- Email: [email protected]
Recurrent Retroperitoneal Sarcoma: Impact of Biology and Therapy on Outcomes
Recurrent Retroperitoneal Sarcoma: Impact of Biology and Therapy on Outcomes Stephen R Grobmyer, MD, FACS, Jason P Wilson, MD, Brooke Apel, BS, Jacquelyn Knapik, MD, Walter C Bell, MD, Tad Kim, MD, Kirby I Bland, MD, FACS, Edward M Copeland, MD, FACS, Steven N Hochwald, MD, FACS, Martin J Heslin, MD, FACS Local recurrence remains the major cause of death in patients with retroperitoneal sarcoma (RPS). There is no consensus regarding management of patients with recurrent RPS. STUDY DESIGN: We performed a retrospective review of patients with recurrent RPS managed at 2 tertiary care centers between 1983 and 2008. Presentation, treatments, and outcomes were analyzed. RESULTS: Seventy-eight patients were identified and analyzed. Sixteen patients (22%) presented with concurrent metastatic disease; survival in this subset of patients was poor (median 12 months). Forty-eight patients underwent resection of the first local recurrence of RPS. Palliation of tumor-related symptoms was achieved in 79% with operation. Survival was significantly better in patients having complete (p ⫽ 0.001) and incomplete resection (p ⫽ 0.02) compared with patients having biopsy only. Among patients with first local recurrence, high grade tumor (p ⫽ 0.0001) and no resection (p ⫽ 0.007) were significantly associated with reduced survival. On multivariate analysis, radiation therapy, multifocality, histologic subtype, and time to local recurrence did not significantly correlate with survival. Second and third local recurrences occurred at shorter intervals compared with first local recurrence and were less likely to be completely resectable. Patients undergoing resection of second and third local recurrences had survival similar to that in patients undergoing resection of first local recurrence. CONCLUSIONS: Tumor biology (high grade) is a significant prognostic factor for patients with recurrent RPS. Resection should be considered in patients with first and subsequent local recurrences (even if multifocal) of RPS because it is associated with improved survival. Operation should also be considered for palliation of symptoms in patients in whom resection is not possible. (J Am Coll Surg 2010;210:602–610. © 2010 by the American College of Surgeons) BACKGROUND:
ment of primary retroperitoneal sarcoma.3-8 Complete excision rates for primary RPS have been reported to be 65% to 99%.1 Complete tumor resection and grade have been shown to correlate with improved outcomes in patients with primary RPS.4-6,9-13 The role of adjuvant strategies for management of RPS, especially radiation therapy, remain ill defined and controversial.1 The primary site of failure for RPS is local.4,12,14,15 Local recurrence rates are higher in patients with high grade tumors compared with those with low grade tumors.16 Patients with RPS most commonly die of locally recurrent disease associated with multifocal intestinal obstruction and cachexia.4,17-19 There have been several studies that have analyzed patterns of recurrence and outcomes of patients with recurrent RPS; however, most of these reports are small series of patients with variable results and patient outcomes. As a result, controversy persists over the optimal strategy for management of patients with recurrent RPS and the im-
The retroperitoneum is an uncommon site of soft tissue sarcoma, comprising approximately 15% of all soft tissue sarcomas.1,2 Soft tissue sarcoma of the retroperitoneum has a pattern of presentation and biologic behavior distinct from soft tissue sarcoma of the extremity.1 These differences have led to unique therapeutic considerations for management of patients with retroperitoneal sarcoma (RPS). Aggressive surgical resection has long been established and continues to be the most effective strategy for manageDisclosure Information: Nothing to disclose. Presented at Southern Surgical Association 121st Annual Meeting, Hot Springs, VA, December 2009. Received December 10, 2009; Accepted December 15, 2009. From the Departments of Surgery, Division of Surgical Oncology (Grobmyer, Wilson, Kim, Copeland, Hochwald) and Pathology (Knapik), University of Florida, Gainesville, FL; and the Departments of Surgery, Division of Surgical Oncology (Apel, Bland, Heslin) and Pathology (Bell), University of Alabama at Birmingham, Birmingham, AL. Correspondence address: Stephen R Grobmyer, MD, 1600 SW Archer Rd, PO Box 100109, Gainesville, FL 32610.
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pact of therapy on outcomes. For instance, Neuhaus and colleagues6 recently advocated that “recurrence per se is not an indication for operation.” On the other hand, Gholami and colleagues20 believed that “early recognition (of recurrent disease) allows tumors to be identified early and completely removed.” Other areas of ongoing controversy and investigation include the roles of incomplete resection and multimodality therapy on survival and the impact of multifocality on treatment decision making and outcomes. In this study, we reviewed the combined experience of 2 tertiary care centers with first and subsequent recurrences of RPS to gain insight into the nature of recurrent disease and outcomes associated with therapeutic intervention. Current therapeutic approaches to these patients and remaining controversies will be discussed.
METHODS This study was a retrospective review of the experiences of 2 tertiary care centers (The University of Florida and The University of Alabama at Birmingham) with recurrent RPS. Patients evaluated for locally recurrent RPS were identified from pathology and clinical databases from available medical records of patients treated between 1983 and 2008. All available pathologic slides were re-reviewed for purposes of this investigation by JK and WB. Histologic type and grade (high, intermediate, and low) were assigned. We elected not to use histologic subtypes of liposarcoma to facilitate analysis and comparison with other histologies.21 Date of death was determined by review of medical records or the Social Security Death Index. Patient age, presenting symptoms, tumor size, therapy, pattern of recurrence, operation type, and recurrence data were recorded for all patients. Approval was obtained from the IRB at both institutions to perform the study. For this report, “complete resection” was defined as complete gross removal of tumor (R0 or R1) and “incomplete” was defined as partial tumor removal with remaining gross residual disease. For analysis purposes, data from R0 and R1 resections were combined because it was difficult in many situations to retrospectively determine microscopic margin status, and gross tumor removal has been shown to correlate with survival.5 “Multifocality” was defined as “the presence of more than 1 noncontiguous tumor in the abdomen or retroperitoneum.”22 “Local recurrence” was defined as tumors recurring within the retroperitoneum or peritoneal cavity after previous complete gross removal. “Distant recurrence” was defined as discrete sites of metastatic spread to other organs including liver and lung. Statistical analyses included chi-square test or Fisher’s exact test when comparing groups. Survival analyses were performed using Kaplan Meier analysis and Mantel Cox
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Table 1. Pathologic Features of Tumors in 78 Patients with Recurrent Retroperitoneal Sarcoma Pathologic features
Histologic subtype Liposarcoma Leiomyosarcoma Undifferentiated pleomorphic sarcoma Other sarcoma Unknown Grade High Intermediate Low Unknown or undetermined
n
%
42 15 14 4 3
54 19 18 5 4
37 10 28 3
47 13 36 3
Details are for first local recurrence.
test. Cox univariate and multivariate survival analyses were performed to determine which factors were related to overall survival. Comparisons of groups were performed using a chi-square test or Fisher’s exact test as appropriate. Statistical significance was defined as p ⬍ 0.05. Relative risk was reported with 95% confidence intervals for factors achieving statistical significance on multivariate analysis. Mean values are shown as ⫾ standard error of the mean. Median values are shown with range. SAS statistical software was used to perform statistical analyses.
