Quantification of Histologic Regression of Rectal Cancer After Irradiation

Quantification of Histologic Regression of Rectal Cancer After Irradiation A Proposal for a Modified Staging System J. M. D. Wheeler, M.D., F.R.C.S.,* B. F. Warren, M.R.C.Path., N. J. McC. Mortensen, M.D., F.R.C.S.,* N. Ekanyaka, M.B., B.S., H. Kulacoglu, M.B., B.S., A. C. Jones, M.R.C.P., F.R.C.R., B. D. George, M.S., F.R.C.S.,* M. G. W. Kettlewell, M.Chir., F.R.C.S.* From the Departments of *Colorectal Surgery and Cellular Pathology, John Radcliffe Hospital, and Department of Clinical Oncology, Churchill Hospital, Oxford, United Kingdom J. M. D. Wheeler has been awarded the Ivo Fuchs Colorectal Cancer Research Fellowship funded by the Waverley Trust. Read at The American Society of Colon and Rectal Surgeons 100th Anniversary and Tripartite Meeting, Washington, D.C., May 1 to 6, 1999. No reprints are available. 1051 PURPOSE: Long-course preoperative radiotherapy has been recommended for rectal carcinoma when there is concern about the ability to perform a curative resection, for example, in larger tethered tumors or those sited anteriorly or near the anal sphincter. Downstaging of the tumor may occur, and this is of importance when estimating the prognosis and selecting postoperative therapy for patients. We studied the effects of preoperative chemoradiotherapy on the pathology of rectal cancer, and we propose a simplified measurement of tumor regression, the Rectal Cancer Regression Grade. METHODS: We have reviewed those patients who received preoperative chemoradiotherapy followed by surgical resection for carcinomas of the mid or distal third of the rectum found to be Stage T3/4 on transrectal ultrasound or CT between January 1995 and December 1998. Patients received 45 to 50 Gy irradiation and an infusion of 5-fluorouracil. The surgical specimens were examined by one pathologist, and the Rectal Cancer Regression Grade was quantified. RESULTS: Forty-two patients, mean age 60 (range, 42 86) years, underwent chemoradiotherapy before surgery for rectal carcinoma. There were 28 anterior resections (67 percent; 9 with a colonic pouch), 12 abdominoperineal resections (27 percent), and 2 Hartmann s procedures (5 percent). Comparison of preoperative and pathologic staging revealed that the depth of invasion was downstaged in 17 patients (38 percent), and the status of involved lymph nodes was downstaged in 13 (50 percent) of 26 patients. Tumor regression was more than 50 percent (Rectal Cancer Regression Grades 1 and 2) in 36 patients (86 percent), with 7 patients (17 percent) having complete regression with absence of residual cancer cells. CONCLUSION: Significant tumor regression was seen in 86 percent of cases after chemoradiotherapy, with 19 patients showing a good responsiveness. We propose a modified pathologic staging system for irradiated rectal cancer, the Rectal Cancer Regression Grade, which includes a measurement of tumor regression. The utility of the proposed Rectal Cancer Regression Grade must be tested against long-term outcomes before its value in predicting prognosis and survival can be determined. [Key words: Rectal cancer; Regression; Preoperative radiotherapy; Staging] Wheeler JMD, Warren BF, Mortensen NJMcC, Ekanyaka N, Kulacoglu H, Jones AC, George BD, Kettlewell MGW. Quantification of histologic regression of rectal cancer after irradiation: a proposal for a modified staging system. Dis Colon Rectum 2002;45:1051 1056. T here are 10,000 new cases of rectal cancer, causing 6,000 deaths, in the United Kingdom each year. 1 Rectal cancers relapse locally with recurrence rates of 2.6 to 32 percent. 2,3 Preoperative radiotherapy is aimed at the prevention of local recurrence, and four recent randomized, controlled trials of preoperative radiotherapy vs. surgery alone for rectal cancer have all shown significantly reduced local recurrence rates 4 8 and also a survival advantage. 4,5 Preoperative radiotherapy may be either short course for tumors believed to be amenable to a surgical resection or long course for those tumors that are fixed clinically or in critical sites; selective postoperative radiotherapy should be considered for tumors that involve the circumferential resection margin. After preoperative radiotherapy, downstaging of the tumor may occur, 9 11 and complete regression of tumor has been reported in up to 20 percent of patients. 12,13 Thorough examination of the excised specimen is essential to determine an individual patient s prognosis and to decide whether to offer postoperative adjuvant chemotherapy. A reliable pathologic assessment is also required to compare the effects of preoperative radiotherapy between different groups. Mandard et al. 14 proposed a measurement of tumor response, Tumor Regression Grade, after preoperative chemoradiotherapy in esophageal cancer. This has since been applied to rectal cancer. 15, 16 However, this measurement consisted of five poorly distinct categories, which introduces the problem of subjec-

