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Originally published as JCO Early Release 10.1200/JCO.2008.18.7138 on December 1 2008 © 2009 American Society of Clinical Oncology.
Resection of Some—But Not All—Clinically Uninvolved Adjacent Viscera As Part of Surgery for Retroperitoneal Soft Tissue SarcomasDepartment of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX This issue of Journal of Clinical Oncology includes two retrospective studies evaluating aggressive surgery with wide margins (including resection of clinically uninvolved organs) in patients with primary and recurrent retroperitoneal soft tissue sarcomas.1,2 These reports are thought provoking and should be carefully considered as we evaluate treatment options for patients with retroperitoneal sarcomas. Issues that warrant further discussion in interpreting these findings include the underlying hypothesis, methodologies used, and case selection. The underlying hypothesis behind both reports is that a surgical approach designed to achieve wide macroscopically negative surgical margins may lead to lower rates of microscopically positive surgical margins and presumably lower risks for local recurrence. In the retroperitoneal space, the only way to achieve this objective is to resect clinically uninvolved adjacent organs in an en-bloc fashion. In both studies, patients generally underwent resection of uninvolved ipsilateral kidney, colon, and/or psoas muscle. It is well accepted that the kidney and segments of the colon can usually be resected with relatively low morbidity and that the psoas muscle can be resected with low morbidity if care is taken to preserve the femoral nerve and its roots. However, retroperitoneal sarcomas are also often situated adjacent to other uninvolved retroperitoneal and intra-abdominal viscera (such as the pancreas, spleen, duodenum, and liver), large blood vessels (such as the inferior vena cava, aorta, and portal vein), and functionally significant muscles (such as the rectus abdominis and diaphragm). These adjacent viscera, vessels, and muscles can also be resected when they are clinically involved, but not without substantially greater risks for morbidity and death. The authors of the two retrospective reports did not perform routine resection of these other adjacent viscera, vessels, and muscles, even though these structures were likely just as close to the primary tumor as the colon, kidney, and psoas. Thus the approach of resecting uninvolved adjacent organs was used only selectively—some adjacent organs and muscles were resected en-bloc, but not all adjacent structures that affect final microscopic margins were resected. This is a critical point that is underemphasized in both articles. This strategy extends some, but likely not all, resection margins around sarcomas in the anatomically complex retroperitoneum—a fundamental limitation of the technique that makes it unlikely to confer a clinical benefit for many if not the majority of patients with retroperitoneal sarcomas. Both studies are retrospective and thus have limitations related to the methodology used. Bonvalot et al2 abstracted data from operative reports, pathology reports, and other medical records of 382 patients who underwent surgery at an unspecified number of institutions across France over a 20-year period. Gronchi et al1 retrospectively compared 136 patients treated at a single center over the period 1985 to 2001 and 152 treated after 2001, when more liberal resection was commonly used. Importantly, neither study used standardized methods of performing or reporting preoperative primary tumor imaging (which would enable assessment of which anatomic margins were critical in a given case), neither used standardized reporting of the operative technique or findings (which would enable more precise assessment of whether critical margins were indeed addressed by resection of uninvolved adjacent organs), and neither used standardized methods of processing pathology specimens and reporting pathology findings. Thus numerous data limitations and confounding variables may be at play, and these factors, combined with bias related to case selection (see below), may account in whole or in part for the observed findings. In addition to these substantive issues, we have other interpretative factors to consider. For example, the observed decrease in the cumulative incidence of local recurrence attributed to more frequent resection of uninvolved adjacent organs in the report by Gronchi et al may have arisen because fewer patients in the later period were being treated for recurrent disease (28% v 38% in the early period), and patient follow-up was shorter in the later period (a median of 32 months v 120 months in the early period), both of which could be expected to reduce the cumulative local recurrence incidence. An example of the bias that is introduced into the comparison of patients treated with resection of adjacent uninvolved normal organs with patients who did not undergo this procedure is illustrated by the three computed tomography scans in Figure 1. Clearly, the tumor in Figure 1A can be more easily resected using a