Chemoradiotherapy for Rectal Cancer — When, Why, and How?
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《新英格兰医药杂志》
Although colon cancer and rectal cancer share many features, clinicians should be aware of important differences in the clinical behavior and treatment of these two distinct diseases. Prominent among these is the tendency for rectal cancer — but not colon cancer — to recur locally. Local recurrence of rectal cancer is often catastrophic: it is difficult to cure, and the associated symptoms are debilitating. Accordingly, preventing local recurrence is one of the main goals of rectal-cancer treatment.
In 1990, a National Institutes of Health consensus conference recommended postoperative adjuvant chemoradiotherapy for patients with stage II rectal cancer (node-negative disease with transmural invasion) and stage III rectal cancer (node-positive disease).1 At about the same time, the critical significance of proper operative technique was becoming apparent: pathology studies had demonstrated the importance of clear circumferential resection margins,2 and clinical trials showed very low local recurrence rates after surgery alone.3 Indeed, precise anatomical excision of the rectum and its mesentery (a technique called total mesorectal excision) is now considered the cornerstone of adequate treatment for rectal cancer, and adoption of this technique on the national level has led to impressive improvements in both the rate of sphincter preservation and that of local recurrence.4
Ironically, at a time when official National Institutes of Health recommendations called for postoperative chemoradiotherapy and some surgeons called for no radiotherapy at all, a case began to build for preoperative radiotherapy. Preoperative radiotherapy is enticing for a number of reasons: the theoretical advantage of irradiating tissue not rendered hypoxic by previous surgery; the possibility of enhancing sphincter preservation by shrinking large distal tumors; the decreased likelihood of radiation-induced injury to small bowel trapped in the pelvis by adhesions; the ability to excise the irradiated large-bowel segment and perform an anastomosis with healthy colon to achieve better postoperative function; and the increasing accuracy of preoperative staging by endorectal ultrasonography.
Data supporting the use of preoperative radiotherapy in patients with rectal cancer have been steadily accumulating. The Swedish Rectal Cancer Trial showed that preoperative radiotherapy decreased the rate of local recurrence and improved the survival rate.5 However, patients in that trial did not uniformly undergo total mesorectal excision, and rates of local recurrence were relatively high both with and without radiotherapy. More recently, the Dutch Colorectal Cancer Group showed that preoperative radiotherapy decreased the local-recurrence rate even in patients who underwent total mesorectal excision, although no significant effect on survival was noted at two years' follow-up.6
In both the Swedish and the Dutch trials, preoperative radiotherapy was administered without chemotherapy in daily fractions of 5 Gy over a five-day period (total dosage, 25 Gy) — a common approach in Europe. In contrast, radiotherapy in the United States is generally administered in daily fractions of 1.8 to 2.0 Gy, five days per week, over a period of five to five and a half weeks (total dose, 45 to 50 Gy); chemotherapy is concurrently administered as a radiation sensitizer, most commonly with continuous-infusion fluorouracil. The U.S. (long-course) and European (short-course) radiation dosages seem disparate at first glance, but in fact they are similar in their biologic effect on the tumor, though perhaps not equivalent in terms of late toxicity.
Two major attempts in the United States to conduct a prospective comparison of preoperative and postoperative chemoradiotherapy among patients with rectal cancer were unsuccessful because of limited patient enrollment. Those trials highlight the importance of the study reported in this issue of the Journal by the German Rectal Cancer Study Group.7 In this study, Sauer et al. randomly assigned patients with clinical stage II or III rectal cancer to similar preoperative or postoperative regimens of chemoradiotherapy based on conventional (long-course) radiotherapy and concurrent chemotherapy with continuous-infusion fluorouracil. The surgery used was a standardized technique for total mesorectal excision. The groups were well matched, except that the group assigned to preoperative chemoradiotherapy had a greater number of distal tumors (an adverse risk factor). The median follow-up was almost four years.
Sauer et al. found no significant difference between the groups in overall survival, the primary end point of the study, which had adequate statistical power. However, and of key importance, the local-recurrence rate in the preoperative-chemoradiotherapy group (6 percent) was less than half that in the postoperative-chemoradiotherapy group (13 percent, P=0.006). Several other findings favoring preoperative chemoradiotherapy are noteworthy: evidence of tumor downstaging after preoperative chemoradiotherapy, in terms of the rate of complete pathological response (8 percent, vs. 0 percent in the postoperative-chemoradiotherapy group) and the lower tumor–node–metastasis stage in the preoperative chemoradiotherapy group; the similar rates of sphincter preservation, despite the preponderance of distal tumors in the preoperative-chemoradiotherapy group; similar perioperative morbidity and mortality rates; and improved treatment compliance and decreased rates of severe acute and long-term toxic effects in the preoperative-chemoradiotherapy group.