1052 WHEELER ET AL Dis Colon Rectum, August 2002 tive assessment of response to radiotherapy. To measure tumor response after preoperative radiotherapy, we propose that rectal cancer should be staged in terms of Rectal Cancer Regression Grade (RCRG) 1 to 3. RCRG 1 indicates good radioresponsiveness where the tumor is either sterilized or only microscopic foci of adenocarcinoma remain. RCRG 2 reflects marked fibrosis but with macroscopic tumor still present, and RCRG 3 indicates a poor response with little or no fibrosis in the presence of abundant macroscopic tumor. The response to radiotherapy varies among patients, and by incorporating features found in irradiated specimens into established staging systems, it may be possible to give a better indication of an individual patient s prognosis. We have therefore reviewed all patients who have undergone resection of rectal cancer after preoperative radiotherapy in our institution. The preoperative radiologic staging was compared with the pathologic staging in the resected specimen. An assessment of RCRG was made so that a reproducible measurement of radioresponsiveness can be made for each rectal tumor. PATIENTS AND METHODS We studied 42 consecutive patients (with biopsyproven adenocarcinoma), mean age 60 (range, 42 86) years, who had undergone surgical resection of a carcinoma of the middle (n 12, 29 percent) and distal (n 30, 71 percent) thirds of the rectum, after preoperative chemoradiotherapy, between January 1995 and December 1998 at the John Radcliffe Hospital. Follow-up is too short to allow meaningful analysis of oncologic outcomes. Patients underwent chest x-ray, abdominal/pelvic CT imaging, and transrectal ultrasound (TRUS) as part of their preoperative staging; only those patients with Stage T3/4 tumors received preoperative chemoradiotherapy. In our practice, patients were routinely defunctioned before chemoradiotherapy with a loop ileostomy/colostomy. Irradiation (45 50 Gy; three fields) in 2-Gy fractions was administered. A continuous intravenous infusion of 5-fluorouracil (1.5 g on Days 1 5or1g/m 2 on Days 1 4) was coadministered in Weeks 1 and 5 of radiotherapy. Surgery was performed at approximately sixweek intervals after completion of adjuvant treatment. There were 28 anterior resections (67 percent; 9 with a colonic J-pouch), 12 abdominoperineal resections (29 percent), and 2 Hartmann s procedures (5 percent). Patients remained defunctioned after anterior resection until a satisfactory contrast enema had been performed three months later. The surgical specimens were examined by one pathologist (BFW), and the RCRG was quantified. If no macroscopic tumor was seen in the pathologic specimen, then multiple sections were prepared, having blocked the entire region of scarring. Sections were cut at several levels and examined meticulously to identify any residual foci of adenocarcinoma. RESULTS Results were expressed in terms of T stage, N stage, Dukes stage (Tables 1 and 2), and RCRG (Table 3). Pathologic staging revealed that the depth of invasion was downstaged in 17 patients (38 percent) and the status of involved lymph nodes was downstaged in 13 (50 percent) of 26 patients. Tumor regression was more than 50 percent (RCRG 1 2) in 36 patients (86 Table 1. Preoperative T Stage (TRUS and CT) Compared With Pathologic T Stage After Preoperative pt Stage After Preoperative Preoperative TRUS/CT pt0 pt1 pt2 pt3 pt4 Total T3 5 1 3 17 0 26 T4 2 0 0 6 8 16 Total 7 1 3 23 8 TRUS transrectal ultrasound. Table 2. Preoperative T Stage (TRUS and CT) Compared With Pathologic T Stage After Preoperative Preoperative TRUS/CT Pathology n (%) T stage 0 0 7 (17) 1 0 1 (2) 2 0 3 (7) 3 26 (62%) 23 (55) 4 16 (38%) 8 (19) N stage 0 16 (38%) 29 (69) 1 26 (62%) 13 (31) Dukes No tumor 0 7 (17) A 0 4 (10) B 15 (36%) 17 (40) C 27 (64%) 14 (33) TRUS transrectal ultrasound.