liberal approach that includes resection of uninvolved adjacent viscera than the tumor in Figure 1B, which, although of comparable size, is immediately adjacent to and may involve the aorta. In the case illustrated in Figure 1B, the critical margins include the aorta and vertebral column, and thus a surgical approach that includes resection of nearby uninvolved kidney, colon, or psoas will carry both a morbidity and a defined mortality risk, but should not be expected to improve the critical surgical margins in this case, and thus will not likely result in meaningful improvement in local tumor control. Similarly, in the case in Figure 1C, en-bloc resection of the tumor with a subset of adjacent normal organs and muscle—the kidney and psoas—would not address all critical margins. Thus it is likely that treating the patient in Figure 1A with liberal resection of the tumor plus adjacent uninvolved viscera would result in more durable local control than treating the patients in Figure 1B or 1C with such a resection. Because each patient in the two retrospective reports received the surgical procedure that the operating surgeon considered to be most feasible, the cases selected for resection of uninvolved adjacent viscera were probably more like Figure 1A than Figures 1B or 1C. With such nonrandom procedure selection, a series of patients with tumors similar to that in Figure 1A treated by resection of the primary tumor and adjacent normal colon, kidney, and/or psoas will almost certainly have better local control than a series of patients who have tumors with more locally advanced anatomy (similar to those in Figs 1B and 1C) and are therefore treated by excision of the primary tumor without resection of a subset of the adjacent uninvolved viscera. Given the procedure selection bias that is inherently present in these retrospective comparisons, we must be cautious in extending the findings of these retrospective reports to support routine resection of uninvolved adjacent viscera, vessels, or nerves.
The overall survival data presented in these manuscripts also warrant comment. No overall survival difference attributable to more aggressive surgery was observed in either report. This is of course similar to the experience in extremity soft tissue sarcomas, for which amputation (a definitive method to achieve negative margins) offers no overall survival benefit compared with function-preserving surgery and radiation.3 Thus although liberal resection of adjacent uninvolved viscera may allow a subset of patients to more consistently achieve microscopically negative resection margins, just as amputation does for extremity sarcomas, it is not at all clear that additional resection will translate into an improvement in sarcoma-specific survival. We must also carefully consider these results in the context of the adjuvant therapies offered to these patients. Gronchi et al1 report increased use of adjuvant chemotherapy during the later period of their study, yet statistically significantly more patients during the later period developed metastatic disease (cumulative incidence of metastatic disease, 13% in the early period v 22% in the more recent period; P = .0125). Given that prognostic factors in the two groups were similar, this finding suggests changes in the referral population over time and highlights the relative ineffectiveness of adjuvant chemotherapy for retroperitoneal soft tissue sarcomas. The use of radiation and its potential role in improving local control are also important to consider. Certainly, the use of radiation may abrogate the adverse prognostic significance of a microscopically positive surgical margin. Radiation was used in 32% of patients in the series from Bonvalot et al,2 but its potential impact on local recurrence was not evaluated in their multivariate analysis. Gronchi et al1 also used radiation in a comparable fraction of patients (31%) and found that it was associated with a significant improvement in overall survival (hazard ratio, 0.55; 95% CI, 0.35 to 0.86; P = .0081), but not relapse-free survival. Again, the possibility of selection bias must be considered in interpreting these findings; perhaps only the smaller tumors that could be safely treated with radiation were so treated, whereas the larger tumors, with their intrinsically greater risk of local failure and incomplete surgery, were not treated with pre- or postoperative radiation because of the prohibitively large radiation volumes that would have been required. Thus I do not feel that definitive conclusions can or should yet be drawn about the use of radiation or adjuvant chemotherapy with wide resection of retroperitoneal sarcomas. Of importance in assessing the efficacy of any surgical procedure are the short- and long-term adverse effects of the procedure. Because Bonvalot et al2 were relying on a retrospective review of medical records submitted from hospitals across France over a 20-year period, their ability to evaluate adverse effects was understandably limited. Nonetheless, Bonvalot et al report that 11% of patients underwent re-operation for management of surgical complications. This is an