ORIGINAL ARTICLE
Management of Unplanned Excision for Soft-Tissue Sarcoma With Preoperative Radiotherapy Followed by Definitive Resection Daniel A. Jones, MD,* Charles Shideman, MD, PhD,* Jianling Yuan, MD, PhD,* Kathryn Dusenbery, MD,* J. Carlos Manivel, MD,wz Christian Ogilvie, MD,y Denis R. Clohisy, MD,y Edward Y. Cheng, MD,y Ryan Shanley, MS,8 and L. Chinsoo Cho, MD*
Background and Objectives: The purpose of this study was to review the outcomes after preoperative radiotherapy and definitive surgery for patients who initially had inadvertent excision for sarcoma. Materials and Methods: Treatment records of 44 consecutive patients, who initially underwent unplanned excision of soft-tissue sarcoma between January 2004 and January 2012, were reviewed. All patients had clinically localized disease before treatment and received preoperative external-beam radiotherapy followed by definitive oncologic surgery at our institution. Results: The median follow-up was 36 months. Residual tumor after preoperative radiotherapy and wound bed excision was identified in 39% (17/44) of the cases. Kaplan-Meier estimates for 5-year local control, recurrence-free survival, and overall survival are 95% (95% confidence interval [CI], 80-99), 86% (95% CI, 69-94), and 94% (95% CI, 79-99) respectively. Perioperative morbidity occurred in 25% of patients (11/44.) All patients with perioperative wound complications had lower extremity sarcomas. Conclusions: Optimal management for unplanned excision of softtissue sarcoma is unknown. Our institution has adopted the approach of preoperative radiotherapy, followed by definitive surgery. In our series of 44 patients, local control was excellent at 95%, with perioperative complications seen only in patients with lower extremity sarcomas, suggesting that this is a reasonable approach to manage inadvertently resected sarcoma. Key Words: sarcoma, preoperative radiotherapy, unplanned excision
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n the management of peripheral soft-tissue sarcomas, limbsparing surgery and adjuvant radiotherapy has been standard of care since the landmark NCI study.1 Compared with surgery alone, radiotherapy improves local control, without impacting overall survival (OS).2 Wide local excision with clear margins remains the goal of treatment for soft-tissue sarcoma. Surgical margins have been defined as intralesional, marginal, wide, or radical.3 Uncontrolled or positive surgical margins may result in higher rates of local failure, despite the administration of adjuvant radiotherapy.4–6 Inadvertent surgery is performed when an attempt is made to excise a mass mistakenly believed to be benign. It usually indicates a gross surgical removal of tumor without preoperative staging or oncologic removal of normal tissue around the tumor. Reoperation is often required because of the high likelihood of residual disease.7 Inadvertent simple excision of sarcoma presents a challenge for management. Rates of unplanned excision range from 18% to 54% in selected series.8–10 In 1 report, 47% of patients presented with gross residual disease.9 Reresection and reconstruction may be more difficult after unplanned resection.11,12 Postoperative radiation therapy fields are implicitly larger to include disturbed skin, fascial planes, compartments, and previous drain sites. Since 2004, it has been the policy at the University of Minnesota Medical Center to irradiate all cases of inadvertent surgery before definitive oncologic resection by the orthopedic oncology services. The purpose of this study was to review the outcomes of patients in this cohort.
MATERIALS AND METHODS From the Departments of *Radiation Oncology; wLaboratory Medicine and Pathology; yOrthopedic Surgery, University of Minnesota Affiliated Hospitals; 8Biostatistics and Bioinformatics Core, Masonic Cancer Center, University of Minnesota; and zDepartment of Laboratory Medicine and Pathology, Veterans Administration Medical Center, Minneapolis, MN. D.A.J., C.S., J.Y., K.D., L.C.C., J.C.M., C.O., D.C., E.C., and R.S.: manuscript writing; D.A.J.: data collection; D.A.J., K.D., L.C.C., C.O., D.C., E.C.: management of patients; J.C.M.: interpretation of pathologic specimens; RS: statistical analysis. Presented in poster format, ASTRO, American Society for Radiation Oncology 2013, Atlanta, GA, September 22-25, 2013. The authors declare no conflicts of interest. Reprints: Daniel A. Jones, MD, Masonic Memorial Building, 424 Harvard St. SE, Room M26, Minneapolis, MN 55455. E-mail: [email protected]. Copyright r 2014 by Lippincott Williams & Wilkins ISSN: 0277-3732/14/000-000 DOI: 10.1097/COC.0000000000000095
American Journal of Clinical Oncology
The retrospective study was approved by the University of Minnesota IRB. The treatment records of patients who presented after having undergone an inadvertent excision for soft-tissue sarcoma between the years of January of 2004 and January of 2012 were included. Nearly all patients were referred from outside of the University of Minnesota Medical Center. All patients were evaluated in a multidisciplinary manner before definitive treatment. Preoperative tumor imaging was usually not available. Further workup included physical examination, imaging of the primary site, and soft-tissue compartment with a contrast-enhanced magnetic resonance imaging (MRI), and staging of the chest, usually with computed tomography (CT). Patients with evidence of metastatic disease on presentation or with histologies such as rhabdomyosarcoma, Ewing sarcoma, medullary osteosarcoma, and desmoid tumors were excluded from the analysis. Since 2004,
