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Preoperative chemoradiation for rectal cancer: results of multimodality management and analysis of prognostic factors
The American Journal of Surgery 193 (2007) 389 –394
Preoperative chemoradiation for rectal cancer: results of multimodality management and analysis of prognostic factors Anand T. Shivnani, M.D.a, William Small Jr, M.D.a, Steven J. Stryker, M.D.b, Krystyna D. Kiel, M.D.a, Sherry Lim, M.D.b, Amy L. Halverson, M.D.b, Mark S. Talamonti, M.D.b,* a
b
Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Division of Surgical Oncology, Northwestern University Feinberg School of Medicine, 201 E. Huron, Galter 10-105, Chicago, IL 60611, USA Manuscript received August 12, 2006; revised manuscript September 20, 2006 Presented at the 49th Annual Meeting of the Midwest Surgical Association, Mackinac Island, MI, August 6 –9, 2006
Abstract Background: Our goals were to examine the impact of neoadjuvant chemoradiation for rectal cancer on surgical outcomes and to determine prognostic factors predicting improved survival. Methods: Retrospective cohort of 56 male and 44 female patients. Results: After preoperative chemoradiation, 73% of patients had sphincter-preserving surgery. The 5-year disease-free (DFS) and overall survival rates were 77% and 81%, respectively. Twenty-five percent of patients showed a complete pathologic response. T-level downstaging and pathologic T stage did not correlate with recurrence or survival rates. Pathologic nodal stage was associated with a significant difference in recurrence rates (N0 19%, N1 20%, and N2 75%, P ⫽ .038) and DFS (N0/N1 vs. N2, 79% vs. 25%, P ⫽ .002). Conclusion: Neoadjuvant chemoradiation resulted in a high rate of sphincter preservation. Complete pathologic responses after surgery were frequent and although pathologic T stage after surgery did not affect recurrence rates, pathologic nodal response was associated with improved recurrence and survival rates. © 2007 Excerpta Medica Inc. All rights reserved. Keywords: Neoadjuvant chemoradiation; Rectal cancer; Rectal surgery
Despite improvements in screening protocols, surgical techniques, and adjuvant therapy, carcinoma of the rectum remains one of the leading causes of cancer-related morbidity and deaths in the United States. It is estimated that approximately 40,000 patients will be diagnosed with rectal cancer in 2006, and the management of these patients is focused both on long-term cure as well as sphincter-preservation [1]. Treatment of patients with this malignancy continues to present multiple challenges for the gastrointestinal surgeon. Controversies exist with regard to the selection of patients with low rectal cancers for sphincter-preserving operations and the role of extended mesorectal lymph node dissections. Neoadjuvant chemoradiation for locally advanced rectal cancer is widely accepted as the standard treatment, despite the lack of convincing data from random* Corresponding author. Tel.: ⫹1-312-695-2534; fax: ⫹1-312-695-1462. E-mail address: [email protected]
ized clinical trials. Reported rates of sphincter preservation after neoadjuvant chemoradiation vary widely, and the impact of treatment response on survival is highly controversial. Previous reports have attempted to identify clinical and pathologic factors associated with risk for recurrence after neoadjuvant therapy. These studies have had conflicting results in terms of identifying independent prognostic predictors of survival. The goals of this study were to examine the impact of preoperative treatment on surgical morbidity, mortality, and its effect on the ability to perform sphincterpreserving operations. We also sought to identify factors that affect disease-free survival (DFS) and overall survival (OS) in patients receiving multimodality therapy for rectal carcinoma. Methods The medical records of 152 patients who were diagnosed and treated for rectal adenocarcinoma at Northwestern Me-
0002-9610/07/$ – see front matter © 2007 Excerpta Medica Inc. All rights reserved. doi:10.1016/j.amjsurg.2006.09.030
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A.T. Shivnani et al. / The American Journal of Surgery 193 (2007) 389 –394
morial Hospital were reviewed. We excluded all cases with incomplete records or incomplete follow-up. Patients undergoing palliative resections for stage IV disease were also excluded from the analysis. Patients referred for surgical therapy but who did not receive their preoperative therapy at Northwestern were not included in the overall analysis. Thus, the final study population comprised 100 patients who were treated for rectal cancer between 1992 and 2002. Pretreatment clinical staging was performed by using a combination of physical examination, cross-sectional imaging with either computed tomography or magnetic resonance imaging scan and endoscopic ultrasound. Indications for neoadjuvant therapy were full-thickness tumors (T3) and/or node-positive disease. All patients received 5-fluorouracil (r-FU)-based chemoradiation with the majority of patients receiving a total dose of 5,040 cGy of pelvic irradiation. Radiotherapy usually began the first day of chemotherapy and was administered 5 times per week with a daily fraction of 180 cGy. Patients were treated with megavoltage radiation using 3- or 4-field techniques. Occasionally, additional fields were used to cover inguinal nodes because of tumor proximity to the anal verge. The initial pelvis field was treated to a median dose of 4,500 cGy (range, 3,960 – 5,040 cGy). Most patients received a boost for a median total dose of 5,040 cGy (range, 3,960 – 6,140 cGy). Patients received either concurrent low-dose continuous infusional 5-FU (88%) or bolus 5-FU (12%) during radiation. Postoperative chemotherapy was not routinely given within the timeframe of this analysis. Surgical treatment was performed 4 to 8 weeks after the completion of neoadjuvant chemoradiation. Pathologic staging of the patients was performed according to the postoperative pathology report by using the standard tumor-node metastasis system. Standard demographic data gathered from the medical records included age, race, and sex. Operative reports were reviewed for type of resection and anastomosis performed and extent of lymph node dissection. For the purpose of this study, curative resection was defined as resection of all gross disease with no evidence of distant metastases and negative histological resection margins. All histopathologic slides were reviewed by a single pathologist to confirm the diagnosis of adenocarcinoma and to ensure consistent and accurate classification of several pathologic variables. These variables included tumor location and grade, extent of residual primary tumor after neoadjuvant therapy, and number of positive lymph nodes. Outcome measures included disease-free survival and overall survival. Diseasefree survival was calculated from the time chemoradiation started to first documented recurrence. Overall survival was calculated from the time chemoradiation started to either death or most recent contact. Statistical analysis was performed by using SAS (version 9.0; SAS, Cary, NC). Survival within groups was analyzed by means of the KaplanMeier method with differences compared by use of log-rank tests [2]. Variables shown to be of statistical significance in univariate survival analysis were further assessed by Cox multivariate analysis [3]. OS and DFS medians were presented with 95% confidence intervals. Results from the proportional hazards models were summarized by giving hazard ratios along with 95% confidence intervals.
