Jefferson University Hospital, distant metastases developed in 57% of patients with rectal cancers treated with surgery and conventional postoperative radiotherapy. In contrast, only 13% of patients who received radiation on the day of surgery as well as conventional postopera-
SELECTED SUMMARIES
897
tive radiotherapy developed distant metastasis. Based on these encouraging results RTOG Is conducting a prospective randomized trial that will determine if “sandwich” therapy is superior to standard postoperative radiotherapy (RTOG 81-15). Preliminary unpublished results show no survival benefit. There is probably also a role for intraoperative radiotherapy (IORTJ in patients with locally advanced rectal cancer. In one study, 51 patients with locally advanced colorectal cancer received 4596 5500rads of fractionated, external-beam radiation and an intraoperative dose (IORT) of lOOO-2000rads (Ann Surg 1988;207:52-59). Local recurrence or progression developed within the IORT field in only 2% of patients and within the external-beam field in only 18% of patients. All failures occurred in patients with recurrent cancer or in whom gross tumors had been left at the time of operation. Expected failure rates in these circumstances would be in the range of 39%-50% with standard external-beam techniques. In conclusion, most patients with carcinoma of the rectum should receive adjuvant radiation. If preoperative staging (e.g., computed tomographic scan and transrectal ultrasonography) suggests an early lesion, “sandwich” therapy should be considered with full-dose irradiation for full-thickness or node-positive lesions. Most patients (-85%) should receive preoperative irradiation. The present study shows that local control (disease-free survival) is significantly better and the treatment morbidity rate is lower in patients treated preoperatively compared with those treated postoperatively. There is little proof that preoperative radiation affects the rate of survival (although the EORTC study did find a significant survival benefit in patients ~55 years old). 5FU should be used as a radiosensitizer in most if not all patients. In locally advanced cases, IORT probably enhances local control. R.C.THIRLBY,M.D.
SELECTED SUMMARIES
1990
THE EFFECT OF PROTEIN ON RENAL FUNCTION IN CIRRHOSIS Badalamenti S, Gines P, Arroyo V, et al. (Liver Unit and Hormonal and Nuclear Medicine Laboratories, Hospital Clinic i Provincial, University of Barcelona, 08036-Barcelona, Spain). Effects of intravenous amino acid infusion and dietary proteins on kidney function in cirrhosis. Hepatology 1990:11:379-386. Protein loads, whether given as IV infusions of amino acids (AA] (Am J Physiol1986;25l:Fl31-Fl40) or following a high-protein oral diet (Am J Med 1983;75:943-950) can increase glomerular filtration rate (GFR) and renal plasma flow [RPF) in healthy humans. Low-protein diets have been associated with a decrease in GFR and RPF in normal patients. Brenner (N Engl J Med 1982;307:652-659) has suggested that the hyperfiltration induced by a high-protein diet accelerates the progression of chronic renal failure, whereas a low-protein diet retards it. Patients with cirrhosis are often on a low-protein diet because of anorexia, iatrogenie restriction of protein, or a reliance on alcohol for a substantial portion of caloric intake. Decreased renal function, especially as measured by inadequate sodium excretion and elevated blood urea nitrogen and creatinine levels, is common in cirrhosis. Therefore, there is a possibility that an increased protein load to the kidneys might increase GFR and RPF and perhaps enhance the response to diuretics or other therapeutic maneuvers. The present study investigated the effects of an IV load of AA and of an oral high-protein diet on groups of cirrhotic patients in various stages of hepatic and renal failure. In the first protocol, eight patients without ascites, nine with ascites and normal blood urea nitrogen and creatinine levels, and seven with functional renal failure were studied. After 5 days on a diet of 50 mEq sodium/day, they received a lo%-AA infusion for 3 hours. After catheterization via the antecubital vein, GFR and RPF were determined using standard clearance techniques. All three groups showed a significant increase in GFR and RPF, but there were no significant differences among the three groups in the percentage increase of these parameters. Free water clearance and urinary sodium levels, however, did not increase. As was expected, there was a twofold-to-threefold increase in serum glucagon levels during the infusion period. The second protocol involved nine nonazotemic, cirrhotic patients with ascites. The patients were randomly assigned in a crossover pattern to two II-day periods of either a high-protein diet (1.5 g/kg body wt per day] or a low-protein diet (0.5 g/kg body wt per day]. Both diets contained 50 mEq/day of sodium, 80 mEq/day of potassium, and 30 kcal/kg per day. Up to day 6 of the test periods the patients received diuretics, but these were discontinued on day 7. On day 11, renal function was studied using methods similar to those used in the first protocol. Values of GFR and RPF were significantly higher after the high-protein diet than the low-protein diet: GFR increased 13% (range, 0%-32%). and As with the AA infusion RPF, 12% (range, -12%-30%). protocol, there was no change in free water clearance or serum or urine sodium levels. Serum glucagon concentra-
895
tions were significantly higher after the high-protein diet but were not correlated with changes in GFR or RPF. The authors state that no subject in either protocol developed encephalopathy. Comment.
