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© 2003 American Society for Clinical Oncology Analysis of Surgical Salvage After Failure of Primary Therapy in Rectal Cancer: Results From Intergroup Study 0114From the Department of Radiation Oncology, University of North Carolina, Chapel Hill; CALGB Statistical Office, Duke University Medical Center, Durham, NC; Mayo Clinic Cancer Center Rochester, MN; Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA. Address reprint requests to Joel E. Tepper, MD, Department of Radiation Oncology, Campus Box No. 7512, University of North Carolina, Chapel Hill, NC 27599-7512; e-mail: tepper{at}med.unc.edu.
Purpose: Intergroup Study 0114 was designed to study the effect of various chemotherapy regimens delivered after potentially curative surgical resection of T3, T4, and/or node-positive rectal cancer. A subset analysis was undertaken to investigate the prevalence and influence of salvage therapy among patients with recurrent disease. Patients and Methods: Adjuvant therapy consisted of two cycles of fluorouracil (FU)-based chemotherapy followed by pelvic irradiation with chemotherapy and two more cycles of chemotherapy after radiation therapy. A total of 1,792 patients were entered onto the study and 1,696 were assessable. After a median of 8.9 years of follow-up, 715 patients (42%) had disease recurrence, and an additional 10% died without evidence of disease. Five hundred patients with follow-up information available had a single organ or single site of first recurrence (73.5% of all recurrences). Results: A total of 171 patients (34% of those with a single organ or single site of recurrence) had a potentially curative resection of the metastatic or locally recurrent disease. Single-site first recurrences in the liver, lung, or pelvis occurred in 448 patients (90% of the single-site recurrences), with 159 (35%) of these undergoing surgical resection for attempted cure. Overall survival differed significantly between the resected and nonresected groups (P < .0001), with overall 5-year probabilities of .27 and .06, respectively. Controlling for worst performance status at the time of recurrence does not alter this relationship. Patients who underwent salvage surgery had significantly increased survival (P < .001) for each site. Conclusion: Attempted surgical salvage of rectal cancer recurrence is performed commonly in the United States. The chance of a long-term cure with such intervention is approximately 27%.
FOR MANY years it was assumed that distant metastatic disease implied widespread dissemination of the tumor, and that cure of these patients was not possible. However, it has become clear that this is not the case and that a substantial portion of patients who have all metastatic disease removed can indeed be cured of their disease. During the last two decades, there has been a substantial increase in the information gained regarding the value of resection of metastases to the liver or the lung from colon and rectal cancer. However, most studies have been limited to a single institution where the referral base could substantially influence outcome and where the studies were not based on a defined cohort of patients with colorectal cancer. The Gastrointestinal Intergroup has performed a series of randomized studies in colon and rectal cancer with the aim of defining the optimal adjuvant therapy for patients who have had a potentially curative surgical resection. Intergroup Study 0114 was a randomized study testing four different chemotherapy regimens in patients who had a potentially curative resection of the primary tumor, with all patients receiving postoperative concurrent radiation therapy and chemotherapy. The results of the primary end points of this study have been previously reported and do not show a difference between treatment arms, making it easier to compare results in the entire patient population.1 Although not defined as a primary aim of the study, we believed that this would be an ideal setting in which to determine the prevalence of surgical resections for metastatic disease as well as the likelihood of cure from this surgery. A large percentage of these patients had their surgery and adjuvant therapy performed at community institutions; these data should reflect the standards of practice in much of the United States and Canada, and the long-term outcomes would reflect that which would be obtained in the general medical community. The therapy after treatment failure in this study was not defined, so that no statements can be made about whether all patients who could have benefited from surgical resection received such therapy, and any chemotherapy after resection was likewise not defined. Thus, this report defines practice patterns and outcomes from those practices, rather than defining an optimal management strategy. The objectives of this analysis were to determine the sites of solitary failure after primary therapy of rectal cancer with surgery, radiation therapy, and chemotherapy; to determine the incidence of surgical salvage after primary therapy; to determine the outcomes of this surgical salvage; and to determine these end points in a national trial that would reflect national practice patterns in the United States and Canada.
