|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 22, No 19 (October 1), 2004: pp. 3958-3964 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.01.023 Clinical Nature and Prognosis of Locally Recurrent Rectal Cancer After Total Mesorectal Excision With or Without Preoperative RadiotherapyFrom the Departments of Medical Decision Making, Surgery, and Radiotherapy, Leiden University Medical Center, Leiden; the Department of Pathology, University Medical Center St Radboud, Nijmegen; the Department of Surgery, Catharina Hospital, Eindhoven; and the Department of Surgical Oncology, Groningen University Hospital, Groningen, the Netherlands Address reprint requests to C.J.H. van de Velde, PhD, MD, Department of Surgery, K6-R, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands; e-mail: C.J.H.van_de_Velde{at}lumc.nl
PURPOSE: To document the clinical nature and prognosis of locally recurrent rectal cancer after total mesorectal excision (TME) with or without 5 x 5 Gy preoperative radiotherapy (PRT) and to identify patient-, disease-, and treatment-related factors associated with differences in prognosis after local recurrence. PATIENTS AND METHODS: For 96 Dutch patients with a local recurrence who participated in a multicenter randomized clinical trial, data on treatments and follow-up were gathered from surgeons and radiation and medical oncologists. Twenty-three patients (24%) had previously been treated with PRT plus TME, and 73 patients (76%) had been treated with TME alone. Eighty-one patients (84%) were followed until death; median follow-up time of the alive patients after local recurrence was 21 months (range, 5 to 48 months).
RESULTS: Survival after local recurrence in the PRT + TME group was significantly shorter than in the TME group (median survival, 6.1 v 15.9 months; hazard ratio for death, 2.1; P = .008). Patients with a local recurrence in the PRT + TME group had distant metastases more often (74% v 40%; P = .004), underwent surgical resection of local recurrence less often (17% v 35%; P = .11), and received radiotherapy for local recurrence at a total dose CONCLUSION: The clinical nature and prognosis of patients with locally recurrent rectal cancer has changed since the introduction of PRT. The majority of patients who present with a local recurrence after previous PRT have simultaneous distant metastases, and median survival has decreased to 6 months.
In patients with rectal cancer, local recurrences are difficult to treat, may cause severe disabling symptoms, and usually have a fatal outcome.1-3 For this reason, the focus has been on the prevention of local recurrences by refining imaging and surgical techniques and by assessing the value of adjuvant preoperative or postoperative treatment modalities.4 Nowadays, total mesorectal excision (TME) is widely accepted as the standard of surgery for patients with primary rectal cancer,5-7 and recently, the additional value of preoperative radiotherapy (PRT) was demonstrated.8 New treatment techniques have not only reduced local recurrence rates8-10 but may also have changed the clinical nature and prognosis of locally recurrent rectal cancer. In previous studies, median survival for locally recurrent rectal cancer after conventional surgery with or without PRT was estimated at 7 to 11 months and 15 to 16 months, respectively.1,2 Suggested explanations for the reduced survival after local recurrence in patients treated with PRT have been that in patients previously treated with PRT, local recurrences may be treated less aggressively, because maximal radiotherapy is no longer possible as part of the multimodality treatment for local recurrence, or that the recurrences arising may be more often associated with distant metastases. However, those hypotheses have not been further investigated, possibly owing to the fact that patients with a local recurrence were retrieved over a long time period, from multiple studies, and with varying treatments, thus hampering unequivocal analyses.1,2 This has led to contrasting viewpoints on the prognosis and treatment of local recurrence. For example, Holm et al2 concluded that attempted curative treatment for local recurrence is an attractive option, because local failure is not inevitably an early manifestation of disseminated disease, whereas Frykholm et al1 concluded that the probability of curative treatment of local recurrence is quite low. The purpose of our study was to document the clinical nature and prognosis of locally recurrent rectal cancer after TME surgery, with or without short-term PRT. In addition, we tried to identify patient-, disease-, and treatment-related factors associated with differences in prognosis.