Table 1 Clinical and pathologic characteristics (n ⫽ 100) Variable
Data
Median age, y (range) Sex (male/female) Presenting symptoms (%) Rectal bleeding Change in bowel habits Weight loss Asymptomatic Tumor location Distal rectum Middle rectum Proximal rectum Tumor differentiation Well differentiated Moderately well differentiated Poorly differentiated Pretreatment clinical stage T1 T2 T3 T4 N0 N1 N2 Operative procedures Proctocolectomy with coloanal anastomosis Low anterior resection with colorectal anastomosis Abdomino-perineal resection Total proctocolectomy with J-pouch ileoanal anastomosis Postoperative pathologic stage T0 T1 T2 T3 N0 N1 N2
61 years (24–86 y) 56/44 84 57 17 8 64 33 3 8 81 11 1 16 80 3 47 41 12 38 33 27 2 25 40 16 19 72 22 6
Differences at P ⬍ .05 were considered statistically significant. Results Clinical presentation The study group included 56 male and 44 female patients (Table 1). The median age of the patients was 61 years (range, 24 – 86 years). The most common symptoms were rectal bleeding (84%), followed by change in bowel movements (57%) and weight loss (17%). More than 50% of patients had more than 1 symptom. Tumor location was defined by the distal most location of visible tumor. Distal, middle, and proximal rectum were defined at 0 to 8 cm, 8 to 12 cm, and 12 to 16 cm from the anal verge, respectively, based on proctoscopic examination performed by the treating surgeon. Tumor location was low rectal 64%, midrectal 33%, and upper rectum 3%. Pretreatment T stage and N stage are listed in Table 1. Pretreatment clinical staging showed T3 lesions in 80% and N-positive disease in 53%.
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391
Surgical management The median interval from the end of radiation therapy to surgery was 56 days (range, 22–103 days). Sphincter-preserving procedures were accomplished in 73% of patients (Table 1). The most common surgical procedure was proctocolectomy with coloanal anastomosis (38%), followed by low anterior resection (33%), abdominal-perineal resection (27%), and total proctocolectomy with J-pouch ileoanal anastomosis (2%). Three patients were found to have metastatic disease during operative exploration and underwent complete resection of their metastatic disease. The median postoperative length of stay was 10 days (range, 6 – 45 days). Histopathologic features Anatomic distribution and pathologic features of the tumors are listed in Table 1. At the time of initial biopsy, most tumors were moderately well differentiated (81%), followed by poorly differentiated tumors (11%) and well-differentiated tumors (8%). Twenty-five patients (25%) had a pathologic complete response (CR), 15% had only microscopic disease, and 60% had gross residual disease. Postoperative T stage and N stage are listed in Table 1. Outcomes During the preoperative phase of therapy, 25% of patients developed either grade III or IV gastrointestinal toxicity. The surgical complication rate was 22%, and the perioperative mortality rate was 1%. Complications included intra-abdominal abscess formation (11%), anastomotic leak (8%), enterocutaneous fistula (5%), perineal wound breakdown (2%), and urethral injury (2%). There was 1 deep vein thrombosis requiring anticoagulation and 1 abdominal fascial dehiscence. With a median follow-up of 52.4 months, 22 patients (22%) have developed a documented recurrence with a median time to recurrence of 19.1 months (range, 3– 88 months). Of these patients with recurrent disease, 17 (77%) have recurred with distant metastases and 5 (23%) have recurred locally within the pelvis. None of the patients with a pathologic CR or microscopic residual disease have developed a local or regional recurrence. The 5-year DFS and
Fig. 1. Overall survival after multimodality therapy (n ⫽ 100). The median overall survival in all patients was 120 months (solid line) (95% confidence intervals, dotted lines).
Fig. 2. Disease-free survival after multimodality therapy (n ⫽ 100). The median disease-free survival in all patients was 102 months (solid line) (95% confidence intervals months, dotted lines).
OS rates for the entire cohort were 77% and 81%, respectively (Figs. 1 and 2). The 5-year DFS was 89% for patients who had a pathologic complete response, 77% for those with any microscopic disease, and 75% for those patients with gross residual disease (P ⫽ .62). In patients with a pathologic CR, 5-year OS was 91.3%, whereas patients with either microscopic or gross residual disease had a 5-year OS of 79.5% (P ⫽ .59). Prognostic factors Prognostic factors analyzed for effect on survival included age, tumor location, tumor grade, preoperative clinical stage, pathologic T stage, and pathologic N stage. In univariate analysis, no variables were significantly associated with OS (Table 2). No significant differences in DFS Table 2 Hazard ratios for overall survival and disease-free survival (n ⫽ 100) Predictor Overall survival (univariate analysis) Age Tumor location Tumor grade Pretreatment clinical stage Pathologic T stage Pathologic N stage Disease-free survival (univariate analysis) Age Tumor location Tumor grade Pretreatment clinical stage Pathologic T stage Pathologic N stage Disease-free survival (multivariate analysis) Pathologic T status Pathologic N status CI, confidence interval.