Eligibility Patients were eligible for the adjuvant study if they had adenocarcinoma of the rectum and had a potentially curative resection of the primary tumor and regional lymph nodes performed with neither gross nor microscopic residual disease. The tumor had to have extension of the primary tumor through the bowel wall and/or positive lymph nodes without evidence of distant metastatic disease (T3, T4, or N1-N3, and M0). A tumor was considered to be a rectal cancer if a portion of the tumor was located below the peritoneal reflection or if the lower margin of the tumor was within 12 cm of the anal verge on endoscopy. All patients were older than 18 years of age, had a performance status (Zubrod) of 0 to 2, were not pregnant or lactating, and had normal hematopoietic function. Exclusion criteria included prior radiation therapy to the pelvis, prior chemotherapy or immunotherapy, other malignancy within 5 years, or other serious medical illness that would limit the ability of the patient to receive protocol therapy. Patients began therapy between 3 and 10 weeks after surgery. All institutions had appropriate institutional review board approval and informed consent was obtained from all patients. Patients received adjuvant therapy as an initial two cycles of bolus intravenous fluorouracil (FU)-based chemotherapy, followed by pelvic radiation therapy plus chemotherapy, then two more cycles of chemotherapy. The treatment schema has been fully described in an earlier report.1 Patients were entered though their respective cooperative group: Cancer and Leukemia Group B (CALGB), Eastern Cooperative Oncology Group, North Central Cancer Treatment Group, National Cancer Institute of Canada, Radiation Therapy Oncology Group, and Southwest Oncology Group. CALGB was the statistical center for the study.
Chemotherapy Arm 2. The regimen was FU 425 mg/m2/d and leucovorin 20 mg/m2/d on days 1 to 5 and 29 to 33. During radiation therapy, the regimen was FU 400 mg/m2/d and leucovorin 20 mg/m2/d for 4 days during weeks 1 and 5. After radiation therapy, the regimen was FU 380 mg/m2/d and leucovorin 20 mg/m2/d for 5 consecutive days for two cycles. Arm 3. The regimen was FU 450 mg/m2/d on days 1 to 5 and 29 to 33 and levamisole 50 mg tid for 3 days every 14 days for four cycles. During radiation, the regimen was FU 500 mg/m2/d for 3 days during weeks 1 and 5. After radiation therapy, the regimen was FU 400 mg/m2/d for 5 consecutive days for two cycles and levamisole as described for four cycles. Arm 4. The regimen was FU 425 mg/m2/d and leucovorin 20 mg/m2/d on days 1 to 5 and 29 to 33, plus levamisole as described for arm 3. During radiation therapy, the regimen was FU 400 mg/m2/d with leucovorin 20 mg/m2/d for 4 days during weeks 1 and 5. After radiation therapy, the regimen was FU 380 mg/m2/d and leucovorin 20 mg/m2/d for 5 consecutive days for two cycles, plus levamisole as described.
Radiation Therapy A boost dose of 5.4 Gy in three fractions was given to a reduced field that encompassed, as a minimum, the tumor bed and adjacent lymph nodes with a margin of 2 cm. A second boost field of 3.6 Gy was given in two fractions to the tumor bed plus a margin of 2 cm if all small bowel could be excluded from the field.
Follow-Up
Statistical Analysis
A total of 1,792 patients were entered onto the study and 1,695 were fully assessable. At the time of this analysis, the median follow-up of the survivors was 8.9 years, and as previously reported, there was no difference in outcome by treatment arm. A total of 715 (42%) patients developed disease recurrence, of whom 511 had disease that seemed to be confined to a single organ or site (solitary site of recurrence). For 11 of these patients, no additional follow-up information was available and they were not considered in the analysis, leaving 500 patients with tumors in a single site for evaluation. Ten percent of all patients died without evidence of disease. The vast majority of solitary site recurrences were in the liver, lung, or pelvis, with a fairly even distribution among these three sites (Table 1  ). Other sites of solitary recurrences included peritoneum (14 patients); lymph nodes (13 patients); brain (10 patients); bone (seven patients); abdominal wall (three patients); ureter, kidney, and thyroid (one patient each); and two indeterminate sites. Overall, 34% of patients with tumors in a solitary site had a resection performed with curative intent. This percentage was also fairly consistent across lung, liver, and pelvis, whereas tumors in other anatomic sites had a lower incidence of resection for cure.