RESULTS Seventy-eight patients with locally recurrent RPS were identified. Forty patients were identified at the University of Alabama Birmingham and 38 were identified at the University of Florida. The mean age of patients at the time of first local recurrence (FLR) in this series was 60 ⫾ 1.5 years. Fifty-three percent of the patients were male and 47% were female. Mean follow-up from the time of FLR for patients in this series was 28 months. Sixty-two patients in this series presented with local recurrence only, and 16 patients presented with local and distant recurrence. The mean time to local recurrence was 36.1 ⫾ 5.2 months. Liposarcoma and leiomyosarcoma were the most common tumor types (Table 1). The grade distribution of tumors is shown in Table 1. Fifty-one percent of patients had FLR detected on routine follow-up imaging examinations. Among documented symptomatic patients at the time of FLR (n ⫽ 33), the most common presenting symptoms were abdominal pain (52%), abdominal fullness (18%), and abdominal cramping/nausea/ vomiting (18%). Operative intervention was successful in improving or eliminating symptoms in most patients (79%). Sixteen patients presented with both local and metastatic disease; 8 patients underwent further operative pro-
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Table 2. Characteristics of 62 Patients with First Local/ Nonmetastatic Recurrence of Retroperitoneal Sarcoma Characteristic
Figure 1. Time after recurrence. Overall survival of 16 patients with both local and distant recurrence of retroperitoneal sarcoma.
cedures, which included resection of recurrent tumor (n ⫽ 4), exploratory celiotomy with biopsy only (n ⫽ 3), and palliative intestinal bypass for obstruction (n ⫽ 1). Median overall survival in this patient group was 12 months. The Kaplan-Meier overall survival curve for this group of patients is shown in Figure 1. Characteristics of patients with FLR without distant recurrence are shown in Table 2. The median total number of operations for patients in this series was 2 (range 1 to 5). A significant difference in survival was associated with resection status of the FLR (p ⫽ 0.0001) (Fig. 2). Patients undergoing complete (p ⫽ 0.001) and incomplete (p ⫽ 0.02) resection of FLR had improved survival compared with those having palliation or biopsy only. Patients undergoing complete resection (R0 or R1) had a significantly
Data
Mean time to first local recurrence ⫾ SE, mo Mean greatest tumor size, ⫾ SE, cm Multifocal tumors,* n (%) Resection type, n (%) R0-R1 R2 None Unknown Contiguous organ resection, n (%) Radiation therapy, n (%) Treatment of first Treatment of recurrence None Chemotherapy, n (%) Treatment of primary Treatment of recurrence None
35 ⫾ 6 14.1 ⫾ 1.5 21 (35) 37 (60) 10 (16) 14 (22) 1 (2) 24 (39) (51)† 19 (31) 22 (35) 21 (34) 2 (3) 6 (10) 54 (87)
*Status not known in 2 patients. † Fifty-one percent of patients undergoing resection for first local recurrence.
improved survival compared with patients having incomplete local resection (R2) (p ⫽ 0.03). Patients undergoing complete local resection of FLR were analyzed to determine which clinical and/or biologic factors were associated with overall survival. The results of this analysis are shown in Table 3. No tumor resection (p ⫽ 0.007) and high grade (p ⫽ 0.0001) were the factors significantly associated with decreased overall survival in patients with FLR. A multifocal recurrence was observed in 35% of patients with FLR of RPS. Multifocal recurrence was significantly more common in patients having an incomplete resection Table 3. Analysis of Factors Associated with Overall Survival among Patients with First Local Recurrence of Nonmetastatic Retroperitoneal Soft Tissue Sarcoma (n ⫽ 62)
Variable
Figure 2. Time after first local recurrence. Overall survival of 62 patients with locally recurrent, nonmetastatic retroperitoneal sarcoma after R0-1 resection (ⴛ, n ⫽ 37); R2 resection (, n ⫽ 10); and supportive therapy (, n ⫽ 14). There is a statistically significant difference between the groups (p ⫽ 0.0001). Resection type was unknown in 1 patient.
Age Time to FLR Size Histology High grade Radiation Multifocal No resection
Univariate analysis p Value
0.32 0.06 0.81 0.18 0.0001 0.48 0.045 0.0001
Multivariate analysis p Value Relative risk (95% CI)
0.0001
5.3* (2.1–14.2)
0.14 0.007
3.6 (1.4–9.2)
*Relative risk of high grade versus low or intermediate grade. FLR, first local recurrence.
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Figure 3. Time after resection for first local recurrence retroperitoneal sarcoma. Overall survival of 47 patients, comparing patients who had nonmetastatic, multifocal tumors (Œ, n ⫽ 16) versus unifocal tumors (, n ⫽ 31). Multifocality was associated with a significantly worse overall survival in these patients (p ⫽ 0.03).
(80%) of FLR compared with patients having a complete resection of FLR (22%) (p ⫽ 0.001). The association of multifocality and overall survival for patients undergoing resection of FLR (complete and incomplete) is demonstrated in Figure 3. Multifocality was associated with a significantly worse overall survival in these patients (p ⫽ 0.03). Patients undergoing resection of high grade FLRs had a worse survival compared with patients with low grade tumors. Survival curves for these patients are shown in Figure 4. Thirty-three patients with second local recurrence presented for management and 11 patients presented with third local recurrence for management. The presenting features of these patients are shown in Table 4. Fewer patients were evaluated with each subsequent local recurrence of RPS. The percentage of resected recurrent tumors that were high grade declined with each subsequent local recurrence: first (35%), second (25%), and third (17%). Kaplan Meier survival analysis of these patients demonstrated that long-
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Figure 4. Time after resection for first local recurrence of retroperitoneal sarcoma. Overall survival of 47 patients, comparing patients who had nonmetastatic, high grade tumors (Œ, n ⫽ 17) versus low/intermediate grade tumors (, n ⫽ 30). High grade was associated with a significantly worse overall survival (p ⫽ 0.004) in these patients.
term survival is possible in the selected patients after resection of second and third recurrences of RPS (Fig. 5). There was no significant difference in overall survival in patients undergoing resection for second versus third local recurrence (Fig. 5). There was also no significant difference in overall survival between selected patients undergoing resection of first, second, or third recurrences (p ⫽ 0.51). In selected patients undergoing operation for third local recurrence, survivals of 51 and 125 months were observed.