Hazard ratio (95% CI)
P value
1.048 (1.001–1.097) 0.845 (0.678–1.053) 0.989 (0.868–1.127) 1.087 (0.300–3.946) 1.400 (0.800–2.500) 1.610 (1.100–2.220)
0.82 0.57 0.63 0.72 0.08 0.06
1.001 (0.961–1.004) 0.981 (0.856–1.123) 1.008 (0.952–1.066) 1.106 (0.361–5.477) 1.706 (0.902–2.554) 2.043 (1.201–4.861)
0.95 0.78 0.80 0.62 0.06 0.04
1.710 (0.822–2.555) 2.216 (1.110–4.429)
0.18 0.02
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Fig. 3. Disease-free survival by pathologic nodal status.
and OS were seen between any clinical or pretreatment staging variables. T-level down staging, and pathologic T stage after neoadjuvant therapy and surgery did not correlate with recurrence or survival rates; however, pathologic nodal stage was associated with a significant difference in recurrence rates (N0, 19%; N1, 20%; N2, 75%; P ⫽ .038) and 5-year DFS (N0/N1 vs. N2; 79% vs. 25%, P ⫽ .002; Fig. 3). Comments Theoretical advantages for neoadjuvant chemoradiation include a well-defined tumor target with an intact tumor oxygen supply that may maximize tumor response rates, the absence of adhesions and postoperative surgical changes that may minimize radiation-related small bowel toxicity, and patients with distal rectal cancers might experience significant enough tumor reduction to facilitate resection of the distal rectum and preservation of the anal sphincter. Finally, the ability to measure treatment response could theoretically have prognostic value and implications for subsequent postoperative treatment recommendations. Potential disadvantages have been thought to include a possible increase in postoperative complications and mortality with a questionable effect on OS. Therefore, the goals of this study were to examine the impact of preoperative treatment on surgical outcomes and to determine prognostic factors predicting improved survival rates. In the current series, the complication rate (22%) and the perioperative mortality rate (1%) were comparable to previous series using neoadjuvant chemoradiation. Onaitis et al. [4] from Duke University Medical Center reported a postoperative complication rate of 22% in 141 patients treated with similar 5-FU– based chemoradiation protocols. Most recent large, single-institutional experiences report complication rates between 20% and 30% with operative mortality less than 3% [4 –10]. The largest multi-institutional trial of preoperative versus postoperative chemoradiation for rectal cancer performed by the German Rectal Cancer Study Group and reported by Sauer et al [11] noted a 36% complication rate in the preoperative treatment group compared with 34% in the postoperative treatment group. Operative mortality in the preoperative group was 0.7%. We
believe the lack of significant anastomotic leaks with major pelvic sepsis in the current series was at least partially because of the standardization and utilization of radical rectal resection with total mesorectal lymph node dissection and low anastomosis, usually with a coloanal technique and diverting ileostomy. We also attribute this evolving expertise for the increase in sphincter-preserving operations during the timeframe of this study. Whether the rate of sphincter preservation (73%) in the current series could be attributable to either the increasing use of coloanal anastomosis or the significant response of the primary tumor and downstaging to a sphincter-preserving operation is difficult to discern. Nonetheless, sphincter-preserving operations were performed in 63% of patients recently reported by Crane et al [5] from the MD Anderson Cancer Center, and Onaitis et al [4] have shown a progressive increase in the percentage of sphincter-sparing procedures from 20% before 1996 to 76% after 1996. This was again attributed to the increasing utilization of ultralow anastomosis, most protected by a temporary diverting ileostomy. The impact of pathologic downstaging on performing sphincter-preserving operations is difficult to determine in retrospective reviews. In the prospective study noted earlier by Sauer et al [11], the ability to perform sphincter-preserving surgery was thought to be markedly increased after chemoradiation. After restaging and at the time of surgery, a sphincter-preserving operation could be performed in 39% of those patients in which abdominoperineal resection was initially deemed necessary. The second objective of our study was to identify predictive factors for DFS and OS. Probably no other topic in the management of patients with rectal cancer is as controversial as the impact of treatment response on survival after neoadjuvant chemoradiation. That a significant treatment response (25% complete pathologic response rate) was seen in the current series was not unexpected based on results of previous reports [4,6 –10]. Onaitis et al [4] reported a complete response rate of 24% and significant pathologic downstaging in 80% of their patients. Similar to our series, there were no clinical or treatment variables that significantly affected OS rates. Postoperative tumor downstaging did not have a significant impact on local recurrence, DFS, or OS. On multivariate analysis, only the pathologic nodal stage independently predicted OS. Janjan et al [7] from the MD Anderson Cancer Center reported an updated experience of 117 patients treated with preoperative chemoradiation for locally advanced rectal cancer. They graded the extent of downstaging and then examined the extent of treatment response as a predictor of local recurrence, DFS, and OS. A complete response was seen in 27% of patients, and tumor downstaging occurred in 62% of cases. The level of response (complete response vs. downstaging vs. no response) had statistically significant impact on both DFS and distant metastatic-free survival. When any response to chemoradiation occurred, the distant metastatic-free survival was 44 months as compared with 37 months if there was no pathologic evidence of response to preoperative therapy. Unclear in this study were the relative effects of tumor downstaging compared with nodal downstaging. Guillem et al [10] from Memorial Sloan Kettering Cancer Center reported the largest single-institution analysis of long-term follow-up in pa-
A.T. Shivnani et al. / The American Journal of Surgery 193 (2007) 389 –394
tients with locally advanced rectal cancer treated with preoperative chemoradiation. In their review of 297 patients treated with 5-FU– based chemoradiation, the estimated 10-year OS rate was 58% and 10-year recurrence-free survival was 62%. Importantly, these authors emphasized the necessity for longer follow-up (⬎5 years) to determine truly significant predictors of outcomes in patients treated in this fashion. A potential limitation of the current series and other retrospective reviews is a relatively shorter follow-up time. In studies designed to address long-term follow-up with median follow-ups of greater than 5 years, other pathologic variables may be shown to affect OS. With a median follow-up of 69 months, Ruo et al [8] reported a 5-year relapse-free survival rate of 79%. Relapse was significantly worse for patients with aggressive pathologic features and positive nodal status. Five-year relapse-free survival for patients with node positive cancer was significantly worse (53% vs. 89%, P ⬍ .03) than for those with node-negative disease. Prognostic factors were also evaluated in the German Intergroup trial comparing preoperative and postoperative chemoradiation. Among the 406 patients in the preoperative chemoradiation arm, pathologic T stage, pathologic N stage, grade, lymphatic invasion, and extent of tumor regression significantly predicted for DFS on univariate analysis. On multivariate analysis, pathologic N stage significantly predicted for relapse-free survival, and pathologic T and N stages significantly predicted for DFS and metastasis-free survival. All of these studies point to at least some impact of treatment response on survival after neoadjuvant chemoradiation, and, on multivariate analysis, extent of residual nodal disease and pathologic N stage after treatment is a consistent and strong predictor of survival rates. In conclusion, neoadjuvant chemoradiation for rectal cancer resulted in a high rate of sphincter preservation with acceptable morbidity and mortality rates. Local recurrence was seen in only 5% of our patients. Complete pathologic responses after surgery were frequent and, although the pathologic T stage after surgery, in our experience, did not affect recurrence rates, a complete pathologic nodal response was associated with improved recurrence and disease-free survival rates. This finding may have implications for subsequent postoperative treatment recommendations. References [1] Colorectal Cancer Facts and Figures—Special Edition 2005. American Cancer Society. Available at: http://www.cancer.org/downloads/ STT/CAFF2005CR4PWSecured.pdf. Accessed February 24, 2005. [2] Kaplan E, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457– 81. [3] Cox DR. Regression models and life tables. J R Stat Soc 1972;34: 187–220. [4] Onaitis MW, Noone RB, Hartwig M, et al. Neoadjuvant chemoradiation for rectal cancer: analysis of clinical outcomes from a 13-year institutional experience. Ann Surg 2001;233:778 – 85. [5] Crane CH, Skibber JM, Feig BW, et al. Response to preoperative chemoradiation increases the use of sphincter-preserving surgery in patients with locally advanced low rectal carcinoma. Cancer 2003; 97:517–24. [6] Das P, Skibber JM, Rodriguez-Bigas MA, et al. Clinical and pathologic predictors of locoregional recurrence, distant metastasis, and overall survival in patients treated with chemoradiation and mesorectal excision for rectal cancer. Am J Clin Oncol 2006;29:219 –24.