Study Population Patients were retrieved from the TME trial. The design and results of the TME trial at a median follow-up time of 24 months have been published previously.8 Between January 1996 and December 1999, 1,861 patients with resectable rectal cancer from 84 Dutch hospitals, 23 other European hospitals, and one hospital in Canada were randomly assigned to receive standardized TME surgery with or without short-term PRT (a total dose of 25 Gy in five fractions over 5 to 7 days). Surgery had to be performed within 10 days after the first irradiation. Local recurrence was the primary outcome measure of the TME trial, and all patients were clinically evaluated for local recurrence every 3 months during the first year after surgery and annually thereafter. Local recurrence was defined as radiologic and/or histologic evidence of a tumor within the lesser pelvis or the perineal wound after a macroscopically complete resection. For the purpose of this article, non-Dutch patients (n = 331), ineligible patients (n = 50), and patients without a local resection or with a macroscopically incomplete local resection (n = 46) were excluded, leaving 1,434 patients for the analyses of local recurrence rates. Local recurrence location was categorized according to an adapted version of the subdivision proposed by Philipsen et al11 into recurrences located at the level of the anastomosis or perineum, and pelvic recurrences. Distant recurrences were defined as radiologic and/or histologic evidence of a tumor in any other area. A radiation oncologist checked all reported local and distant recurrences.
Design
Statistical Analyses
Response and Follow-Up At a median follow-up of 43 months, the actuarial rate of local recurrence was 4.1% in the PRT + TME group (n = 719) and 11.5% in the TME group (n = 715; P < .0001; Fig 1). The hazard ratio for local recurrence after PRT + TME was 0.33 (95% CI, 0.21 to 0.53). In the PRT + TME group, 74% and 91% of observed local recurrences had occurred within 2 and 3 years, respectively. In the TME group, 78% and 93% of observed local recurrences had occurred within 2 and 3 years, respectively (P = .98 for the difference between randomization groups).
Of the 96 patients with a local recurrence, 81 patients (84%) were followed until death. For the remaining 15 patients, median time between date of local recurrence and date of last contact was 21 months (range, 5 to 48 months). For 94 patients (98%), we received additional information on treatments after local recurrence from surgeons or radiation or medical oncologists. Surgeons returned information on 88 (92%) of 96 patients, radiation oncologists on 49 (74%) of 66 patients, and medical oncologists on 28 (76%) of 37 patients.
Patient Characteristics
Treatments for Local Recurrence Table 2 lists the treatments for local recurrence. Surgical resection of local recurrence took place more often in the TME group (35%) than in the PRT + TME group (17%), although not significantly so (P = .11). However, patients in the PRT + TME group were significantly more often treated with hyperthermia (P = .02) and chemotherapy (P = .03). Patients in the TME group received radiotherapy treatment for local recurrence at a dose  45 Gy (42%) significantly more often than patients in the PRT + TME group (4%; P = .001).
Despite distant metastases, 11% and 7% of patients underwent a surgical resection of local recurrence and were irradiated at a dose 45 Gy, respectively, compared with 48% and 56% of patients without distant metastases, respectively (all P < .0001). Patients with pelvic recurrences underwent significantly less frequent surgical resection of local recurrence than patients with recurrences located at the anastomosis or perineum only (22% v 46%; P = .02). The difference in radiotherapy treatment at a dose 45 Gy for local recurrence was not statistically significant between patients with and without pelvic recurrences (29% v 40%; P = .27).
Survival
The results of the univariate analyses of survival after local recurrence are shown in Tables 3 and 4. PRT + TME, abdominoperineal resection of the primary tumor, positive circumferential resection margin of the primary tumor, pelvic recurrences, distant metastases diagnosed before and within 1 month of local recurrence diagnosis, no surgical resection of local recurrence, and radiotherapy treatment for local recurrence at a dose less than 45 Gy were all related to a shorter survival after local recurrence diagnosis.