Table 4. Comparison of Features of First, Second, and Third Local Recurrence Variable
Mean time interval from prior resection ⫾ SEM, mo With associated distant recurrence, % With multifocal recurrence, % Undergoing complete resection, % total patients/% undergoing resection
FLR (n ⴝ 62)
SLR (n ⴝ 33)
TLR (n ⴝ 11)
35 ⫾ 6
24 ⫾ 3
25 ⫾ 9
21 35
12 48
27 36
60/77
39/65
36/50
FLR, first local recurrence; SLR, second local recurrence; TLR, third local recurrence.
Figure 5. Time after operation for recurrence. Overall survival in patients undergoing operation for second (, n ⫽ 20) and third (Œ, n ⫽ 6) recurrences of retroperitoneal (nonmetastatic) sarcoma. There is no significant difference between the overall survival in the 2 groups (p ⫽ 0.7). Overall survival in these groups is similar to that in patients undergoing operation for first local recurrence (p ⫽ 0.51).
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Table 5. Reported Series of Patients with Recurrent Retroperitoneal Sarcoma of Mixed Histologic Subtypes First author (year)
Jaques (1990)12 Lewis (1998)4 Baustista (2000)32 Van Dalen (2001)23 Chiappa (2004)25 Erzen (2005)28 Pacelli (2008)38 Gholami (2009)20 Lehnert (2009)31 Grobmyer (this series)
Patients with recurrent RPS analyzed, n
Mean time to local recurrence, mo (1st/2nd/3rd)
Complete resection of local recurrence, % (1st/2nd/3rd)
Survival after resection of FLR
47 61* 11 32 19 41 19 15 39 72
NR/NR/NR NR/NR/NR 46/23/26 22/NR/NR 20/NR/NR NR/NR/NR 14/NR/NR 20/NR/NR 12/NR/NR 35/24/25
49/42/33 57/22/10 82/NR/NR 54/NR/NR 62/NR/NR NR/NR/NR NR/NR/NR 100/86/100 61/NR/NR 60/39/36
NR Median 60 mo Median 91 mo 37% @ 60 mo NR 42% @ 60 mo NR NR NR 30% @ 60 mo
*Total number of patients ⫽ 119. FLR, first local recurrence; NR, not reported; RPS, retroperitoneal sarcoma.
DISCUSSION Local recurrence is the primary pattern of recurrence and the major cause of ultimate mortality in patients with RPS.4,12,14,15 FLRs have been reported to occur between 24 and 40 months after primary tumor resection (Table 5). In patients with FLR of RPS, this study found that low grade and complete resection are associated with improved overall survival. These findings are similar to those in some other reports.4 We found disease-free interval, size of recurrent tumor, patient age, histology, mutlifocality, and use of radiation therapy to have no significant relationship to overall survival. Others have reported multifocality,22,23 histology,23,24 blood loss,25 growth rate,16 and disease-free interval26 to be associated with outcomes in patients with recurrent RPS. Complete resection of FLR was accomplished in many patients in this series and in other reported series (Table 5). Resectability rates of FLR are, in general, lower than those reported for primary resections.6 Gholami and associates20 reported, however, 100% complete resectability rates for locally recurrent RPS. Resection of recurrent disease involved contiguous organ resection in 50% of patients in this series. Others have reported similar rates of contiguous organ resection for recurrent RPS.6,12 Some authors have reported that resection of FLR results in survival similar to that after resection of primary disease;23,27,28 others have found that resection of recurrent disease is associated with a decreased overall survival4,12,26 compared with resection of primary disease. In a recent large series from MD Anderson, Anaya and coworkers24 found that locally recurrent presentation was not independently associated with overall survival. Observed differences in outcomes in patients with locally recurrent disease are most likely related to variable case selection and tumor grades in small reported series. In this report, we found that second and third recurrences of retroperitoneal soft tissue sarcoma occur at
shorter intervals after previous resection than FLRs (Tables 4 and 5). Resection of second and third recurrences can result in long-term survival in selected patients (Fig. 5). We and others have found that the ability to achieve complete resection is diminished in second and third recurrences compared with FLRs (Table 5).29 However, resection of second and third recurrences is associated with survival similar to that associated with resection of FLR in this and other series.28 Long-term survival is possible in selected patients undergoing more than 3 reoperations for recurrent RPS, as demonstrated in this study.6,30-33 The goal of reoperation should be complete removal of recurrent disease; however, this is not always technically possible. The association of incomplete resection with improved survival has been controversial.26 Storm and Mahvi34 performed a meta-analysis of reports of incomplete resection for RPS and found improved survival at 5 years (44%) compared with survival in patients having biopsy only (17%). In single institutional series, others have reported no significant difference in survival in patients undergoing incomplete resection compared with biopsy.12,25 This report found that incomplete resection is associated with improved survival compared with no resection. This finding supports attempts to debulk recurrent disease in selected patients in whom complete resection cannot be performed because it may prolong survival in addition to alleviating symptoms related to tumor bulk. Many patients presenting with recurrent retroperitoneal soft tissue sarcoma have symptoms related to the recurrence. Most patients in this series realized symptom relief as a result of reoperation for recurrent RPS. Others similarly have demonstrated that symptoms were improved in 70% of patients undergoing incomplete resection of primary and recurrent retroperitoneal liposarcoma.26,35 Palliation of symptoms alone in selected patients with recur-
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rent RPS is a good indication for operation because it is often successful. A minority of patients in this series (22%) presented with distant recurrence at the time of local recurrence (Table 5). Other series have reported rates of concurrent metastatic disease to be 20%15,20 to 41%.31 Overall survival of these patients is very poor (Fig. 1), and it is unlikely that resection of locally recurrent disease affects overall survival of these patients. Operation in these patients is, in general, best suited for management of symptoms related to local recurrence, such as intestinal blockage or severe abdominal distention.23 Multifocal presentation of primary and recurrent RPS has been suggested to have a negative impact on survival.23,24 In this study, multifocality was not found to be significantly related to survival in patients with recurrent RPS on multivariate analysis. Stojadinovic and colleagues17 similarly demonstrated that the presence of multifocal disease was not associated with reduced survival after resection of recurrent disease. Multifocality likely has its greatest impact on the surgeon’s ability to obtain complete resection. Anaya and colleagues22 recently reported that patients with greater than 7 sites of disease have a worse prognosis. We were unable to accurately quantitate the exact number of sites of multifocal recurrent disease in this series, but this is something