Although it was not possible to determine the precise manner in which the recurrent disease came to the attention of the physicians, most seemed to be found on routine visits to the physicians and without specific symptoms mentioned (56%). Other recurrences were found on the basis of elevations of the CEA (17%), pain (15%), small bowel obstruction (4%), or rectal bleeding (2%). The tests used to define the recurrence were mostly computed tomography scans (59%), but also included chest x-ray (19%), colonoscopy (4%), and ultrasound (4%). There was not an obvious difference in symptoms or means of detection of recurrence between the patients who had a resection and those with a solitary site who did not have a resection.
Patients who had a solitary site recurrence had significantly improved survival at 5 years compared with those patients with tumors in multiple sites (13% v 5%; 95% CIs, 11% to 17% v 2% to 10%, respectively; P < .0001). Of patients with tumors in a solitary site, the survival was dramatically improved if the patient had a surgical resection performed (Fig 1
Previous studies have shown a significant influence of a number of factors on outcome after surgical resection of metastatic disease, including time to recurrence and the original stage of disease. We evaluated these factors and found that neither was important in the outcome after resection of the metastatic tumor. Time to recurrence was dichotomized on the mean value of 1.67 years and the survival after resection was compared. There was no outcome difference depending on whether the patients had a shorter or longer time to the development of metastases (Fig 3 ). Because this result was somewhat unexpected, we also analyzed outcome on the basis of time to recurrence of 1, 2, 3, or 5 years and still found minimal effect on outcome. Likewise, neither initial tumor stage (T2 v 3 v 4) nor node stage (0 v 1 v 2) influenced outcome, although it should be kept in mind that all patients on this study presented with either T3 or T4 tumors and/or positive nodal disease. (Model results were confirmed using proportional hazards methodology.)
As has been mentioned, therapy after recurrence was not controlled. However, we determined that of the 171 patients who had resections, 109 had no additional therapy, whereas 59 had additional chemotherapy or radiation therapy of various types. In the patients who received additional therapy, there was no obvious benefit compared with those who had no additional therapy (Fig 4 ).
A second recurrence occurred in 107 patients after resection of the initial metastasis and 20 of those patients had a second operation for cure. Five of those patients are alive without evidence of disease, with a median survival after second operation of 2.2 years and a maximum survival of 5.2 years.
The studies in the literature on the use of salvage surgery after recurrence of rectal cancer to date generally have been derived from single-institution experience and have emphasized the results for either resection of liver or lung metastases.5–13 Sasson and Sigurdson14 reviewed a large number of series of hepatic resections for liver metastases from colon and rectal cancer (a total of more than 4,000 patients) and showed an overall survival of more than 30%. However, these are generally single-institution studies. In addition, combining both colon and rectal cancers may be misleading because these cancers could have different prognoses after recurrence. In most of these studies in the literature it is unclear how many patients were evaluated for surgery or how large was the cohort of patients who had initial operations from whom recurrences would have been evaluated. To our knowledge, this is the first report of this type that has observed a large cohort of patients with rectal cancer to assess the sites of treatment failure and the prevalence of surgical resection among the patients experiencing a treatment failure at the primary or at a metastatic site. A similar study has been reported by Goldberg15 on 1,247 patients with colon cancer. Their findings were similar to ours: 548 patients had disease recurrence, salvage surgery was attempted in 41% of the patients (only 20% actually had a curative resection), and 5-year survival was 23%. It is clear that the concept of resection of metastases to the liver or lung is now part of standard medical practice in the United States and Canada, and that it can be an effective mode of therapy after recurrence. The fact that 5-year survival after resection of the metastasis is on the order of 25% to 30% clearly establishes this as the preferred method of treatment because no other therapy has a significant likelihood of producing long-term cure. There is a small but likely real benefit from a second resection of metastases, consistent with that found in the literature from single-institution studies.16,17 Because the primary drainage of rectal cancer is usually considered to be through the portal circulation where the liver is the first organ that is reached, the assumption had been made by many that liver metastases might be curable, whereas lung recurrences, not being in the initial drainage pattern, would not have as high an incidence of cure. On the basis of the data in this report, that is clearly not the case. The cure rate of liver and lung metastases was essentially the same. Because low-lying rectal cancer can drain through the iliac system, it is possible that many of these tumors have initial access to the systemic rather than the portal circulation, producing a higher incidence of spread to the lung