All variables that were univariately related (P < .10) to survival were included in a multivariate Cox regression analysis to investigate whether those variables could explain the observed difference in survival between randomization groups (Table 5). In this analysis, the difference in survival after local recurrence between randomization groups was no longer statistically significant (hazard ratio for death of PRT, 1.53; P = .16). No surgical resection of local recurrence and radiotherapy at a dose less than 45 Gy were associated with shorter survival after local recurrence (P = .06 and P = .001, respectively). Note, however, that the results of this analysis may not be interpreted as evidence of the effect of treatment, because patients with a more favorable prognosis are likely to be selected for treatment.
The purpose of this study was to document the clinical nature and prognosis of locally recurrent rectal cancer after TME surgery with or without short-term 5 x 5 Gy PRT. We extensively followed-up 96 patients with locally recurrent cancer who participated in a large multicenter clinical trial and had been randomly assigned to receive quality-controlled, standardized TME surgery with or without PRT for the primary tumor. Our analyses show that although PRT reduces local recurrence rates and thus may increase overall survival,8,12 patients who do develop a local recurrence after previous PRT have a significantly shorter survival duration than local recurrence patients who have not received PRT for the primary tumor. Median survival after local recurrence has been reduced from 16 months after previous TME surgery without PRT to only 6 months for patients with PRT. There are several possible explanations for this finding. The first explanation concerns the nature of recurrences. PRT may be less effective for patients with unfavorable primary tumor characteristics (eg, positive resection margins, higher primary tumor load), who are more at risk of developing distant metastases.8,13,14 Our results indeed showed that the majority of patients (74%) with a local recurrence after PRT + TME had simultaneous distant metastases, compared with 40% of patients in the TME group. In addition, local recurrences that develop after previous PRT may have different characteristics locally that negatively affect survival. In univariate analyses, the difference in survival after local recurrence between patients with and without PRT was not only associated with differences in distant metastases, but also with differences in circumferential resection margins and recurrence location. Further histopathologic and molecular research of primary tumor and recurrence characteristics is needed to gain more insight into the pathway by which local recurrences develop after PRT.
The second explanation concerns the types of treatments for local recurrences. PRT may limit the possibilities for aggressive treatment of local recurrence (eg, high-dose radiotherapy treatments for local recurrence cannot be given to patients who have previously been irradiated, because of the maximum-tolerated dose). Our results confirm that patients of the PRT group received radiotherapy treatment for local recurrence at a dose A limitation of our study could be that PRT may postpone recurrences and patients with an unfavorable prognosis may present themselves with shorter follow-up. For several reasons, we do not believe that longer follow-up would significantly affect our results. First, median time between TME surgery and local recurrence diagnosis was not significantly different between randomization groups and was also not significantly related to survival after local recurrence diagnosis. Second, we selected local recurrence patients from the TME study at a median follow-up time of 43 months, and the local recurrence curves in both randomization groups were flattening out, suggesting that most of the recurrences have become overt. The high number of patients with simultaneous distant recurrences in the PRT + TME group as compared with the TME-alone group may give rise to the thought that the addition of chemotherapy, either adjuvantly or neoadjuvantly, could have improved the prognosis of patients in the PRT + TME group.25 We believe it is thereby important to distinguish