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[7] Janjan NA, Crane C, Feig BW, et al. Improved overall survival among responders to preoperative chemoradiation for locally advanced rectal cancer. Am J Clin Oncol 2001;24:107–12. [8] Ruo L, Tickoo S, Klimstra DS, et al. Long-term prognostic significance of extent of rectal cancer response to preoperative radiation and chemotherapy. Ann Surg 2002;236:75– 81. [9] Rullier E, Goffre B, Bonnel C, et al. Preoperative radiochemotherapy and sphincter-saving resection for T3 carcinomas of the lower third of the rectum. Ann Surg 2001;234:633– 40. [10] Guillem JG, Chessin DB, Cohen AM, et al. Long-term oncologic outcome following preoperative combined modality therapy and total mesorectal excision of locally advanced rectal cancer. Ann Surg 2005;241:829 –37. [11] Sauer R, Becker H, Hohenberger W. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351: 1731– 40.
Discussion Anthony J. Senagore, M.D. (Toledo, OH): You suggested a postoperative N0 status confers a survival advantage. Do you have any data on the distribution of those patients with respect to their preoperative nodal staging by ultrasound or by some other modality, and are there patients that were felt to be positive on ultrasound that ultimately proved to be negative postoperatively? Numbers of nodes has become a quality measure by CMS and a variety of insurance companies. Do you have any guidance for us regarding the number of nodes per patient after chemoradiotherapy? Were there patients that were deemed N0 simply because no nodes could be found in the specimen? There is a common impression among our radiotherapy colleagues that they are responsible for the increased rate of sphincter presentation. Your results are more circumspect, however, regarding that conclusion. Does your group use the preradiotherapy distal margin of the tumor when planning the surgical procedure or the postradiotherapy intraoperative assessment of the distal margin to decide whether or not you will do a restorative proctocolectomy? Mark S. Talamonti, M.D. (Chicago, IL): In terms of the postoperative N0 status, we did see on multivariate analysis a statistically significant improvement in disease-free survival, although not in overall survival. Forty-seven percent of the patients were thought to be N0 or node negative before their treatment. Those patients received chemoradiation because of what we thought were full-thickness tumors. Our indications for adjuvant chemotherapy are T3, T4, or any evidence of node positivity. Postoperatively, 72% of the patients were deemed as N0 patients, so there was 25% gain in nodal negativity after chemotherapy and radiation. The problem is there is no way to know who is going to be that responder. There were no variables that we could decide on. But, clearly, 25% of the patients ended up that way. Being able to assure the quality of the operation by the amount of lymph nodes that are resected, no doubt that is now a mandate in colon surgery. It becomes a very complicated issue when you talk about rectal surgery or esophageal surgery or any of these operations in which the patients get chemotherapy and radiation. Although primary tumors will shrink, you will do a great job of eradicating nodal disease in many of these patients. In terms of the number of nodes
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that assure quality resection after chemoradiation, I think that number is still unknown. You asked if there were patients that were deemed N0 because no lymph nodes could be found on their final pathology report. As I said, 72% of the patients were node negative on their final pathology report, and, of those 72 patients, 22 had no evidence of any lymph nodes left in the specimen. The radiation therapy delivered in 1992 was pretty similar to the radiation delivered in 2002. What changed was the increase in performance of coloanal resections and coloanal anastomoses. I think that had as much, if not more, to do with the increasing rate of sphincter preservation. Our indications for coloanal resection are any rectal cancer in which it does not invade the anal sphincters on preoperative endoscopic ultrasound, and we will use the final treatment margin in determining whether or not we will perform that operation. When these studies first started, many of the decisions regarding AP resection versus restorative proctocolectomy had to do with the pretreatment margin, and we have just seen too good of responses without invasion of the anal
sphincters to obligate all of those patients to an AP resection. The fact that our recurrence rate was only 5% is good data to support that approach. John P. Hoffman, M.D. (Philadelphia, PA): I wondered if you had looked at those patients who were complete pathologic responders, whether or not their survival was significantly better stage for stage than those who did not have complete pathologic responses. For those with the recurrent tumors locally, were those patients with very low tumors with close margins? Mark S. Talamonti, M.D. (Chicago, IL): The extent of pathologic response did correlate with survival, and the complete pathologic responders had a better overall survival rate and disease-free survival rate. Patients who had local recurrences in the pelvis were not necessarily the patients who started out with the lowest most distal rectal cancers. They were, however, the patients who had significant residual nodal disease. It was nodal disease and bulk of tumor to start with, rather than distal margin that predicted local recurrence.