that should be considered in subsequent analyses. The role of radiation therapy has been controversial in the management of primary RPS.1,36 Although numerous reports suggest improved local control of disease with the use of radiation,15,30,37,38 the association of radiation therapy with improved overall survival has been difficult to demonstrate and has dampened widespread enthusiasm for its routine use. We have not found a significant association between radiation and overall survival in patients with recurrent RPS. Based on results of this study and other available data, we advocate regularly scheduled imaging (CT scan of chest, abdomen, and pelvis) after resection of primary RPS every 3 to 6 months for 3 years and then annually thereafter for up to 10 years because many late recurrences have been observed after resection of primary RPS.2,39 In general, we advocate aggressive resection of first and subsequent recurrences of retroperitoneal soft tissue sarcoma (including multifocal recurrences) because resection is associated with improved survival. Resectability rates for FLR among patients with nonmetastatic disease are relatively high (Table 5). Optimal timing of surgical resection remains incompletely defined, and the impact of timing of resection of the recurrent disease on survival remains unknown. It is unclear whether early operation for recurrence improves over-
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all survival or adds to lead time bias associated with survival after resection of recurrent disease.4,25 Delaying operations for resection of recurrent tumors (especially second and third local recurrences) may be a reasonable strategy as long as the delay does not compromise complete resectability and a patient’s symptoms permit continued clinical monitoring. In addition, careful observation of some recurrent tumors, especially those recurring over a short interval, may allow one to identify patients with very aggressive tumor biology who may not benefit from aggressive re-resection.16 Factors that should be considered in deciding on operation include patient comorbidities and age, particularly in light of high reported rates of perioperative complications and the potential mortality associated with performing these complex reoperations.6,12,28,40 Radiation therapy may have a role in reducing further local recurrence and can be considered in patients with unifocal recurrent RPS. We prefer preoperative radiotherapy for patients with recurrent RPS when it is being used. In summary, local recurrence remains a major clinical challenge in the management of patients with recurrent RPS. Although complete excision is less likely in patients with recurrent RPS compared with primary presentation, the ability to achieve complete tumor removal is associated with improved survival and should be strongly considered. Multifocality alone should not preclude operative intervention for locally recurrent RPS. Author Contributions Study conception and design: Grobmyer, Hochwald, Heslin Acquisition of data: Wilson, Apel, Knapik, Bell Analysis and interpretation of data: Grobmyer, Kim, Wilson, Hochwald, Heslin Drafting of manuscript: Grobmyer, Copeland, Bland Critical revision: Copeland, Bland, Hochwald, Heslin
REFERENCES 1. Grobmyer SR, Brennan MF. Treatment of retroperitoneal sarcomas. Adv Surg 2004;38:13–29. 2. Liles JS, Tzeng CW, Short JJ, et al. Retroperitoneal and intraabdominal sarcoma. Curr Probl Surg 2009;46:445–503. 3. Pack GT, Tabah EJ. Primary retroperitoneal tumors: a study of 120 cases. Int Abstr Surg 1954;99:313–341. 4. Lewis JJ, Leung D, Woodruff JM, et al. Retroperitoneal softtissue sarcoma: analysis of 500 patients treated and followed at a single institution. Ann Surg 1998;228:355–365. 5. Singer S, Corson JM, Demetri GD, et al. Prognostic factors predictive of survival for truncal and retroperitoneal soft-tissue sarcoma. Ann Surg 1995;221:185–195. 6. Neuhaus SJ, Barry P, Clark MA, et al. Surgical management of primary and recurrent retroperitoneal liposarcoma. Br J Surg 2005;92:246–252.
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7. Gronchi A, Lo Vullo S, Fiore M, et al. Aggressive surgical policies in a retrospectively reviewed single-institution case series of retroperitoneal soft tissue sarcoma patients. J Clin Oncol 2009;27:24–30. 8. Kilkenny JW 3rd, Bland KI, Copeland EM 3rd. Retroperitoneal sarcoma: the University of Florida experience. J Am Coll Surg 1996;182:329–339. 9. Bevilacqua RG, Rogatko A, Hajdu SI, et al. Prognostic factors in primary retroperitoneal soft-tissue sarcomas. Arch Surg 1991; 126:328–334. 10. Catton CN, O’Sullivan B, Kotwall C, et al. Outcome and prognosis in retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol Phys 1994;29:1005–1010. 11. Karakousis CP, Gerstenbluth R, Kontzoglou K, et al. Retroperitoneal sarcomas and their management. Arch Surg 1995;130: 1104–1109. 12. Jaques DP, Coit DG, Hajdu SI, et al. Management of primary and recurrent soft-tissue sarcoma of the retroperitoneum. Ann Surg 1990;212:51–59. 13. Grobmyer SR, Brennan MF. Predictive variables detailing the recurrence rate of soft tissue sarcomas. Curr Opin Oncol 2003; 15:319–326. 14. Cody HS 3rd, Turnbull AD, Fortner JG, et al. The continuing challenge of retroperitoneal sarcomas. Cancer 1981;47:2147– 2152. 15. Stoeckle E, Coindre JM, Bonvalot S, et al. Prognostic factors in retroperitoneal sarcoma: a multivariate analysis of a series of 165 patients of the French Cancer Center Federation Sarcoma Group. Cancer 2001;92:359–368. 16. Park JO, Qin L, Prete FP, et al. Predicting outcome by growth rate of locally recurrent retroperitoneal liposarcoma. Ann Surg 2009;250:1–6. 17. Stojadinovic A, Yeh A, Brennan MF. Completely resected recurrent soft tissue sarcoma: primary anatomic site governs outcomes. J Am Coll Surg 2002;194:436–447. 18. Potter DA, Glenn J, Kinsella T, et al. Patterns of recurrence in patients with high-grade soft-tissue sarcomas. J Clin Oncol 1985;3:353–366. 19. Linehan DC, Lewis JJ, Leung D, et al. Influence of biologic factors and anatomic site in completely resected liposarcoma. J Clin Oncol 2000;18:1637–1643. 20. Gholami S, Jacobs CD, Kapp DS, et al. The value of surgery for retroperitoneal sarcoma. Sarcoma 2009;2009:605840. Epub 2009 Oct 8. 21. Singer S, Antonescu CR, Riedel E, et al. Histologic subtype and margin of resection predict pattern of recurrence and survival for retroperitoneal liposarcoma. Ann Surg 2003;238:358–370; discussion 370–371. 22. Anaya DA, Lahat G, Liu J, et al. Multifocality in retroperitoneal sarcoma: a prognostic factor critical to surgical decision-making. Ann Surg 2009;249:137–142. 23. van Dalen T, Hoekstra HJ, van Geel AN, et al. Locoregional recurrence of retroperitoneal soft tissue sarcoma: second chance of cure for selected patients. Eur J Surg Oncol 2001;27:564– 568. 24. Anaya DA, Lahat G, Wang X, et al. Postoperative nomogram for survival of patients with retroperitoneal sarcoma treated with curative intent. Ann Oncol 2009 Jul 21. [Epub ahead of print]. 25. Chiappa A, Zbar AP, Biffi R, et al. Primary and recurrent retroperitoneal sarcoma: factors affecting survival and long-term outcome. Hepatogastroenterology 2004;51:1304–1309.