Vol. 45, No. 8 RADIOTHERAPY AND RECTAL CANCER REGRESSION 1053 Table 3. Rectal Cancer Regression Grade RCRG Histologic Features No. of patients (%) 1 Sterilization or only microscopic foci of adenocarcinoma remaining, with marked fibrosis 19 (46) 2 Marked fibrosis but macroscopic disease present 17 (40) 3 Little or no fibrosis, with abundant macroscopic disease 6 (14) RCRG Rectal Cancer Regression Grade. percent), with 7 (17 percent) patients having complete regression with absence of residual cancer cells and 12 patients having only microscopic foci of adenocarcinoma remaining. At least some regression was seen in all specimens. A mean of 9.3 (range, 0 22) lymph nodes were found, with a mean of 1.1 (range, 0 8) lymph nodes having residual adenocarcinoma. The mean size of the largest lymph node was 4 (range, 1 15) mm. Two patients (5 percent) had macroscopic disease (R2) at the resection margin, and four patients (10 percent) had microscopic disease (R1). The many histologic features, some of which are peculiar to rectal cancers that have been irradiated, are shown in Table 4. DISCUSSION In our study, the depth of tumor invasion after preoperative chemoradiotherapy was downstaged in 17 patients (38 percent), and the status of involved lymph nodes was downstaged in 13 (50 percent) of 26 patients. There was a shift to an earlier Dukes staging, with a 48 percent reduction in the number of Dukes C tumors. This compares well with other studies that have combined preoperative radiotherapy with adjuvant chemotherapy 9,11 and observed similar responses. Seven patients (17 percent) had no residual tumor in the specimen, and although others have described sterilization rates up to 36 percent, 9 this has been in a smaller cohort of patients. Unfortunately, both TRUS and CT are unable to give accurate staging after radiotherapy, 9, 17 and subsequently we continue to perform oncologically appropriate, major operations to minimize the risk of leaving radiologically undetected, residual tumor. In a recent study, 30 T1 to T3 tumors that were radiologically believed to have had a complete response to radiotherapy were not operated on. However, at follow-up of 3 to 14 months, eight of these patients have required surgery and two have died from their tumor. 18 Fourteen patients (33 percent) did not have a sphincter-saving procedure after attempted downstaging with preoperative radiotherapy. Although it is Table 4. Histologic Changes After Preoperative for Rectal Cancer Histologic Feature Incidence n (%) Tumor after DXT Increased necrosis 24 (57) Increased stromal fibrosis 42 (100) Mucin pools 13 (31) Foreign body giant cells at site of 6 (14) previous tumor Absence of vascular invasion 8 (19) Decreased lymphocytic response 41 (98) Lymph nodes after DXT Eosinophilic necrosis 6 (14) DXT radiotherapy. accepted that preoperative radiotherapy may allow a fixed tumor to become operable, it is our policy to make a decision to treat (anterior resection or abdominoperineal resection) before radiotherapy despite any subsequent downstaging. Others describe preoperative radiotherapy being used to increase the proportion of sphincter-saving operations being performed 19,20 with impressive local recurrence and survival rates. Many surgeons are concerned about anastomotic integrity after preoperative radiotherapy, but there is no evidence in animal models to suggest 21, 22 that clinical outcome is adversely affected. Downstaging may result in postoperative adjuvant chemotherapy not being offered to patients with formerly Dukes Stage C tumors. In this study, patients who had involved lymph nodes on preoperative CT or TRUS were offered postoperative chemotherapy if their clinical condition allowed. However, not all patients who had no residual tumor have accepted this, despite four of these seven patients having apparent lymph node involvement on preoperative CT or TRUS. Because a small survival benefit has been described in rectal cancer after postoperative chemoradiotherapy, 23,24 this may be a cause for concern. There are no data, however, to suggest that our patients who have previously had chemotherapy are disadvantaged. The accuracy of TRUS and CT in the assessment of