Preoperative chemoradiation for rectal cancer: results of multimodality management and analysis of prognostic factors Anand T. Shivnani, M.D.a, William Small Jr, M.D.a, Steven J. Stryker, M.D.b, Krystyna D. Kiel, M.D.a, Sherry Lim, M.D.b, Amy L. Halverson, M.D.b, Mark S. Talamonti, M.D.b,* a
b
Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Division of Surgical Oncology, Northwestern University Feinberg School of Medicine, 201 E. Huron, Galter 10-105, Chicago, IL 60611, USA Manuscript received August 12, 2006; revised manuscript September 20, 2006 Presented at the 49th Annual Meeting of the Midwest Surgical Association, Mackinac Island, MI, August 6 –9, 2006
Abstract Background: Our goals were to examine the impact of neoadjuvant chemoradiation for rectal cancer on surgical outcomes and to determine prognostic factors predicting improved survival. Methods: Retrospective cohort of 56 male and 44 female patients. Results: After preoperative chemoradiation, 73% of patients had sphincter-preserving surgery. The 5-year disease-free (DFS) and overall survival rates were 77% and 81%, respectively. Twenty-five percent of patients showed a complete pathologic response. T-level downstaging and pathologic T stage did not correlate with recurrence or survival rates. Pathologic nodal stage was associated with a significant difference in recurrence rates (N0 19%, N1 20%, and N2 75%, P ⫽ .038) and DFS (N0/N1 vs. N2, 79% vs. 25%, P ⫽ .002). Conclusion: Neoadjuvant chemoradiation resulted in a high rate of sphincter preservation. Complete pathologic responses after surgery were frequent and although pathologic T stage after surgery did not affect recurrence rates, pathologic nodal response was associated with improved recurrence and survival rates. © 2007 Excerpta Medica Inc. All rights reserved. Keywords: Neoadjuvant chemoradiation; Rectal cancer; Rectal surgery
Despite improvements in screening protocols, surgical techniques, and adjuvant therapy, carcinoma of the rectum remains one of the leading causes of cancer-related morbidity and deaths in the United States. It is estimated that approximately 40,000 patients will be diagnosed with rectal cancer in 2006, and the management of these patients is focused both on long-term cure as well as sphincter-preservation [1]. Treatment of patients with this malignancy continues to present multiple challenges for the gastrointestinal surgeon. Controversies exist with regard to the selection of patients with low rectal cancers for sphincter-preserving operations and the role of extended mesorectal lymph node dissections. Neoadjuvant chemoradiation for locally advanced rectal cancer is widely accepted as the standard treatment, despite the lack of convincing data from random* Corresponding author. Tel.: ⫹1-312-695-2534; fax: ⫹1-312-695-1462. E-mail address: [email protected]
ized clinical trials. Reported rates of sphincter preservation after neoadjuvant chemoradiation vary widely, and the impact of treatment response on survival is highly controversial. Previous reports have attempted to identify clinical and pathologic factors associated with risk for recurrence after neoadjuvant therapy. These studies have had conflicting results in terms of identifying independent prognostic predictors of survival. The goals of this study were to examine the impact of preoperative treatment on surgical morbidity, mortality, and its effect on the ability to perform sphincterpreserving operations. We also sought to identify factors that affect disease-free survival (DFS) and overall survival (OS) in patients receiving multimodality therapy for rectal carcinoma. Methods The medical records of 152 patients who were diagnosed and treated for rectal adenocarcinoma at Northwestern Me-
0002-9610/07/$ – see front matter © 2007 Excerpta Medica Inc. All rights reserved. doi:10.1016/j.amjsurg.2006.09.030
390
A.T. Shivnani et al. / The American Journal of Surgery 193 (2007) 389 –394
morial Hospital were reviewed. We excluded all cases with incomplete records or incomplete follow-up. Patients undergoing palliative resections for stage IV disease were also excluded from the analysis. Patients referred for surgical therapy but who did not receive their preoperative therapy at Northwestern were not included in the overall analysis. Thus, the final study population comprised 100 patients who were treated for rectal cancer between 1992 and 2002. Pretreatment clinical staging was performed by using a combination of physical examination, cross-sectional imaging with either computed tomography or magnetic resonance imaging scan and endoscopic ultrasound. Indications for neoadjuvant therapy were full-thickness tumors (T3) and/or node-positive disease. All patients received 5-fluorouracil (r-FU)-based chemoradiation with the majority of patients receiving a total dose of 5,040 cGy of pelvic irradiation. Radiotherapy usually began the first day of chemotherapy and was administered 5 times per week with a daily fraction of 180 cGy. Patients were treated with megavoltage radiation using 3- or 4-field techniques. Occasionally, additional fields were used to cover inguinal nodes because of tumor proximity to the anal verge. The initial pelvis field was treated to a median dose of 4,500 cGy (range, 3,960 – 5,040 cGy). Most patients received a boost for a median total dose of 5,040 cGy (range, 3,960 – 6,140 cGy). Patients received either concurrent low-dose continuous infusional 5-FU (88%) or bolus 5-FU (12%) during radiation. Postoperative chemotherapy was not routinely given within the timeframe of this analysis. Surgical treatment was performed 4 to 8 weeks after the completion of neoadjuvant chemoradiation. Pathologic staging of the patients was performed according to the postoperative pathology report by using the standard tumor-node metastasis system. Standard demographic data gathered from the medical records included age, race, and sex. Operative reports were reviewed for type of resection and anastomosis performed and extent of lymph node dissection. For the purpose of this study, curative resection was defined as resection of all gross disease with no evidence of distant metastases and negative histological resection margins. All histopathologic slides were reviewed by a single pathologist to confirm the diagnosis of adenocarcinoma and to ensure consistent and accurate classification of several pathologic variables. These variables included tumor location and grade, extent of residual primary tumor after neoadjuvant therapy, and number of positive lymph nodes. Outcome measures included disease-free survival and overall survival. Diseasefree survival was calculated from the time chemoradiation started to first documented recurrence. Overall survival was calculated from the time chemoradiation started to either death or most recent contact. Statistical analysis was performed by using SAS (version 9.0; SAS, Cary, NC). Survival within groups was analyzed by means of the KaplanMeier method with differences compared by use of log-rank tests [2]. Variables shown to be of statistical significance in univariate survival analysis were further assessed by Cox multivariate analysis [3]. OS and DFS medians were presented with 95% confidence intervals. Results from the proportional hazards models were summarized by giving hazard ratios along with 95% confidence intervals.