unusually high (arguably unacceptably high) rate of re-operation, although it is not clear from the article to what extent this rate was due to resection of uninvolved normal viscera. Gronchi et al1 provided no data on short- or long-term risks associated with resecting uninvolved adjacent viscera. Future studies of aggressive surgical approaches need to include rigorous assessment of the adverse effects of the treatment. Regarding resection of uninvolved viscera in treating retroperitoneal sarcoma, of particular interest would be the long-term incidence of femoral neuropathy and renal insufficiency and any limitations on subsequent ifosfamide chemotherapy for adjuvant or metastatic treatment. What about the possibility that resection of the tumor plus uninvolved adjacent viscera might be best used for patients with low- or intermediate-grade tumors? Gronchi et al1 make this point in the discussion of their findings and speculate that more aggressive local therapy may benefit patients with less aggressive tumors who have the potential to be cured through local treatment alone. This seems logical in that the majority of patients with low-grade tumors have an extremely low risk for metastatic disease and thus, by definition, can be considered potentially curable with local treatment. Paradoxically, the same patients may have indolent disease that can remain asymptomatic for years. Indeed, in some circumstances, asymptomatic patients can be "treated" by active surveillance, with surgery reserved for the subset of patients who develop symptoms or unequivocal radiologic evidence of disease progression (Fig 2). Thus we have polar opposite management options for the subset of patients with asymptomatic low-grade retroperitoneal liposarcoma: active surveillance until symptoms or disease progression versus surgery with multivisceral resection including a subset of uninvolved adjacent organs. To date, no studies have directly compared these management approaches from the perspectives of quality of life, morbidity, economic cost, or sarcoma-specific outcomes. In fact, many issues remain unresolved in these patients, including the optimal management of primary disease, the role of radiation therapy, and the role and timing of reoperative surgery for locally recurrent disease.
So we are left with the conundrum of how to interpret these two articles that evaluate a new treatment strategy for patients with retroperitoneal sarcomas. Until better safety data and more convincing outcome data are available, we should not use the retrospective data from these studies, given the myriad of interpretative issues and the presence of various forms of bias, to change the surgical approach to patients with retroperitoneal sarcomas. Instead, I believe these articles should be considered hypothesis-generating rather than practice-changing. Unfortunately, the challenges of studying the question of more extensive surgery in a randomized trial are formidable. A North American phase III trial designed to evaluate the role of radiation for retroperitoneal soft tissue sarcomas closed owing to slow accrual, which itself was due to factors that included lack of clinical equipoise within and between multidisciplinary groups on whether radiation should be included in the local treatment of nonmetastatic retroperitoneal sarcomas. Studying the question of more extensive surgery might also be met with lack of agreement among surgeons and challenges in defining eligibility criteria. Examples of such challenges include the issue of defining objective anatomic criteria for eligibility (eg, would the patients in Figs 1B or 1C be eligible for a trial of resection of adjacent uninvolved viscera and vessels?) and whether such a trial should include patients with high-grade disease, who face a competing risk from distant metastatic disease that is not impacted in any way by more aggressive surgery. If such a trial were restricted to patients with low-grade disease (predominantly atypical lipomatous tumors or low-grade liposarcomas), would asymptomatic patients who could arguably be treated with risk-adapted active surveillance accept a therapy that includes resection of normal uninvolved viscera? There is no question that the surgical community should carefully consider these feasibility and design issues while simultaneously working to scale the barriers to multicenter and international collaboration—an essential element of such a trial. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES
1. 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 doi:10.1200/JCO.2008.17.8871 [epub ahead of print on December 1, 2008] 2. Bonvalot S, Rivoire M, Castaing M, et al: Primary retroperitoneal sarcomas: A multivariate analysis of surgical factors associated with local control. J Clin Oncol doi:10.1200/JCO.2008.18.0802 [epub ahead of print on December 1, 2008] 3. Rosenberg SA, Tepper JE, Glatstein EJ, et al: The treatment of soft-tissue sarcomas of the extremities: Prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 196:305-315, 1982[Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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