increased
These studies indicate that the renal response to an protein load, whether IV or from a high-protein diet, is
similar in cirrhotics and normal patients. The mechanism for the increased GFR and RPF in these situations is unclear. It does not seem to be a result of plasma volume expansion secondary to an increased osmotic load because hypertonic mannitol or isotonic saline solutions do not have this effect (Nephron 1985;41:193-199). Even without an increased osmotic load, AA infusion can increase GFR and RPF. Glucagon seems to play an essential role in these reactions. Infusions of AA have been previously shown to increase serum glucagon levels, and when glucagon release is blocked by somotostatin AA, infusions do not change renal hemodynamics. There are problems with accepting the central role of glucagon in these reactions; there is a decreased renal sensitivity to glucagon in cirrhosis and there is no correlation between glucagon serum levels and changes in GFR and RPF. Castellino [Am J Physiol 1988;255: F444-F449) has presented several lines of evidence indicating that both IV AA infusions and glucagon, either endogenous or exogenous, are required to produce the increased GFR and RPF. Levels of
other hormones such as renin and norepinepbrine, although they tend to increase in the presence of ascites and renal failure, did not increase during the AA infusions; therefore, it is unlikely that they are important factors in these hemodynamic changes. Prostaglandins have also been suggested as playing a role because it is known that nonsteroidal antiinflammatory drugs can blunt the renal hemodynamic response to acute protein loading, presumably by blocking prostaglandin effects. Overall, the changes observed in this study were not large, although there was a wide splay to the data, a few results showing a 40%-50% change. There was no demonstrable alteration in sodium clearance. It is not immediately apparent, therefore, whether such increases in GFR and RPF have any particular therapeutic implications. The studies were of short term, however, and it is possible that a lo%-20% increase in GFR and RPF that was sustained over a longer period of time cirrhosis. Perhaps the recognition that the functioning normally capable of responding
might lead to an improved management of most encouraging finding of the study is the kidney in cirrhosis, which clearly is not even before the development of ascites, is to protein loads in a manner comparable with
normal kidneys. This at least raises the possibility of manipulating renal function therapeutically in cirrhosis. It also raises the question of whether protein restriction, which has become so fixed a part of out treatment of cirrhosis, is appropriate for all patients. i. SWEETING,
M.D.
PREOPERATIVE RADIOTHERAPY IS BETTER THAN POSTOPERATIVE RADIOTHERAPY IN PATIENTS WITH RECTAL CANCER Pahlman L, Glimelius B (Departments of Surgery and Oncology, Uppsala University, Uppsala, Sweden). Pre- or postoperative radiotherapy in rectal and rectosigmoid carcinoma: report from a randomized multicenter trial. Ann Surg 1990;211:187-195.
Between 1980 and 1985,471 patients with resectable rectal carcinomas were entered into a randomized multicenter
898 SELECTED SUMMARIES
trial for comparison of preoperative and postoperative adjuvant irradiation. Patients with metastatic disease, locally unresectable tumors, or large fixed tumors were excluded. Patients randomized to preoperative radiotherapy (n = 236) received a total dose of 25.5 Gy in five fractions of 5.1 Gy daily over a period of 5-7 days, which corresponds to 47-49 Gy given with fractions of 2 Gy daily (10 Gy/wk). The patients underwent surgery within 1 week of radiotherapy. Two hundred thirty-five patients were randomized to the postoperative group. Radiation was administered in a dose of 2 Gy daily, five days per week for 4 weeks. After an interval of lo-14 days, further radiation was given for a period of 2 weeks for a total dose of 60 Gy. The patients were followed up clinically every third month during the first year, every fourth month in the second year, and twice yearly up to a least 5 years. Pelvic computed tomographic scans were performed at least once 6-9 months after surgery. Fine-needle or Tru-cut (Travenol Lab., Deerfield, IL) biopsies of any clinically or roentgenologically suspicious areas were performed, and only patients with morphologically proven recurrent cancers within the pelvic cavity were recorded as having local recurrences. In the group undergoing preoperative radiotherapy, all patients but one received the intended radiation. Preoperative radiotherapy was very well tolerated. The operations were locally curative in 209 (89%) patients. In the postoperative radiotherapy group, 204 (87%) patients underwent resections that were locally curative. Of these, 137 were potential candidates for radiotherapy (i.e., Dukes stages B2, Cl, or C2). Radiotherapy was started, however, in only 115 patients (84%). The reasons for patients not receiving radiotherapy