Table 1 Clinical and pathologic characteristics (n ⫽ 100) Variable
Data
Median age, y (range) Sex (male/female) Presenting symptoms (%) Rectal bleeding Change in bowel habits Weight loss Asymptomatic Tumor location Distal rectum Middle rectum Proximal rectum Tumor differentiation Well differentiated Moderately well differentiated Poorly differentiated Pretreatment clinical stage T1 T2 T3 T4 N0 N1 N2 Operative procedures Proctocolectomy with coloanal anastomosis Low anterior resection with colorectal anastomosis Abdomino-perineal resection Total proctocolectomy with J-pouch ileoanal anastomosis Postoperative pathologic stage T0 T1 T2 T3 N0 N1 N2
61 years (24–86 y) 56/44 84 57 17 8 64 33 3 8 81 11 1 16 80 3 47 41 12 38 33 27 2 25 40 16 19 72 22 6
Differences at P ⬍ .05 were considered statistically significant. Results Clinical presentation The study group included 56 male and 44 female patients (Table 1). The median age of the patients was 61 years (range, 24 – 86 years). The most common symptoms were rectal bleeding (84%), followed by change in bowel movements (57%) and weight loss (17%). More than 50% of patients had more than 1 symptom. Tumor location was defined by the distal most location of visible tumor. Distal, middle, and proximal rectum were defined at 0 to 8 cm, 8 to 12 cm, and 12 to 16 cm from the anal verge, respectively, based on proctoscopic examination performed by the treating surgeon. Tumor location was low rectal 64%, midrectal 33%, and upper rectum 3%. Pretreatment T stage and N stage are listed in Table 1. Pretreatment clinical staging showed T3 lesions in 80% and N-positive disease in 53%.
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Surgical management The median interval from the end of radiation therapy to surgery was 56 days (range, 22–103 days). Sphincter-preserving procedures were accomplished in 73% of patients (Table 1). The most common surgical procedure was proctocolectomy with coloanal anastomosis (38%), followed by low anterior resection (33%), abdominal-perineal resection (27%), and total proctocolectomy with J-pouch ileoanal anastomosis (2%). Three patients were found to have metastatic disease during operative exploration and underwent complete resection of their metastatic disease. The median postoperative length of stay was 10 days (range, 6 – 45 days). Histopathologic features Anatomic distribution and pathologic features of the tumors are listed in Table 1. At the time of initial biopsy, most tumors were moderately well differentiated (81%), followed by poorly differentiated tumors (11%) and well-differentiated tumors (8%). Twenty-five patients (25%) had a pathologic complete response (CR), 15% had only microscopic disease, and 60% had gross residual disease. Postoperative T stage and N stage are listed in Table 1. Outcomes During the preoperative phase of therapy, 25% of patients developed either grade III or IV gastrointestinal toxicity. The surgical complication rate was 22%, and the perioperative mortality rate was 1%. Complications included intra-abdominal abscess formation (11%), anastomotic leak (8%), enterocutaneous fistula (5%), perineal wound breakdown (2%), and urethral injury (2%). There was 1 deep vein thrombosis requiring anticoagulation and 1 abdominal fascial dehiscence. With a median follow-up of 52.4 months, 22 patients (22%) have developed a documented recurrence with a median time to recurrence of 19.1 months (range, 3– 88 months). Of these patients with recurrent disease, 17 (77%) have recurred with distant metastases and 5 (23%) have recurred locally within the pelvis. None of the patients with a pathologic CR or microscopic residual disease have developed a local or regional recurrence. The 5-year DFS and
Fig. 1. Overall survival after multimodality therapy (n ⫽ 100). The median overall survival in all patients was 120 months (solid line) (95% confidence intervals, dotted lines).
Fig. 2. Disease-free survival after multimodality therapy (n ⫽ 100). The median disease-free survival in all patients was 102 months (solid line) (95% confidence intervals months, dotted lines).
OS rates for the entire cohort were 77% and 81%, respectively (Figs. 1 and 2). The 5-year DFS was 89% for patients who had a pathologic complete response, 77% for those with any microscopic disease, and 75% for those patients with gross residual disease (P ⫽ .62). In patients with a pathologic CR, 5-year OS was 91.3%, whereas patients with either microscopic or gross residual disease had a 5-year OS of 79.5% (P ⫽ .59). Prognostic factors Prognostic factors analyzed for effect on survival included age, tumor location, tumor grade, preoperative clinical stage, pathologic T stage, and pathologic N stage. In univariate analysis, no variables were significantly associated with OS (Table 2). No significant differences in DFS Table 2 Hazard ratios for overall survival and disease-free survival (n ⫽ 100) Predictor Overall survival (univariate analysis) Age Tumor location Tumor grade Pretreatment clinical stage Pathologic T stage Pathologic N stage Disease-free survival (univariate analysis) Age Tumor location Tumor grade Pretreatment clinical stage Pathologic T stage Pathologic N stage Disease-free survival (multivariate analysis) Pathologic T status Pathologic N status CI, confidence interval.