compared with colon cancer. Local pelvic recurrences likely occur not by additional tumor spread, but rather by inadequate initial treatment of the primary site with surgery and radiochemotherapy. Thus, local control of pelvic recurrences might be expected to produce a higher incidence of long-term survival than liver or lung metastases. The fact that this result was not seen, and that the survival was, if anything, a little worse for the patients who experienced local treatment failures, shows that either local control could not be obtained in these patients who were heavily pretreated to the pelvis or that local recurrence also portends a high incidence of distant metastases. We were not able to make that distinction in this study. There is extensive discussion in the literature about the prognostic factors that could influence outcome after resection of metastatic disease, usually in the liver.18–22 These possible factors include the initial primary tumor stage, the number of lesions or the extent of the liver disease, the disease-free interval from the initial surgery, the surgical margins of the second resection, age, CEA level, and the presence of extrahepatic disease. None of these have been generally accepted to define who should or should not have a resection except for the amount of liver that would be remaining after surgery and the patient’s general medical condition. Because of the nature of this study, we were not able to determine the importance of many of these factors, but we were able to evaluate the initial stage of disease and the interval from the resection of the primary site as prognostic factors. In contrast to some other studies, we were not able to detect a correlation with either of these factors. However, because no patient with early disease (T1–2, N0) was entered onto this study, we could not compare early initial presentation with more advanced disease. There is a more modest literature on the value of resection of pulmonary metastases compared with that on liver metastases from colon and rectal cancer. However, the results generally show long-term outcomes similar to those obtained for resection of liver recurrences,23–26 and that good results can even be obtained from simultaneous resection of both liver and lung metastases.27 We were interested in the possibility that additional adjuvant therapy after resection of the metastatic site might improve long-term tumor control. Although there were undoubtedly substantial biases in determining who received additional therapy, we were not able to support the reasonable contention that additional therapy would be of benefit. It is possible that this is because all of the patients in this study had previous therapy with FU-based chemotherapy. This drug exhibits limited efficacy in the adjuvant setting after surgery to the primary site, and it is possible that the efficacy no longer existed at the time of the development of recurrent disease. It is certainly possible that with better agents available, such as irinotecan or oxaliplatin, additional therapy would be of greater benefit. This study demonstrates the value of surgical resection of limited metastatic disease in the liver or the lung, or residual locally recurrent disease in the pelvis. A substantial percentage of patients who develop tumor recurrence will be eligible for a surgical approach and can be cured of their disease. It is not clear from this study that more aggressive evaluation for early detection of metastases would produce an increase in resections, and thus also produce an increase in cure rate. Although some of the early literature do not support the value of more aggressive screening for recurrence in improving outcome,28 more recent data suggest otherwise. Bleeker29 has suggested an advantage to liver imaging and colonoscopy. In addition, a recent meta-analysis of more intensive follow-up by Renehan et al30 has shown a long-term survival advantage to this approach, especially when the follow-up used computed tomography and frequent measurements of CEA. Intensive follow-up was associated with a reduction in all causes of mortality (risk ratio, 0.81). The effect was most pronounced in the four extramural detection trials that used frequent serum CEA measurements. The value of more aggressive follow-up is consistent with the results of this study, which show that there is a substantial cure rate when the metastatic disease can be resected. It is likely that improved imaging could further improve outcomes for recurrent disease. Earlier detection of recurrence could result in more patients being offered potentially curative surgery at earlier time points in their disease. Improved screening for additional evidence of disseminated disease should allow surgery to be performed on a more selected group of patients who would then be more likely to benefit from a surgical procedure. Specifically, the wider availability of fluorodeoxyglucose–positron emission tomography scans will likely screen out patients with a poorer prognosis in the future. Because this study was done in the early 1990s, positron emission tomography was not widely available and would not have affected the outcome in this trial. Patients need to be treated in centers where the complicated hepatic and pulmonary resections can be safely performed and the patients properly managed, with a multidisciplinary team of physicians who are experienced in the management of these complicated clinical situations.
The authors indicated no potential conflicts of interest.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