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26. Shibata D, Lewis JJ, Leung DH, et al. Is there a role for incomplete resection in the management of retroperitoneal liposarcomas? J Am Coll Surg 2001;193:373–379. 27. Alldinger I, Yang Q, Pilarsky C, et al. Retroperitoneal soft tissue sarcomas: prognosis and treatment of primary and recurrent disease in 117 patients. Anticancer Res 2006;26:1577–1581. 28. Erzen D, Sencar M, Novak J. Retroperitoneal sarcoma: 25 years of experience with aggressive surgical treatment at the Institute of Oncology, Ljubljana. J Surg Oncol 2005;91:1–9. 29. Marinello P, Montresor E, Iacono C, et al. Long-term results of aggressive surgical treatment of primary and recurrent retroperitoneal liposarcomas. Chir Ital 2001;53:149–157. 30. Heslin MJ, Lewis JJ, Nadler E, et al. Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management. J Clin Oncol 1997;15:2832–2839. 31. Lehnert T, Cardona S, Hinz U, et al. Primary and locally recurrent retroperitoneal soft-tissue sarcoma: local control and survival. Eur J Surg Oncol 2009;35:986–993. 32. Bautista N, Su W, O’Connell TX. Retroperitoneal soft-tissue sarcomas: prognosis and treatment of primary and recurrent disease. Am Surg 2000;66:832–836. 33. Sato T, Yamaguchi T, Azekura K, et al. Repeated resection for intra-abdominal and retroperitoneal liposarcomas: long-term experience in a single cancer center in Japan. Int Surg 2006;91: 267–271. 34. Storm FK, Mahvi DM. Diagnosis and management of retroperitoneal soft-tissue sarcoma. Ann Surg 1991;214:2–10. 35. Yeh JJ, Singer S, Brennan MF, et al. Effectiveness of palliative procedures for intra-abdominal sarcomas. Ann Surg Oncol 2005;12:1084–1089. 36. Pawlik TM, Ahuja N, Herman JM. The role of radiation in retroperitoneal sarcomas: a surgical perspective. Curr Opin Oncol 2007;19:359–366. 37. Pawlik TM, Pisters PW, Mikula L, et al. Long-term results of two prospective trials of preoperative external beam radiotherapy for localized intermediate- or high-grade retroperitoneal soft tissue sarcoma. Ann Surg Oncol 2006;13:508–517. 38. Pacelli F, Tortorelli AP, Rosa F, et al. Retroperitoneal soft tissue sarcoma: prognostic factors and therapeutic approaches. Tumori 2008;94:497–504. 39. Tzeng CW, Smith JK, Heslin MJ. Soft tissue sarcoma: preoperative and postoperative imaging for staging. Surg Oncol Clin North Am 2007;16:389–402. 40. Wente MN, Schwarzbach MH, Hinz U, et al. Perioperative outcome in sarcoma surgery. Langenbecks Arch Surg 2007;392:83–93.
Discussion DR DOUGLAS TYLER (Durham, NC): The authors presented one of the largest series of recurrent retroperitoneal sarcomas, and their management centered around 2 institutions that don’t just play football but have extensive experience in managing sarcomas. Sarcomas are tough to treat, as you heard. They are uncommon. They have multiple histologic subtypes that also have a lot of genetic variation, and they are relatively resistant to chemotherapy and radiation. So, in a time when there are few good treatment options for
ment of primary retroperitoneal sarcoma.3-8 Complete excision rates for primary RPS have been reported to be 65% to 99%.1 Complete tumor resection and grade have been shown to correlate with improved outcomes in patients with primary RPS.4-6,9-13 The role of adjuvant strategies for management of RPS, especially radiation therapy, remain ill defined and controversial.1 The primary site of failure for RPS is local.4,12,14,15 Local recurrence rates are higher in patients with high grade tumors compared with those with low grade tumors.16 Patients with RPS most commonly die of locally recurrent disease associated with multifocal intestinal obstruction and cachexia.4,17-19 There have been several studies that have analyzed patterns of recurrence and outcomes of patients with recurrent RPS; however, most of these reports are small series of patients with variable results and patient outcomes. As a result, controversy persists over the optimal strategy for management of patients with recurrent RPS and the im-
The retroperitoneum is an uncommon site of soft tissue sarcoma, comprising approximately 15% of all soft tissue sarcomas.1,2 Soft tissue sarcoma of the retroperitoneum has a pattern of presentation and biologic behavior distinct from soft tissue sarcoma of the extremity.1 These differences have led to unique therapeutic considerations for management of patients with retroperitoneal sarcoma (RPS). Aggressive surgical resection has long been established and continues to be the most effective strategy for manageDisclosure Information: Nothing to disclose. Presented at Southern Surgical Association 121st Annual Meeting, Hot Springs, VA, December 2009. Received December 10, 2009; Accepted December 15, 2009. From the Departments of Surgery, Division of Surgical Oncology (Grobmyer, Wilson, Kim, Copeland, Hochwald) and Pathology (Knapik), University of Florida, Gainesville, FL; and the Departments of Surgery, Division of Surgical Oncology (Apel, Bland, Heslin) and Pathology (Bell), University of Alabama at Birmingham, Birmingham, AL. Correspondence address: Stephen R Grobmyer, MD, 1600 SW Archer Rd, PO Box 100109, Gainesville, FL 32610.