Hazard ratio (95% CI)
P value
1.048 (1.001–1.097) 0.845 (0.678–1.053) 0.989 (0.868–1.127) 1.087 (0.300–3.946) 1.400 (0.800–2.500) 1.610 (1.100–2.220)
0.82 0.57 0.63 0.72 0.08 0.06
1.001 (0.961–1.004) 0.981 (0.856–1.123) 1.008 (0.952–1.066) 1.106 (0.361–5.477) 1.706 (0.902–2.554) 2.043 (1.201–4.861)
0.95 0.78 0.80 0.62 0.06 0.04
1.710 (0.822–2.555) 2.216 (1.110–4.429)
0.18 0.02
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Fig. 3. Disease-free survival by pathologic nodal status.
and OS were seen between any clinical or pretreatment staging variables. T-level down staging, and pathologic T stage after neoadjuvant therapy and surgery did not correlate with recurrence or survival rates; however, pathologic nodal stage was associated with a significant difference in recurrence rates (N0, 19%; N1, 20%; N2, 75%; P ⫽ .038) and 5-year DFS (N0/N1 vs. N2; 79% vs. 25%, P ⫽ .002; Fig. 3). Comments Theoretical advantages for neoadjuvant chemoradiation include a well-defined tumor target with an intact tumor oxygen supply that may maximize tumor response rates, the absence of adhesions and postoperative surgical changes that may minimize radiation-related small bowel toxicity, and patients with distal rectal cancers might experience significant enough tumor reduction to facilitate resection of the distal rectum and preservation of the anal sphincter. Finally, the ability to measure treatment response could theoretically have prognostic value and implications for subsequent postoperative treatment recommendations. Potential disadvantages have been thought to include a possible increase in postoperative complications and mortality with a questionable effect on OS. Therefore, the goals of this study were to examine the impact of preoperative treatment on surgical outcomes and to determine prognostic factors predicting improved survival rates. In the current series, the complication rate (22%) and the perioperative mortality rate (1%) were comparable to previous series using neoadjuvant chemoradiation. Onaitis et al. [4] from Duke University Medical Center reported a postoperative complication rate of 22% in 141 patients treated with similar 5-FU– based chemoradiation protocols. Most recent large, single-institutional experiences report complication rates between 20% and 30% with operative mortality less than 3% [4 –10]. The largest multi-institutional trial of preoperative versus postoperative chemoradiation for rectal cancer performed by the German Rectal Cancer Study Group and reported by Sauer et al [11] noted a 36% complication rate in the preoperative treatment group compared with 34% in the postoperative treatment group. Operative mortality in the preoperative group was 0.7%. We
believe the lack of significant anastomotic leaks with major pelvic sepsis in the current series was at least partially because of the standardization and utilization of radical rectal resection with total mesorectal lymph node dissection and low anastomosis, usually with a coloanal technique and diverting ileostomy. We also attribute this evolving expertise for the increase in sphincter-preserving operations during the timeframe of this study. Whether the rate of sphincter preservation (73%) in the current series could be attributable to either the increasing use of coloanal anastomosis or the significant response of the primary tumor and downstaging to a sphincter-preserving operation is difficult to discern. Nonetheless, sphincter-preserving operations were performed in 63% of patients recently reported by Crane et al [5] from the MD Anderson Cancer Center, and Onaitis et al [4] have shown a progressive increase in the percentage of sphincter-sparing procedures from 20% before 1996 to 76% after 1996. This was again attributed to the increasing utilization of ultralow anastomosis, most protected by a temporary diverting ileostomy. The impact of pathologic downstaging on performing sphincter-preserving operations is difficult to determine in retrospective reviews. In the prospective study noted earlier by Sauer et al [11], the ability to perform sphincter-preserving surgery was thought to be markedly increased after chemoradiation. After restaging and at the time of surgery, a sphincter-preserving operation could be performed in 39% of those patients in which abdominoperineal resection was initially deemed necessary. The second objective of our study was to identify predictive factors for DFS and OS. Probably no other topic in the management of patients with rectal cancer is as controversial as the impact of treatment response on survival after neoadjuvant chemoradiation. That a significant treatment response (25% complete pathologic response rate) was seen in the current series was not unexpected based on results of previous reports [4,6 –10]. Onaitis et al [4] reported a complete response rate of 24% and significant pathologic downstaging in 80% of their patients. Similar to our series, there were no clinical or treatment variables that significantly affected OS rates. Postoperative tumor downstaging did not have a significant impact on local recurrence, DFS, or OS. On multivariate analysis, only the pathologic nodal stage independently predicted OS. Janjan et al [7] from the MD Anderson Cancer Center reported an updated experience of 117 patients treated with preoperative chemoradiation for locally advanced rectal cancer. They graded the extent of downstaging and then examined the extent of treatment response as a predictor of local recurrence, DFS, and OS. A complete response was seen in 27% of patients, and tumor downstaging occurred in 62% of cases. The level of response (complete response vs. downstaging vs. no response) had statistically significant impact on both DFS and distant metastatic-free survival. When any response to chemoradiation occurred, the distant metastatic-free survival was 44 months as compared with 37 months if there was no pathologic evidence of response to preoperative therapy. Unclear in this study were the relative effects of tumor downstaging compared with nodal downstaging. Guillem et al [10] from Memorial Sloan Kettering Cancer Center reported the largest single-institution analysis of long-term follow-up in pa-
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tients with locally advanced rectal cancer treated with preoperative chemoradiation. In their review of 297 patients treated with 5-FU– based chemoradiation, the estimated 10-year OS rate was 58% and 10-year recurrence-free survival was 62%. Importantly, these authors emphasized the necessity for longer follow-up (⬎5 years) to determine truly significant predictors of outcomes in patients treated in this fashion. A potential limitation of the current series and other retrospective reviews is a relatively shorter follow-up time. In studies designed to address long-term follow-up with median follow-ups of greater than 5 years, other pathologic variables may be shown to affect OS. With a median follow-up of 69 months, Ruo et al [8] reported a 5-year relapse-free survival rate of 79%. Relapse was significantly worse for patients with aggressive pathologic features and positive nodal status. Five-year relapse-free survival for patients with node positive cancer was significantly worse (53% vs. 89%, P ⬍ .03) than for those with node-negative disease. Prognostic factors were also evaluated in the German Intergroup trial comparing preoperative and postoperative chemoradiation. Among the 406 patients in the preoperative chemoradiation arm, pathologic T stage, pathologic N stage, grade, lymphatic invasion, and extent of tumor regression significantly predicted for DFS on univariate analysis. On multivariate analysis, pathologic N stage significantly predicted for relapse-free survival, and pathologic T and N stages significantly predicted for DFS and metastasis-free survival. All of these studies point to at least some impact of treatment response on survival after neoadjuvant chemoradiation, and, on multivariate analysis, extent of residual nodal disease and pathologic N stage after treatment is a consistent and strong predictor of survival rates. In conclusion, neoadjuvant chemoradiation for rectal cancer resulted in a high rate of sphincter preservation with acceptable morbidity and mortality rates. Local recurrence was seen in only 5% of our patients. Complete pathologic responses after surgery were frequent and, although the pathologic T stage after surgery, in our experience, did not affect recurrence rates, a complete pathologic nodal response was associated with improved recurrence and disease-free survival rates. This finding may have implications for subsequent postoperative treatment recommendations. References [1] Colorectal Cancer Facts and Figures—Special Edition 2005. American Cancer Society. Available at: http://www.cancer.org/downloads/ STT/CAFF2005CR4PWSecured.pdf. Accessed February 24, 2005. [2] Kaplan E, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457– 81. [3] Cox DR. Regression models and life tables. J R Stat Soc 1972;34: 187–220. [4] Onaitis MW, Noone RB, Hartwig M, et al. Neoadjuvant chemoradiation for rectal cancer: analysis of clinical outcomes from a 13-year institutional experience. Ann Surg 2001;233:778 – 85. [5] Crane CH, Skibber JM, Feig BW, et al. Response to preoperative chemoradiation increases the use of sphincter-preserving surgery in patients with locally advanced low rectal carcinoma. Cancer 2003; 97:517–24. [6] Das P, Skibber JM, Rodriguez-Bigas MA, et al. Clinical and pathologic predictors of locoregional recurrence, distant metastasis, and overall survival in patients treated with chemoradiation and mesorectal excision for rectal cancer. Am J Clin Oncol 2006;29:219 –24.