were postoperative deaths (n = 91, prolonged recovery (n = 8), distant metastasis (n = 4), and treatment refusal (n = 1). The length of time from operation to initiation of radiation was ~6 weeks in 62 patients (54%), between 7 and 8 weeks in 26 patients (23%), and >8 weeks in 27 patients (23%). In most patients, the reason for delay was prolonged postoperative recovery. Many patients did not tolerate the postoperative radiotherapy. Only nine patients completed the treatment without adverse effects. Nine patients did not complete treatment. The postoperative mortality rates were 3% in the preoperative group and 5% in the postoperative group. Perineal wound infections occurred more frequently in the preoperative radiotherapy group (33% vs. 18%). The local recurrence rates in the preoperative and postoperative radiotherapy groups were 12% and 21%, respectively (P = 0.02). There was no difference in overall rates of survival between groups (all patients or patients who underwent surgery for cure). The report did not stratify data by any other patient groups (e.g., tumor stage, patient age, protocol violations, etc.]. Comment. Most patients with carcinomas of the rectum should receive adjuvant radiotherapy to decrease the chance of local recurrence. Patients with minimally invasive tumors (Dukes stages A and Bl) are usually cured by surgery alone. However, the local recurrence rate in patients with Dukes stage B2 or C cancers who do not receive adjuvant radiotherapy is 30%-50%. Preoperative or postoperative adjuvant radiotherapy decreases the incidence of local recurrences in these patients to x0%-30% depending on the size and/or stage of the tumor. This study is the first randomized
GASTROENTEROLOGY
comparison
of preoperative
and postoperative
Vol. 99, No. 3
radiotherapies
in
Why should preoperative radiotherapy be better than postoperative? First, radiotherapy may shrink large, fixed tumors, making complete resection feasible. Second, postoperative radiotherapy may damage the small bowel because the bowel usually descends into the pelvis after proctectomy, placing it in the radiation field. Third, wound complications are frequent after abdominoperineal resections (APR), frequently postponing radiotherapy for weeks. There are also theoretical or unproven advantages of preoperative radiotherapy. For example, it has been suggested that residual pelvic tumor cells after APR are disrupted or hypoxic, making them less susceptible to postoperative radiation damage. It is also possible that preoperative radiation, short of tumoricidal doses, may render tumor cells unable to metastasize. thus decreasing the chance of distant metastasis at the time of surgery (Am J Roentgen01 1968;102: 176-192). Preoperative irradiation, therefore, could potentially improve the rate of survival in patients with cancer of the rectum. Several retrospective studies have suggested that preoperative radiotherapy does improve the survival rates of patients with rectal cancers (Surgery 1988;103:161-167; Ann Surg 1989;209:194-199). For example, one study compared 65 patients who received radiotherapy before curative operations with 135 historical controls treated with surgery alone (Dis Colon Rectum 1988;31:287-290). The 5-year local-regional failure rates were 7.7% for the preoperative radiotherapy group and 29% in the historical controls (P < 0.001). The B-year determinate disease-free survival rates were 66% and 38% for patients with and without radiotherapy, respectively (P < O.OOl]. The results of prospective studies are conflicting. A recently published trial from Brazil involved patients with rectal cancers (n = 68) randomized to groups undergoing preoperative radiotherapy or surgery alone (Dis Colon Rectum 1989;32:702-710). Local recurrence rates in the preoperative-radiotherapy group and the operation-only group were 2.9% and 23.5%) respectively. Corrected survival rates were 80% and 34.4%. respectively. A much larger study performed by the European Organization for Research and Treatment of Cancer (EORTC) found little or no survival benefit with preoperative radiotherapy compared with surgery alone (Ann Surg 1988;208:606-614). Four hundred sixty-six patients with rectal cancer were randomized. The local recurrence rates at 5 years were 30% and 15% in the control and adjuvant-radiotherapy groups, respectively (P = 0.003). Considering only the 341 patients resected for potential cure, the 5-year survival rates were 59.1% and 69.1% in the control group and the combined modality group, respectively (P = 0.08). One subgroup analysis did show a significant treatment difference in patients t55 years of age (n = 103). The 5-year survival rates were 48% and 80% for the control group and the combined modality group, respectively (P = 0.004). Because it is unclear whether adjuvant preoperative radiotherapy improves survival rates over surgery alone in patients with carcinoma of the rectum, it is not surprising that the present study did not show an overall survival benefit of preoperative