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pact of therapy on outcomes. For instance, Neuhaus and colleagues6 recently advocated that “recurrence per se is not an indication for operation.” On the other hand, Gholami and colleagues20 believed that “early recognition (of recurrent disease) allows tumors to be identified early and completely removed.” Other areas of ongoing controversy and investigation include the roles of incomplete resection and multimodality therapy on survival and the impact of multifocality on treatment decision making and outcomes. In this study, we reviewed the combined experience of 2 tertiary care centers with first and subsequent recurrences of RPS to gain insight into the nature of recurrent disease and outcomes associated with therapeutic intervention. Current therapeutic approaches to these patients and remaining controversies will be discussed.
METHODS This study was a retrospective review of the experiences of 2 tertiary care centers (The University of Florida and The University of Alabama at Birmingham) with recurrent RPS. Patients evaluated for locally recurrent RPS were identified from pathology and clinical databases from available medical records of patients treated between 1983 and 2008. All available pathologic slides were re-reviewed for purposes of this investigation by JK and WB. Histologic type and grade (high, intermediate, and low) were assigned. We elected not to use histologic subtypes of liposarcoma to facilitate analysis and comparison with other histologies.21 Date of death was determined by review of medical records or the Social Security Death Index. Patient age, presenting symptoms, tumor size, therapy, pattern of recurrence, operation type, and recurrence data were recorded for all patients. Approval was obtained from the IRB at both institutions to perform the study. For this report, “complete resection” was defined as complete gross removal of tumor (R0 or R1) and “incomplete” was defined as partial tumor removal with remaining gross residual disease. For analysis purposes, data from R0 and R1 resections were combined because it was difficult in many situations to retrospectively determine microscopic margin status, and gross tumor removal has been shown to correlate with survival.5 “Multifocality” was defined as “the presence of more than 1 noncontiguous tumor in the abdomen or retroperitoneum.”22 “Local recurrence” was defined as tumors recurring within the retroperitoneum or peritoneal cavity after previous complete gross removal. “Distant recurrence” was defined as discrete sites of metastatic spread to other organs including liver and lung. Statistical analyses included chi-square test or Fisher’s exact test when comparing groups. Survival analyses were performed using Kaplan Meier analysis and Mantel Cox
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Table 1. Pathologic Features of Tumors in 78 Patients with Recurrent Retroperitoneal Sarcoma Pathologic features
Histologic subtype Liposarcoma Leiomyosarcoma Undifferentiated pleomorphic sarcoma Other sarcoma Unknown Grade High Intermediate Low Unknown or undetermined
n
%
42 15 14 4 3
54 19 18 5 4
37 10 28 3
47 13 36 3
Details are for first local recurrence.
test. Cox univariate and multivariate survival analyses were performed to determine which factors were related to overall survival. Comparisons of groups were performed using a chi-square test or Fisher’s exact test as appropriate. Statistical significance was defined as p ⬍ 0.05. Relative risk was reported with 95% confidence intervals for factors achieving statistical significance on multivariate analysis. Mean values are shown as ⫾ standard error of the mean. Median values are shown with range. SAS statistical software was used to perform statistical analyses.
RESULTS Seventy-eight patients with locally recurrent RPS were identified. Forty patients were identified at the University of Alabama Birmingham and 38 were identified at the University of Florida. The mean age of patients at the time of first local recurrence (FLR) in this series was 60 ⫾ 1.5 years. Fifty-three percent of the patients were male and 47% were female. Mean follow-up from the time of FLR for patients in this series was 28 months. Sixty-two patients in this series presented with local recurrence only, and 16 patients presented with local and distant recurrence. The mean time to local recurrence was 36.1 ⫾ 5.2 months. Liposarcoma and leiomyosarcoma were the most common tumor types (Table 1). The grade distribution of tumors is shown in Table 1. Fifty-one percent of patients had FLR detected on routine follow-up imaging examinations. Among documented symptomatic patients at the time of FLR (n ⫽ 33), the most common presenting symptoms were abdominal pain (52%), abdominal fullness (18%), and abdominal cramping/nausea/ vomiting (18%). Operative intervention was successful in improving or eliminating symptoms in most patients (79%). Sixteen patients presented with both local and metastatic disease; 8 patients underwent further operative pro-
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Table 2. Characteristics of 62 Patients with First Local/ Nonmetastatic Recurrence of Retroperitoneal Sarcoma Characteristic
Figure 1. Time after recurrence. Overall survival of 16 patients with both local and distant recurrence of retroperitoneal sarcoma.
cedures, which included resection of recurrent tumor (n ⫽ 4), exploratory celiotomy with biopsy only (n ⫽ 3), and palliative intestinal bypass for obstruction (n ⫽ 1). Median overall survival in this patient group was 12 months. The Kaplan-Meier overall survival curve for this group of patients is shown in Figure 1. Characteristics of patients with FLR without distant recurrence are shown in Table 2. The median total number of operations for patients in this series was 2 (range 1 to 5). A significant difference in survival was associated with resection status of the FLR (p ⫽ 0.0001) (Fig. 2). Patients undergoing complete (p ⫽ 0.001) and incomplete (p ⫽ 0.02) resection of FLR had improved survival compared with those having palliation or biopsy only. Patients undergoing complete resection (R0 or R1) had a significantly
Data
Mean time to first local recurrence ⫾ SE, mo Mean greatest tumor size, ⫾ SE, cm Multifocal tumors,* n (%) Resection type, n (%) R0-R1 R2 None Unknown Contiguous organ resection, n (%) Radiation therapy, n (%) Treatment of first Treatment of recurrence None Chemotherapy, n (%) Treatment of primary Treatment of recurrence None
35 ⫾ 6 14.1 ⫾ 1.5 21 (35) 37 (60) 10 (16) 14 (22) 1 (2) 24 (39) (51)† 19 (31) 22 (35) 21 (34) 2 (3) 6 (10) 54 (87)
*Status not known in 2 patients. † Fifty-one percent of patients undergoing resection for first local recurrence.