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[7] Janjan NA, Crane C, Feig BW, et al. Improved overall survival among responders to preoperative chemoradiation for locally advanced rectal cancer. Am J Clin Oncol 2001;24:107–12. [8] Ruo L, Tickoo S, Klimstra DS, et al. Long-term prognostic significance of extent of rectal cancer response to preoperative radiation and chemotherapy. Ann Surg 2002;236:75– 81. [9] Rullier E, Goffre B, Bonnel C, et al. Preoperative radiochemotherapy and sphincter-saving resection for T3 carcinomas of the lower third of the rectum. Ann Surg 2001;234:633– 40. [10] Guillem JG, Chessin DB, Cohen AM, et al. Long-term oncologic outcome following preoperative combined modality therapy and total mesorectal excision of locally advanced rectal cancer. Ann Surg 2005;241:829 –37. [11] Sauer R, Becker H, Hohenberger W. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351: 1731– 40.
Discussion Anthony J. Senagore, M.D. (Toledo, OH): You suggested a postoperative N0 status confers a survival advantage. Do you have any data on the distribution of those patients with respect to their preoperative nodal staging by ultrasound or by some other modality, and are there patients that were felt to be positive on ultrasound that ultimately proved to be negative postoperatively? Numbers of nodes has become a quality measure by CMS and a variety of insurance companies. Do you have any guidance for us regarding the number of nodes per patient after chemoradiotherapy? Were there patients that were deemed N0 simply because no nodes could be found in the specimen? There is a common impression among our radiotherapy colleagues that they are responsible for the increased rate of sphincter presentation. Your results are more circumspect, however, regarding that conclusion. Does your group use the preradiotherapy distal margin of the tumor when planning the surgical procedure or the postradiotherapy intraoperative assessment of the distal margin to decide whether or not you will do a restorative proctocolectomy? Mark S. Talamonti, M.D. (Chicago, IL): In terms of the postoperative N0 status, we did see on multivariate analysis a statistically significant improvement in disease-free survival, although not in overall survival. Forty-seven percent of the patients were thought to be N0 or node negative before their treatment. Those patients received chemoradiation because of what we thought were full-thickness tumors. Our indications for adjuvant chemotherapy are T3, T4, or any evidence of node positivity. Postoperatively, 72% of the patients were deemed as N0 patients, so there was 25% gain in nodal negativity after chemotherapy and radiation. The problem is there is no way to know who is going to be that responder. There were no variables that we could decide on. But, clearly, 25% of the patients ended up that way. Being able to assure the quality of the operation by the amount of lymph nodes that are resected, no doubt that is now a mandate in colon surgery. It becomes a very complicated issue when you talk about rectal surgery or esophageal surgery or any of these operations in which the patients get chemotherapy and radiation. Although primary tumors will shrink, you will do a great job of eradicating nodal disease in many of these patients. In terms of the number of nodes
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that assure quality resection after chemoradiation, I think that number is still unknown. You asked if there were patients that were deemed N0 because no lymph nodes could be found on their final pathology report. As I said, 72% of the patients were node negative on their final pathology report, and, of those 72 patients, 22 had no evidence of any lymph nodes left in the specimen. The radiation therapy delivered in 1992 was pretty similar to the radiation delivered in 2002. What changed was the increase in performance of coloanal resections and coloanal anastomoses. I think that had as much, if not more, to do with the increasing rate of sphincter preservation. Our indications for coloanal resection are any rectal cancer in which it does not invade the anal sphincters on preoperative endoscopic ultrasound, and we will use the final treatment margin in determining whether or not we will perform that operation. When these studies first started, many of the decisions regarding AP resection versus restorative proctocolectomy had to do with the pretreatment margin, and we have just seen too good of responses without invasion of the anal
sphincters to obligate all of those patients to an AP resection. The fact that our recurrence rate was only 5% is good data to support that approach. John P. Hoffman, M.D. (Philadelphia, PA): I wondered if you had looked at those patients who were complete pathologic responders, whether or not their survival was significantly better stage for stage than those who did not have complete pathologic responses. For those with the recurrent tumors locally, were those patients with very low tumors with close margins? Mark S. Talamonti, M.D. (Chicago, IL): The extent of pathologic response did correlate with survival, and the complete pathologic responders had a better overall survival rate and disease-free survival rate. Patients who had local recurrences in the pelvis were not necessarily the patients who started out with the lowest most distal rectal cancers. They were, however, the patients who had significant residual nodal disease. It was nodal disease and bulk of tumor to start with, rather than distal margin that predicted local recurrence.