1054 WHEELER ET AL Dis Colon Rectum, August 2002 Figure 1. A. A tumor that has had a poor response to radiotherapy and is relatively radioresistant, but is described as being downstaged to T2. B. In contrast, although this tumor has clearly regressed, having had a good response to radiotherapy, it remains T3 and is said not to have been downstaged. It is argued that a measurement of regression (together with the TNM stage) may be an important prognostic indicator in patients receiving preoperative radiotherapy for advanced rectal cancer. Table 5. Pathologic T Stage Compared With RCRG in Rectal Cancer Specimens After Preoperative RCRG 1 2 3 pt0 7 0 0 pt1 1 0 0 pt2 1 2 0 pt3 9 10 4 pt4 1 5 2 RCRG Rectal Cancer Regression Grade. local invasion in rectal cancer (before preoperative radiotherapy) has been reported at 91 and 82 percent, respectively, 25 and the accuracy of CT is known to increase when staging advanced tumors. 26 The accuracy of assessing involvement of lymph nodes by TRUS and CT has been reported to be as high as 87 and 70 percent, respectively. 27,28 This is important when quantifying downstaging. Surgeons and pathologists have traditionally assessed downstaging of rectal cancer with regard to T stage and N stage (using the prefix y), but these may be inappropriate parameters. Often a tumor that is Stage T3 or T4 at preoperative CT or TRUS may still be a T3 or T4 tumor after irradiation. However, in some of these tumors, all that remains is a microscopic focus of adenocarcinoma in the subserosa with normal overlying mucosa and intense fibrosis. This tumor has clearly responded well to radiotherapy and may have an improved prognosis compared with T3 tumors that still have macroscopic, transmural disease. In our study, 10 (83 percent) of the 12 patients who had RCRG 1 but still had microscopic foci of adenocarcinoma, and who therefore had a good response to radiotherapy with possibly improved prognosis, still had T3 or T4 tumors at TNM staging. In contrast, a tumor that is Stage T3 or T4 at preoperative CT or TRUS may be downstaged to a T2 tumor after irradiation, yet may have regressed very little and be relatively radioresistant with a poor prognosis (Fig. 1). In our study, 31 cancers remained T3 or T4 after irradiation, yet 10 (32 percent) of these cancers were RCRG 1 and this could have implications for long-term prognosis (Table 5). It should be remembered that although colorectal cancer progresses in a stepwise fashion both genetically 29 and morphologically, 30 radiotherapy does not reverse these changes but instead reduces the number of viable cancer cells (and normal cells) that are in the field of treatment. It would, therefore, seem appropriate to use a pathologic staging system that measures tumor regression of an irradiated rectal cancer, in addition to the yptnm stage. Because it has been shown that postoperative staging remains an important prognostic factor for five-year survival, 31 the RCRG may aid predictions of prognosis in patients such as those with only microscopic foci of remaining adenocarcinoma equating to a Stage T3 tumor. It is significant that after preoperative chemoradiotherapy in esophageal cancer, multivariate analysis showed that only a measurement of tumor regression remained a significant predictor of disease-free survival at three years. 14 However, the utility of RCRG is still to be assessed, and it is therefore a proposed staging system. Until long-term survival figures for our study (and studies of others who have reported im-

Vol. 45, No. 8 RADIOTHERAPY AND RECTAL CANCER REGRESSION 1055 pressive responses to preoperative radiotherapy) are available, it is not possible to make firm conclusions with regard to measurement of tumor regression as a prognostic indicator. The effect of radiotherapy on the tumor and lymph nodes includes several important histologic changes (Table 5) that accompany regression, 32 and these may lead to diagnostic confusion. After long-course radiotherapy, lymph nodes may be shrunken and difficult to find. In our study, we found a mean of 9.3 (range, 0 22) lymph nodes, and this compares poorly with a mean of 19 lymph nodes found in rectal cancer specimens by the same pathologist in cases without preoperative