Sauer et al. provide convincing evidence of the superiority of preoperative chemoradiotherapy over postoperative chemoradiotherapy in patients with stage II or III rectal cancer. However, several problems remain unresolved. One disadvantage of preoperative chemoradiotherapy is the possibility of overtreating early-stage tumors. Sauer et al. found that in 18 percent of the patients randomly assigned to postoperative chemoradiotherapy, the tumor had been overstaged during the initial evaluation, despite the use of endorectal ultrasonography. As a practical matter, endorectal ultrasonography is neither perfectly accurate nor universally available. Improved clinical staging, perhaps with the use of magnetic resonance imaging, may lead to improved patient selection for preoperative adjuvant therapy in the future.8
Another important issue is the choice of radiation fractionation. Short-course radiotherapy has distinct advantages in cost and convenience, and data supporting its efficacy are plentiful outside the United States. However, there is little experience with short-course radiotherapy in the United States, and many clinicians are concerned that it will be associated with an excessively high rate of late complications.9 European data confirm that an optimal irradiation technique must be used to minimize complications.7,9 Moreover, concurrent chemotherapy is not administered with short-course radiotherapy, and the role of postoperative chemotherapy has not been defined.
The effect of chemoradiotherapy on functional outcome is important and deserves additional scrutiny. Postoperative bowel function after low colorectal anastomosis is often imperfect: some patients have excessively frequent bowel movements, incomplete evacuation, or varying degrees of fecal incontinence. Radiotherapy often makes such matters worse10,11 and may also contribute to bladder and sexual dysfunction. Construction of a neorectum using a J pouch or a coloplasty technique can ameliorate some postoperative bowel problems, as can careful attention to the irradiation technique by minimizing the amount of anus and small bowel within the radiation field. Future trials need to include detailed quality-of-life assessments, and patients' preferences must be considered in clinical decision-making.
Optimizing outcome after treatment for rectal cancer includes minimizing both the recurrence rate and the number of cancer-related deaths, as well as maximizing patients' quality of life. Yet, even as we await future trials to refine our treatment strategies, we must ensure best practices for patients with rectal cancer today. Preoperative staging is important, and imaging by endorectal ultrasound or magnetic resonance should be routine. Surgery for rectal cancer should be performed only by surgeons with training in the technique of total mesorectal excision and adequate experience. Specific, formal pathological assessment of resected rectal specimens should be performed. Pelvic radiation should be delivered by the optimal technique, and both radiotherapy and surgery need to be coordinated with evolving chemotherapy regimens.
Treatment for rectal cancer can range from simple local excision to radical surgery with chemoradiotherapy, but the choice can involve a trade-off between functional results and the risk of recurrence. Sauer et al. have helped to clarify one important aspect of adjuvant therapy. However, even as the details of combined therapy continue to evolve, the best outcomes will be obtained only when patients' preferences are understood and the interlocking expertise of multiple specialists is routinely provided.
Source Information
From the Division of Colon and Rectal Surgery, Department of Surgery, University of Minnesota, Minneapolis.
References
NIH consensus conference: adjuvant therapy for patients with colon and rectal cancer. JAMA 1990;264:1444-1450.
Quirke P, Durdey P, Dixon MF, Williams NS. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection: histopathological study of lateral tumour spread and surgical excision. Lancet 1986;2:996-999.
MacFarlane JK, Ryall RD, Heald RJ. Mesorectal excision for rectal cancer. Lancet 1993;341:457-460.
Martling AL, Holm T, Rutqvist LE, Moran BJ, Heald RJ, Cedermark B. Effect of a surgical training programme on outcome of rectal cancer in the County of Stockholm. Lancet 2000;356:93-96.
Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 1997;336:980-987.
Kapiteijn E, Marijnen CAM, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638-646.
Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-1740.
Beets-Tan RG, Beets GL, Vliegen RF, et al. Accuracy of magnetic resonance imaging in prediction of tumour-free resection margin in rectal cancer surgery. Lancet 2001;357:497-504.
Holm T, Singnomklao T, Rutqvist LE, Cedermark B. Adjuvant preoperative radiotherapy in patients with rectal carcinoma: adverse effects during long term follow-up of two randomized trials. Cancer 1996;78:968-976.
Kollmorgen CF, Meagher AP, Wolff BG, Pemberton JH, Martenson JA, Illstrup DM. The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel function. Ann Surg 1994;220:676-682.