vs. postoperative radiotherapy. Nevertheless, the present study is important for several reasons. First, it showed a significantly decreased local recurrence rate in patients treated preoperatively (12% vs. 21%; P = 0.02). This improved “disease-free” survival rate may eventually translate into improved overall survival rates with longer periods of follow-up. Regardless, local recurrence is a devastating outcome. Second, the preoperative treatment was tolerated very well. Radiotherapy was administered at high doses (5.1 Gy) in only five fractions, and surgery was performed within 1 week of radiotherapy. Typical protocols in this country require at least 25 fractions over 5-6 weeks and cause considerable local morbidity (e.g., perianal excoriation]. Surgery is usually performed 6 weeks after completion of radiotherapy; therefore, the entire process takes 11-12 weeks. The protocol in this study took lo-14 days and achieved local control rates as good as or better than previously
September
1996
reported protocols. This important study establishes preoperative radiotherapy as the superior technique of adjuvant radiotherapy. Other controversies still exist in the care of patients with rectal cancer [a] what is the role of chemoradiotherapy? (b] what is the role of “sandwich’ therapy? and (c] what is the role of intraoperative radiotherapy? The data suggest that radiosensitizing agents [e.g., 5FU) should be added to all radiotherapy protocols. The Gastrointestinal Tumor Study Group reported a prospective, four-arm, randomized trial comparing surgery alone, surgery plus postoperative radiotherapy (XRT), surgery plus chemotherapy, and surgery plus XRT plus chemotherapy (N Engl J Med 1985;312:1465-1472). The recurrence rate at 5 years in the control group was 55% compared with a rate of 33 % in patients receiving adjuvant treatment (P < 0.94). Chemotherapy seemed to enhance the effect of radiation on local control. Cancer recurred in 48% of patients in the irradiation arm and in 33% of patients in the chemoradiotherapy arm. In a retrospective analysis of patients with advanced rectal cancer treated at the Mayo Clinic with preoperative external-beam radiotherapy, the risk of local failure was lower in patients who received 5FU during external-beam radiotherapy (9% vs. 19%) (Ann Surg 1988;207:52-66). The “sandwich’ technique of radiotherapy was popularized by a report from the Thomas Jefferson University Hospital (Cancer 1985;55359-353). This technique involves radiation (566-1969 rads) within 24 hours of surgery followed by full-dose postoperative radiotherapy for Dukes stage B2 or C lesions. Irradiation on the day of surgery is held to render tumor cells nonviable and thus incapable of distant metastasis at the time of surgery (Am J Roentgen01 1968;102:176-192). At the Thomas Jefferson University Hospital, distant metastases developed in 57% of patients with rectal cancers treated with surgery and conventional postoperative radiotherapy. In contrast, only 13% of patients who received radiation on the day of surgery as well as conventional postopera-
SELECTED SUMMARIES
897
tive radiotherapy developed distant metastasis. Based on these encouraging results RTOG Is conducting a prospective randomized trial that will determine if “sandwich” therapy is superior to standard postoperative radiotherapy (RTOG 81-15). Preliminary unpublished results show no survival benefit. There is probably also a role for intraoperative radiotherapy (IORTJ in patients with locally advanced rectal cancer. In one study, 51 patients with locally advanced colorectal cancer received 4596 5500rads of fractionated, external-beam radiation and an intraoperative dose (IORT) of lOOO-2000rads (Ann Surg 1988;207:52-59). Local recurrence or progression developed within the IORT field in only 2% of patients and within the external-beam field in only 18% of patients. All failures occurred in patients with recurrent cancer or in whom gross tumors had been left at the time of operation. Expected failure rates in these circumstances would be in the range of 39%-50% with standard external-beam techniques. In conclusion, most patients with carcinoma of the rectum should receive adjuvant radiation. If preoperative staging (e.g., computed tomographic scan and transrectal ultrasonography) suggests an early lesion, “sandwich” therapy should be considered with full-dose irradiation for full-thickness or node-positive lesions. Most patients (-85%) should receive preoperative irradiation. The present study shows that local control (disease-free survival) is significantly better and the treatment morbidity rate is lower in patients treated preoperatively compared with those treated postoperatively. There is little proof that preoperative radiation affects the rate of survival (although the EORTC study did find a significant survival benefit in patients ~55 years old). 5FU should be used as a radiosensitizer in most if not all patients. In locally advanced cases, IORT probably enhances local control. R.C.THIRLBY,M.D.