radiotherapy. The mean size of the largest lymph node found was 4 mm, and this compares with 7 mm for rectal cancer specimens that have not been irradiated. In our opinion, the entire scarred area of rectum needs to be blocked and sectioned at several levels before issuing a ypt0 report. Because some lymph nodes may be shrunken and difficult to find, multiple blocks of mesorectal fat should be processed blindly and then examined histologically before issuing a ypn0 report. Mucin pools may be seen, after preoperative radiotherapy, throughout the rectal wall at the site of previous tumor. Sometimes small areas of dysplastic epithelium or crypts will be identified within the mucin pools, whereas in other areas mucin pools will be seen in the absence of any dysplastic epithelium. These mucin pools are, in our opinion, quite different from those of colitis cystica profunda (misplaced epithelium), which may be seen after radiotherapy to previously normal large bowel. In the region of tumor-related mucin pools, they represent areas throughout the bowel wall that were previously occupied by tumor. CONCLUSIONS In our study, significant tumor regression (RCRG 1 2, at least 50 percent reduction in tumor) was seen in 36 patients (86 percent) after chemoradiotherapy. Nineteen patients (46 percent) had good radioresponsiveness (RCRG 1). A pathologic staging system for irradiated rectal cancer, as proposed here and which includes a measurement of tumor regression, when tested against the outcomes of patients with long-term follow-up may reveal which histologic features predict prognosis. Comparisons of RCRG with long-term outcome of patients will allow us to establish the value of regression staging in rectal cancer. REFERENCES 1. Office of Population Censuses and Surveys. Mortality statistics: general review of the registrar-general on deaths in England and Wales 1990. Series DH11: No. 24. London: Her Majesty s Stationery Office, 1992. 2. Karanjia ND, Scache DJ, North WR, Heald RJ. Close shave in anterior resection. Br J Surg 1990;277:510 2. 3. Hurst PA, Prout WG, Kelly JM, Bannister JJ, Walker RT. Local recurrence after low anterior resection using the staple gun. Br J Surg 1982;69:275 6. 4. Marsh PJ, James RD, Schofield PF. Adjuvant preoperative radiotherapy for locally advanced rectal carcinoma: results of a prospective, randomized trial. Dis Colon Rectum 1994;37:1205 14. 5. Anonymous. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Eng J Med 1997;336:980 7. 6. Anonymous. Preoperative short-term radiation therapy in operable rectal carcinoma: a prospective randomized trial. Stockholm Colorectal Cancer Study Group. Cancer 1990;66:49 55. 7. Gerard A, Buyse M, Nordlinger B, et al. Preoperative radiotherapy as adjuvant treatment in rectal cancer: final results of a randomised study of the European Organisation for Research and Treatment of Cancer (EORTC). Ann Surg 1988;208:606 14. 8. Goldberg PA, Nicholls RJ, Porter NH, Love S, Grimsey JE. Long-term results of a randomised trial of shortcourse low-dose adjuvant pre-operative radiotherapy for rectal cancer: reduction in local treatment failure. Eur J Cancer 1994;30:1602 06. 9. Williamson PR, Hellinger MD, Larach SW, Ferrara A. Endorectal ultrasound of T3 and T4 rectal cancers after preoperative chemoradiation. Dis Colon Rectum 1996; 39:45 9. 10. Chari RS, Tyler DS, Anscher MS, et al. Preoperative radiation and chemotherapy in the treatment of adenocarcinoma of the rectum. Ann Surg 1995;221:778 87. 11. Chen ET, Mohiuddin M, Brodovsky H, Fishbein G, Marks G. Downstaging of advanced rectal cancer following combined preoperative chemotherapy and high dose radiation. Int J Radiat Oncol Biol Phys 1994;30: 169 75. 12. Buroker T, Nigro N, Correa J, Vaitkevicius VK, Samson M, Considine B. Combination preoperative radiation and chemotherapy in adenocarcinoma of the rectum. Dis Colon Rectum 1976;19:660 3. 13. Minsky BD, Cohen AM, Kemeny N, et al. Efficacy of preoperative 5-FU, high dose leucovorin, and sequential radiation therapy for unresectable rectal cancer. Cancer 1994;73:273 80. 14. Mandard AM, Dalibard F, Mandard JC, et al. Pathological assessment of tumor regression after preoperative

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