Dahlberg M, Glimelius B, Graf W, Pahlman L. Preoperative irradiation affects functional results after surgery for rectal cancer: results from a randomized study. Dis Colon Rectum 1998;41:543-551.(Robert D. Madoff, M.D.)
In 1990, a National Institutes of Health consensus conference recommended postoperative adjuvant chemoradiotherapy for patients with stage II rectal cancer (node-negative disease with transmural invasion) and stage III rectal cancer (node-positive disease).1 At about the same time, the critical significance of proper operative technique was becoming apparent: pathology studies had demonstrated the importance of clear circumferential resection margins,2 and clinical trials showed very low local recurrence rates after surgery alone.3 Indeed, precise anatomical excision of the rectum and its mesentery (a technique called total mesorectal excision) is now considered the cornerstone of adequate treatment for rectal cancer, and adoption of this technique on the national level has led to impressive improvements in both the rate of sphincter preservation and that of local recurrence.4
Ironically, at a time when official National Institutes of Health recommendations called for postoperative chemoradiotherapy and some surgeons called for no radiotherapy at all, a case began to build for preoperative radiotherapy. Preoperative radiotherapy is enticing for a number of reasons: the theoretical advantage of irradiating tissue not rendered hypoxic by previous surgery; the possibility of enhancing sphincter preservation by shrinking large distal tumors; the decreased likelihood of radiation-induced injury to small bowel trapped in the pelvis by adhesions; the ability to excise the irradiated large-bowel segment and perform an anastomosis with healthy colon to achieve better postoperative function; and the increasing accuracy of preoperative staging by endorectal ultrasonography.
Data supporting the use of preoperative radiotherapy in patients with rectal cancer have been steadily accumulating. The Swedish Rectal Cancer Trial showed that preoperative radiotherapy decreased the rate of local recurrence and improved the survival rate.5 However, patients in that trial did not uniformly undergo total mesorectal excision, and rates of local recurrence were relatively high both with and without radiotherapy. More recently, the Dutch Colorectal Cancer Group showed that preoperative radiotherapy decreased the local-recurrence rate even in patients who underwent total mesorectal excision, although no significant effect on survival was noted at two years' follow-up.6
In both the Swedish and the Dutch trials, preoperative radiotherapy was administered without chemotherapy in daily fractions of 5 Gy over a five-day period (total dosage, 25 Gy) — a common approach in Europe. In contrast, radiotherapy in the United States is generally administered in daily fractions of 1.8 to 2.0 Gy, five days per week, over a period of five to five and a half weeks (total dose, 45 to 50 Gy); chemotherapy is concurrently administered as a radiation sensitizer, most commonly with continuous-infusion fluorouracil. The U.S. (long-course) and European (short-course) radiation dosages seem disparate at first glance, but in fact they are similar in their biologic effect on the tumor, though perhaps not equivalent in terms of late toxicity.
Two major attempts in the United States to conduct a prospective comparison of preoperative and postoperative chemoradiotherapy among patients with rectal cancer were unsuccessful because of limited patient enrollment. Those trials highlight the importance of the study reported in this issue of the Journal by the German Rectal Cancer Study Group.7 In this study, Sauer et al. randomly assigned patients with clinical stage II or III rectal cancer to similar preoperative or postoperative regimens of chemoradiotherapy based on conventional (long-course) radiotherapy and concurrent chemotherapy with continuous-infusion fluorouracil. The surgery used was a standardized technique for total mesorectal excision. The groups were well matched, except that the group assigned to preoperative chemoradiotherapy had a greater number of distal tumors (an adverse risk factor). The median follow-up was almost four years.
Sauer et al. found no significant difference between the groups in overall survival, the primary end point of the study, which had adequate statistical power. However, and of key importance, the local-recurrence rate in the preoperative-chemoradiotherapy group (6 percent) was less than half that in the postoperative-chemoradiotherapy group (13 percent, P=0.006). Several other findings favoring preoperative chemoradiotherapy are noteworthy: evidence of tumor downstaging after preoperative chemoradiotherapy, in terms of the rate of complete pathological response (8 percent, vs. 0 percent in the postoperative-chemoradiotherapy group) and the lower tumor–node–metastasis stage in the preoperative chemoradiotherapy group; the similar rates of sphincter preservation, despite the preponderance of distal tumors in the preoperative-chemoradiotherapy group; similar perioperative morbidity and mortality rates; and improved treatment compliance and decreased rates of severe acute and long-term toxic effects in the preoperative-chemoradiotherapy group.