improved survival compared with patients having incomplete local resection (R2) (p ⫽ 0.03). Patients undergoing complete local resection of FLR were analyzed to determine which clinical and/or biologic factors were associated with overall survival. The results of this analysis are shown in Table 3. No tumor resection (p ⫽ 0.007) and high grade (p ⫽ 0.0001) were the factors significantly associated with decreased overall survival in patients with FLR. A multifocal recurrence was observed in 35% of patients with FLR of RPS. Multifocal recurrence was significantly more common in patients having an incomplete resection Table 3. Analysis of Factors Associated with Overall Survival among Patients with First Local Recurrence of Nonmetastatic Retroperitoneal Soft Tissue Sarcoma (n ⫽ 62)
Variable
Figure 2. Time after first local recurrence. Overall survival of 62 patients with locally recurrent, nonmetastatic retroperitoneal sarcoma after R0-1 resection (ⴛ, n ⫽ 37); R2 resection (, n ⫽ 10); and supportive therapy (, n ⫽ 14). There is a statistically significant difference between the groups (p ⫽ 0.0001). Resection type was unknown in 1 patient.
Age Time to FLR Size Histology High grade Radiation Multifocal No resection
Univariate analysis p Value
0.32 0.06 0.81 0.18 0.0001 0.48 0.045 0.0001
Multivariate analysis p Value Relative risk (95% CI)
0.0001
5.3* (2.1–14.2)
0.14 0.007
3.6 (1.4–9.2)
*Relative risk of high grade versus low or intermediate grade. FLR, first local recurrence.
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Figure 3. Time after resection for first local recurrence retroperitoneal sarcoma. Overall survival of 47 patients, comparing patients who had nonmetastatic, multifocal tumors (Œ, n ⫽ 16) versus unifocal tumors (, n ⫽ 31). Multifocality was associated with a significantly worse overall survival in these patients (p ⫽ 0.03).
(80%) of FLR compared with patients having a complete resection of FLR (22%) (p ⫽ 0.001). The association of multifocality and overall survival for patients undergoing resection of FLR (complete and incomplete) is demonstrated in Figure 3. Multifocality was associated with a significantly worse overall survival in these patients (p ⫽ 0.03). Patients undergoing resection of high grade FLRs had a worse survival compared with patients with low grade tumors. Survival curves for these patients are shown in Figure 4. Thirty-three patients with second local recurrence presented for management and 11 patients presented with third local recurrence for management. The presenting features of these patients are shown in Table 4. Fewer patients were evaluated with each subsequent local recurrence of RPS. The percentage of resected recurrent tumors that were high grade declined with each subsequent local recurrence: first (35%), second (25%), and third (17%). Kaplan Meier survival analysis of these patients demonstrated that long-
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Figure 4. Time after resection for first local recurrence of retroperitoneal sarcoma. Overall survival of 47 patients, comparing patients who had nonmetastatic, high grade tumors (Œ, n ⫽ 17) versus low/intermediate grade tumors (, n ⫽ 30). High grade was associated with a significantly worse overall survival (p ⫽ 0.004) in these patients.
term survival is possible in the selected patients after resection of second and third recurrences of RPS (Fig. 5). There was no significant difference in overall survival in patients undergoing resection for second versus third local recurrence (Fig. 5). There was also no significant difference in overall survival between selected patients undergoing resection of first, second, or third recurrences (p ⫽ 0.51). In selected patients undergoing operation for third local recurrence, survivals of 51 and 125 months were observed.
Table 4. Comparison of Features of First, Second, and Third Local Recurrence Variable
Mean time interval from prior resection ⫾ SEM, mo With associated distant recurrence, % With multifocal recurrence, % Undergoing complete resection, % total patients/% undergoing resection
FLR (n ⴝ 62)
SLR (n ⴝ 33)
TLR (n ⴝ 11)
35 ⫾ 6
24 ⫾ 3
25 ⫾ 9
21 35
12 48
27 36
60/77
39/65
36/50
FLR, first local recurrence; SLR, second local recurrence; TLR, third local recurrence.
Figure 5. Time after operation for recurrence. Overall survival in patients undergoing operation for second (, n ⫽ 20) and third (Œ, n ⫽ 6) recurrences of retroperitoneal (nonmetastatic) sarcoma. There is no significant difference between the overall survival in the 2 groups (p ⫽ 0.7). Overall survival in these groups is similar to that in patients undergoing operation for first local recurrence (p ⫽ 0.51).
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Table 5. Reported Series of Patients with Recurrent Retroperitoneal Sarcoma of Mixed Histologic Subtypes First author (year)
Jaques (1990)12 Lewis (1998)4 Baustista (2000)32 Van Dalen (2001)23 Chiappa (2004)25 Erzen (2005)28 Pacelli (2008)38 Gholami (2009)20 Lehnert (2009)31 Grobmyer (this series)
Patients with recurrent RPS analyzed, n
Mean time to local recurrence, mo (1st/2nd/3rd)
Complete resection of local recurrence, % (1st/2nd/3rd)
Survival after resection of FLR
47 61* 11 32 19 41 19 15 39 72
NR/NR/NR NR/NR/NR 46/23/26 22/NR/NR 20/NR/NR NR/NR/NR 14/NR/NR 20/NR/NR 12/NR/NR 35/24/25
49/42/33 57/22/10 82/NR/NR 54/NR/NR 62/NR/NR NR/NR/NR NR/NR/NR 100/86/100 61/NR/NR 60/39/36
NR Median 60 mo Median 91 mo 37% @ 60 mo NR 42% @ 60 mo NR NR NR 30% @ 60 mo
*Total number of patients ⫽ 119. FLR, first local recurrence; NR, not reported; RPS, retroperitoneal sarcoma.