the different purposes of chemotherapy. The main aim of concurrent chemoradiotherapy is radiosensitization, that is to improve local control and attack any micrometastases. Patients who develop a local recurrence despite chemoradiotherapy may have very unfavorable primary tumor characteristics, and we would expect the results for those patients to be at best equal to, but probably worse than, the results in our patients. The main aim of postoperative adjuvant chemotherapy is to prevent distant recurrences in selected groups of patients. For some patients in our study, the addition of postoperative chemotherapy could have prevented or delayed the occurrence of distant metastases, and as a result, we would expect a more favorable prognosis after local recurrence. Note however that a decision on the addition of chemotherapy should be based on the results of chemotherapy in all patients, including the large majority of patients who do not develop a local recurrence. So far, studies that investigate the results of postoperative chemotherapy combined with preoperative short-term radiotherapy have not yet reported their results. In the past, many studies have focused on the development of aggressive treatment modalities for locally recurrent rectal cancer to improve survival and reduce re-recurrence rates. The main rationale for this focus was that 50% to 80% of patients had no manifest distant metastases at the time of local recurrence diagnosis, and that 21% to 50% of patients died without distant metastases, suggesting that there were patients who could be cured and that local recurrence was not inevitably an early manifestation of widespread disease.1-3,15,17-20 The adoption of PRT + TME as the new standard of treatment for patients with rectal cancer calls for reconsideration of this viewpoint. Our results showed that at least 74% of patients with a local recurrence after previous PRT + TME have simultaneous distant metastases. For many patients, aggressive treatment approaches that may also be associated with significant morbidity and mortality16,18-24 may no longer be appropriate. In conclusion, the introduction of PRT has reduced local recurrence rates and may thus increase overall survival, but has also changed the clinical nature and prognosis of those patients who do develop locally recurrent rectal cancer. Median survival after local recurrence has decreased from 16 months without previous PRT to 6 months with previous PRT. The majority of patients who present with a local recurrence after previous PRT have simultaneous distant metastases. Patients with a local recurrence after previous PRT should be meticulously scanned for distant metastases before aggressive treatments for local recurrence are administered.
The authors indicated no potential conflicts of interest.
We thank all investigators of the Dutch Colorectal Cancer Group for their help in the conduct of this study and Truuske de Bock, PhD, from the Department of Clinical Epidemiology, Groningen University Hospital, Groningen, the Netherlands, for her valuable comments to earlier drafts of this article.
Supported by grant No. 97-026 from the Health Care Insurance Board, The Hague, the Netherlands, and by grant No. CKVO 95-04 from the Dutch Cancer Society, Amsterdam, the Netherlands. Presented at the Second Multidisciplinary Colorectal Cancer Congress, Noordwijk, the Netherlands, February 15-17, 2004. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Frykholm GJ, Pahlman L, Glimelius B: Treatment of local recurrences of rectal carcinoma. Radiother Oncol 34:185-194, 1995[CrossRef][Medline] 2. Holm T, Cedermark B, Rutqvist LE: Local recurrence of rectal adenocarcinoma after 'curative' surgery with and without preoperative radiotherapy. Br J Surg 81:452-455, 1994[Medline] 3. Wiggers T, de Vries MR, Veeze-Kuypers B: Surgery for local recurrence of rectal carcinoma. Dis Colon Rectum 39:323-328, 1996[CrossRef][Medline] 4. Wiggers T: Staging of rectal cancer. Br J Surg 90:895-896, 2003[CrossRef][Medline] 5. Enker WE, Thaler HT, Cranor ML, et al: Total mesorectal excision in the operative treatment of carcinoma of the rectum. J Am Coll Surg 181:335-346, 1995[Medline] 6. Heald RJ: Total mesorectal excision is optimal surgery for rectal cancer: A Scandinavian consensus. Br J Surg 82:1297-1299, 1995[CrossRef][Medline] 7. MacFarlane JK, Ryall RD, Heald RJ: Mesorectal excision for rectal cancer. Lancet 341:457-460, 1993[CrossRef][Medline]
8. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638-646, 2001
9. Enker WE: Potency, cure, and local control in the operative treatment of rectal cancer. Arch Surg 127:1396-1401, 1992 10. Heald RJ, Karanjia ND: Results of radical surgery for rectal cancer. World J Surg 16:848-857, 1992[CrossRef][Medline] 11. Philipsen SJ, Heilweil M, Quan SH, et al: Patterns of pelvic recurrence following definitive resections of rectal cancer. Cancer 53:1354-1362, 1984[CrossRef][Medline]
12. van den Brink M, van den Hout WB, Stiggelbout AM, et al: Cost-utility analysis of pre-operative radiotherapy in patients with rectal cancer undergoing total mesorectal excision. J Clin Oncol 22:244-253, 2004 13. Marijnen CA, Nagtegaal ID, Kapiteijn E, et al: Radiotherapy does not compensate for positive resection margins in rectal cancer patients: Report of a multicenter randomized trial. Int J Radiat Oncol Biol Phys 55:1311-1320, 2003[CrossRef][Medline] 14. Nagtegaal ID, Marijnen CA, Kranenbarg EK, et al: Circumferential margin involvement is still an important predictor of local recurrence in rectal carcinoma: Not one millimeter but two millimeters is the limit. Am J Surg Pathol 26:350-357, 2002[CrossRef][Medline] 15. Wong CS, Cummings BJ, Brierley JD, et al: Treatment of locally recurrent rectal carcinoma: Results and prognostic factors. Int J Radiat Oncol Biol Phys 40:427-435, 1998[CrossRef][Medline] 16. Suzuki K, Dozois RR, Devine RM, et al: Curative reoperations for locally recurrent rectal cancer. Dis Colon Rectum 39:730-736, 1996[CrossRef][Medline] 17. Valentini V, Morganti AG, De Franco A, et al: Chemoradiation with or without intraoperative radiation therapy in patients with locally recurrent rectal carcinoma: Prognostic factors and long term outcome. Cancer 86:2612-2624, 1999[CrossRef][Medline] 18. Law WL, Chu KW: Resection of local recurrence of rectal cancer: Results. World J Surg 24:486-490, 2000[CrossRef][Medline] 19. Alektiar KM, Zelefsky MJ, Paty PB, et al: High-dose-rate intraoperative brachytherapy for recurrent colorectal cancer. Int J Radiat Oncol Biol Phys 48:219-226, 2000[CrossRef][Medline] 20. Lopez-Kostner F, Fazio VW, Vignali A, et al: Locally recurrent rectal cancer: Predictors and success of salvage surgery. Dis Colon Rectum 44:173-178, 2001[CrossRef][Medline] 21. Salo JC, Paty PB, Guillem J, et al: Surgical salvage of recurrent rectal carcinoma after curative resection: A 10-year experience. Ann Surg Oncol 6:171-177, 1999[CrossRef][Medline] 22. Garcia-Aguilar J, Cromwell JW, Marra C, et al: Treatment of locally recurrent rectal cancer. Dis Colon Rectum 44:1743-1748, 2001[CrossRef][Medline] 23. Mannaerts GH, Rutten HJ, Martijn H, et al: Comparison of intraoperative radiation therapy-containing multimodality treatment with historical treatment modalities for locally recurrent rectal cancer. Dis Colon Rectum 44:1749-1758, 2001[CrossRef][Medline] 24. Wanebo HJ, Koness RJ, Vezeridis MP, et al: Pelvic resection of recurrent rectal cancer. Ann Surg 220:586-595, 1994[CrossRef][Medline]
25. Gunderson LL, Sargent DJ, Tepper JE, et al: Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: A pooled analysis. J Clin Oncol 22:1785-1796, 2004 Submitted January 7, 2004; accepted June 30, 2004.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
2 statistics were used to compare proportions, and Mann-Whitney U tests were used to compare continuous variables. Kaplan-Meier analyses were used to compare local recurrence rates, distant recurrence rates, and overall survival in patients with locally recurrent rectal cancer between randomization groups. We did not analyze disease-free survival, because in most patients complete removal of the locally recurrent tumor (negative resection margins) was not achieved. Cox proportional hazards analyses were used to calculate hazard ratios and 95% CIs. Data on patients who were alive were censored at date of last contact. Because the aim of the study was to document the clinical nature and prognosis of locally recurrent rectal cancer, the starting point for all survival analyses was the date of local recurrence diagnosis. 