Sauer et al. provide convincing evidence of the superiority of preoperative chemoradiotherapy over postoperative chemoradiotherapy in patients with stage II or III rectal cancer. However, several problems remain unresolved. One disadvantage of preoperative chemoradiotherapy is the possibility of overtreating early-stage tumors. Sauer et al. found that in 18 percent of the patients randomly assigned to postoperative chemoradiotherapy, the tumor had been overstaged during the initial evaluation, despite the use of endorectal ultrasonography. As a practical matter, endorectal ultrasonography is neither perfectly accurate nor universally available. Improved clinical staging, perhaps with the use of magnetic resonance imaging, may lead to improved patient selection for preoperative adjuvant therapy in the future.8
Another important issue is the choice of radiation fractionation. Short-course radiotherapy has distinct advantages in cost and convenience, and data supporting its efficacy are plentiful outside the United States. However, there is little experience with short-course radiotherapy in the United States, and many clinicians are concerned that it will be associated with an excessively high rate of late complications.9 European data confirm that an optimal irradiation technique must be used to minimize complications.7,9 Moreover, concurrent chemotherapy is not administered with short-course radiotherapy, and the role of postoperative chemotherapy has not been defined.
The effect of chemoradiotherapy on functional outcome is important and deserves additional scrutiny. Postoperative bowel function after low colorectal anastomosis is often imperfect: some patients have excessively frequent bowel movements, incomplete evacuation, or varying degrees of fecal incontinence. Radiotherapy often makes such matters worse10,11 and may also contribute to bladder and sexual dysfunction. Construction of a neorectum using a J pouch or a coloplasty technique can ameliorate some postoperative bowel problems, as can careful attention to the irradiation technique by minimizing the amount of anus and small bowel within the radiation field. Future trials need to include detailed quality-of-life assessments, and patients' preferences must be considered in clinical decision-making.
Optimizing outcome after treatment for rectal cancer includes minimizing both the recurrence rate and the number of cancer-related deaths, as well as maximizing patients' quality of life. Yet, even as we await future trials to refine our treatment strategies, we must ensure best practices for patients with rectal cancer today. Preoperative staging is important, and imaging by endorectal ultrasound or magnetic resonance should be routine. Surgery for rectal cancer should be performed only by surgeons with training in the technique of total mesorectal excision and adequate experience. Specific, formal pathological assessment of resected rectal specimens should be performed. Pelvic radiation should be delivered by the optimal technique, and both radiotherapy and surgery need to be coordinated with evolving chemotherapy regimens.
Treatment for rectal cancer can range from simple local excision to radical surgery with chemoradiotherapy, but the choice can involve a trade-off between functional results and the risk of recurrence. Sauer et al. have helped to clarify one important aspect of adjuvant therapy. However, even as the details of combined therapy continue to evolve, the best outcomes will be obtained only when patients' preferences are understood and the interlocking expertise of multiple specialists is routinely provided.
Source Information
From the Division of Colon and Rectal Surgery, Department of Surgery, University of Minnesota, Minneapolis.
References
NIH consensus conference: adjuvant therapy for patients with colon and rectal cancer. JAMA 1990;264:1444-1450.
Quirke P, Durdey P, Dixon MF, Williams NS. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection: histopathological study of lateral tumour spread and surgical excision. Lancet 1986;2:996-999.
MacFarlane JK, Ryall RD, Heald RJ. Mesorectal excision for rectal cancer. Lancet 1993;341:457-460.
Martling AL, Holm T, Rutqvist LE, Moran BJ, Heald RJ, Cedermark B. Effect of a surgical training programme on outcome of rectal cancer in the County of Stockholm. Lancet 2000;356:93-96.
Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 1997;336:980-987.
Kapiteijn E, Marijnen CAM, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638-646.
Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-1740.
Beets-Tan RG, Beets GL, Vliegen RF, et al. Accuracy of magnetic resonance imaging in prediction of tumour-free resection margin in rectal cancer surgery. Lancet 2001;357:497-504.
Holm T, Singnomklao T, Rutqvist LE, Cedermark B. Adjuvant preoperative radiotherapy in patients with rectal carcinoma: adverse effects during long term follow-up of two randomized trials. Cancer 1996;78:968-976.
Kollmorgen CF, Meagher AP, Wolff BG, Pemberton JH, Martenson JA, Illstrup DM. The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel function. Ann Surg 1994;220:676-682.
Dahlberg M, Glimelius B, Graf W, Pahlman L. Preoperative irradiation affects functional results after surgery for rectal cancer: results from a randomized study. Dis Colon Rectum 1998;41:543-551.(Robert D. Madoff, M.D.)