DISCUSSION Local recurrence is the primary pattern of recurrence and the major cause of ultimate mortality in patients with RPS.4,12,14,15 FLRs have been reported to occur between 24 and 40 months after primary tumor resection (Table 5). In patients with FLR of RPS, this study found that low grade and complete resection are associated with improved overall survival. These findings are similar to those in some other reports.4 We found disease-free interval, size of recurrent tumor, patient age, histology, mutlifocality, and use of radiation therapy to have no significant relationship to overall survival. Others have reported multifocality,22,23 histology,23,24 blood loss,25 growth rate,16 and disease-free interval26 to be associated with outcomes in patients with recurrent RPS. Complete resection of FLR was accomplished in many patients in this series and in other reported series (Table 5). Resectability rates of FLR are, in general, lower than those reported for primary resections.6 Gholami and associates20 reported, however, 100% complete resectability rates for locally recurrent RPS. Resection of recurrent disease involved contiguous organ resection in 50% of patients in this series. Others have reported similar rates of contiguous organ resection for recurrent RPS.6,12 Some authors have reported that resection of FLR results in survival similar to that after resection of primary disease;23,27,28 others have found that resection of recurrent disease is associated with a decreased overall survival4,12,26 compared with resection of primary disease. In a recent large series from MD Anderson, Anaya and coworkers24 found that locally recurrent presentation was not independently associated with overall survival. Observed differences in outcomes in patients with locally recurrent disease are most likely related to variable case selection and tumor grades in small reported series. In this report, we found that second and third recurrences of retroperitoneal soft tissue sarcoma occur at
shorter intervals after previous resection than FLRs (Tables 4 and 5). Resection of second and third recurrences can result in long-term survival in selected patients (Fig. 5). We and others have found that the ability to achieve complete resection is diminished in second and third recurrences compared with FLRs (Table 5).29 However, resection of second and third recurrences is associated with survival similar to that associated with resection of FLR in this and other series.28 Long-term survival is possible in selected patients undergoing more than 3 reoperations for recurrent RPS, as demonstrated in this study.6,30-33 The goal of reoperation should be complete removal of recurrent disease; however, this is not always technically possible. The association of incomplete resection with improved survival has been controversial.26 Storm and Mahvi34 performed a meta-analysis of reports of incomplete resection for RPS and found improved survival at 5 years (44%) compared with survival in patients having biopsy only (17%). In single institutional series, others have reported no significant difference in survival in patients undergoing incomplete resection compared with biopsy.12,25 This report found that incomplete resection is associated with improved survival compared with no resection. This finding supports attempts to debulk recurrent disease in selected patients in whom complete resection cannot be performed because it may prolong survival in addition to alleviating symptoms related to tumor bulk. Many patients presenting with recurrent retroperitoneal soft tissue sarcoma have symptoms related to the recurrence. Most patients in this series realized symptom relief as a result of reoperation for recurrent RPS. Others similarly have demonstrated that symptoms were improved in 70% of patients undergoing incomplete resection of primary and recurrent retroperitoneal liposarcoma.26,35 Palliation of symptoms alone in selected patients with recur-
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rent RPS is a good indication for operation because it is often successful. A minority of patients in this series (22%) presented with distant recurrence at the time of local recurrence (Table 5). Other series have reported rates of concurrent metastatic disease to be 20%15,20 to 41%.31 Overall survival of these patients is very poor (Fig. 1), and it is unlikely that resection of locally recurrent disease affects overall survival of these patients. Operation in these patients is, in general, best suited for management of symptoms related to local recurrence, such as intestinal blockage or severe abdominal distention.23 Multifocal presentation of primary and recurrent RPS has been suggested to have a negative impact on survival.23,24 In this study, multifocality was not found to be significantly related to survival in patients with recurrent RPS on multivariate analysis. Stojadinovic and colleagues17 similarly demonstrated that the presence of multifocal disease was not associated with reduced survival after resection of recurrent disease. Multifocality likely has its greatest impact on the surgeon’s ability to obtain complete resection. Anaya and colleagues22 recently reported that patients with greater than 7 sites of disease have a worse prognosis. We were unable to accurately quantitate the exact number of sites of multifocal recurrent disease in this series, but this is something that should be considered in subsequent analyses. The role of radiation therapy has been controversial in the management of primary RPS.1,36 Although numerous reports suggest improved local control of disease with the use of radiation,15,30,37,38 the association of radiation therapy with improved overall survival has been difficult to demonstrate and has dampened widespread enthusiasm for its routine use. We have not found a significant association between radiation and overall survival in patients with recurrent RPS. Based on results of this study and other available data, we advocate regularly scheduled imaging (CT scan of chest, abdomen, and pelvis) after resection of primary RPS every 3 to 6 months for 3 years and then annually thereafter for up to 10 years because many late recurrences have been observed after resection of primary RPS.2,39 In general, we advocate aggressive resection of first and subsequent recurrences of retroperitoneal soft tissue sarcoma (including multifocal recurrences) because resection is associated with improved survival. Resectability rates for FLR among patients with nonmetastatic disease are relatively high (Table 5). Optimal timing of surgical resection remains incompletely defined, and the impact of timing of resection of the recurrent disease on survival remains unknown. It is unclear whether early operation for recurrence improves over-
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all survival or adds to lead time bias associated with survival after resection of recurrent disease.4,25 Delaying operations for resection of recurrent tumors (especially second and third local recurrences) may be a reasonable strategy as long as the delay does not compromise complete resectability and a patient’s symptoms permit continued clinical monitoring. In addition, careful observation of some recurrent tumors, especially those recurring over a short interval, may allow one to identify patients with very aggressive tumor biology who may not benefit from aggressive re-resection.16 Factors that should be considered in deciding on operation include patient comorbidities and age, particularly in light of high reported rates of perioperative complications and the potential mortality associated with performing these complex reoperations.6,12,28,40 Radiation therapy may have a role in reducing further local recurrence and can be considered in patients with unifocal recurrent RPS. We prefer preoperative radiotherapy for patients with recurrent RPS when it is being used. In summary, local recurrence remains a major clinical challenge in the management of patients with recurrent RPS. Although complete excision is less likely in patients with recurrent RPS compared with primary presentation, the ability to achieve complete tumor removal is associated with improved survival and should be strongly considered. Multifocality alone should not preclude operative intervention for locally recurrent RPS. Author Contributions Study conception and design: Grobmyer, Hochwald, Heslin Acquisition of data: Wilson, Apel, Knapik, Bell Analysis and interpretation of data: Grobmyer, Kim, Wilson, Hochwald, Heslin Drafting of manuscript: Grobmyer, Copeland, Bland Critical revision: Copeland, Bland, Hochwald, Heslin
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Discussion DR DOUGLAS TYLER (Durham, NC): The authors presented one of the largest series of recurrent retroperitoneal sarcomas, and their management centered around 2 institutions that don’t just play football but have extensive experience in managing sarcomas. Sarcomas are tough to treat, as you heard. They are uncommon. They have multiple histologic subtypes that also have a lot of genetic variation, and they are relatively resistant to chemotherapy and radiation. So, in a time when there are few good treatment options for