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patients presenting with inadvertent excision of sarcoma were managed in a consistent manner of preoperative radiotherapy followed by surgery regardless of the anatomic site, size, or grade of the sarcoma. Treatment records of 44 consecutive patients met the above stated inclusion criteria. For the purpose of this study, the lower extremity is defined the thigh, buttock, leg, and foot. The upper extremity is defined as the supraclavicular fossa, shoulder, arm, forearm, and hand. Preoperative imaging, when available and gross description from the pathology reports were used to estimate the tumor size. The prior inadvertent surgical resection was defined as, as intralesional, marginal, or wide.3 Intralesional or subtotal resection encompassed resection by a piecemeal or intracapsular fashion. Marginal or gross total resection included an attempted simple excisional biopsy. None of the patients had initial resection considered to be oncologically adequate for sarcoma. All patients received preoperative radiotherapy with 3D conformal technique or in some cases with en face electrons. No patient received boost radiotherapy, postoperatively. The preoperative gross tumor volume was reconstructed to the best of our ability based on preoperative clinical and pathologic information. Field sizes varied based on tumor location and extent of the original surgery. Typically, 3 cm was added in craniocaudal directions to both preoperative gross tumor volume and the operative bed, and 1 to 2 cm was added in all directions in the axial plane to create a treatment clinical treatment volume (CTV). The CTV also included the previous surgical scar, changes visible on CT or MRI scan after the inadvertent surgery, and drainage sites. Additional margin of 1 cm was added to the block edge to account for daily set up variability. The prescription dose covered the CTV. Patients were immobilized in a treatment position that allowed optimal gantry angles. Bolus was not routinely added to the skin unless the skin was known to be involved. When possible, the entire circumference of a weight-bearing bone was spared with full dose, such as the femur or the tibia. A portion of skin and soft tissues were spared to facilitate rechanneling of lymphatics in all patients. Generally, at least 1/3 of the circumference received 5 cm) tumors, and those with multiple factors such as deep location, high grade, and large size predict for residual tumor after unplanned excision.10 In addition to the final surgical margin, the evidence of residual disease may be a poor risk factor. Patients with residual disease after definitive surgery are at higher risk for LR which may contribute to a higher rate of distant metastasis and worse survival. Davis et al6 reported that recurrence rates were 16.6% of the patients with residual disease and only 1.6% for patients without residual disease. Similarly, Rehders and colleagues reported superior outcomes in those without residual disease. With a median follow-up of 98 months, those without residual disease had significantly better RFS (P = 0.0002), distant metastasis-free survival (P = 0.0024), and OS (P = 0.0007).21 In a separate report, even patients with evidence of only microscopic residual disease had higher incidence of distant metastasis on multivariate analysis (P = 0.002).22 In the current study, 18 of 44 (40.9%) had residual disease, but ultimately too few events of recurrences occurred to analyze this endpoint. Interestingly, others found no difference and possibly an improvement in outcome for those undergoing unplanned surgery compared with those with standard primary sarcoma treatment. Lewis and colleagues reviewed 1092 patients who underwent both primary management of sarcoma and those who underwent additional surgery after inadvertent excision. The 5-year disease-free survival (DFS) and distant metastasisfree survival (DMFS) rates in those with reresection versus primary resection was (88% vs. 70%, P = 0.001) and (83% vs. 63%, P = 0.0001), respectively. After controlling for patient factors, the DFS difference remained significant. The author credited retrospective bias to the unexpected findings.17 Fiore et al22 found no difference in clinical outcomes between those who underwent reexcision after inadvertent surgery and patients who underwent primary sarcoma management. One of the potential benefits of avoiding an unplanned excision is to reduce treatment related morbidity. After inadvertent excision, many patients present with transverse excisions, remote placement of drains, and other potential sites of contamination. In addition, preoperative imaging studies are often unavailable. Reresection and reconstruction may be more difficult and complex after unplanned excision due to the need to resect a greater amount of tissues.11,12 Furthermore, radiotherapy fields must include greater areas of possible contamination which may increase the possibility of radiotherapy induced acute and chronic complications. Outcomes of patients after unplanned excision are highly variable. Select series have been highlighted in Table 3. It must be understood that this is a heterogeneous group of patients and results are not directly comparable. Differences exist in location, size, and grade of sarcoma. Most reports incorporate reexcision, with adjuvant radiotherapy as part of the regimen. Patients without residual tumor in the operative bed are reported to have good prognosis. After reresection, a study r
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Unplanned Excision
reported a local control rate of 90% in this favorable population.10 Zagars et al8 also reported an estimated local control of 93% at 15 years in 129 patients with negative surgical margin given radiotherapy without reresection. In the current series of 44 patients, 5 patients presented after a marginal excision with a negative margin originally, and thus would have been predicted to do well. However, all 5 either had a high-grade or large ( > 5 cm) tumor and would have required adjuvant radiotherapy. Therefore, the patients in the current study would not have received unnecessary courses of radiotherapy. Most series have used at least selective adjuvant radiotherapy after reexcision for high-risk factors (Table 3). Authors often commented that radiotherapy was given at the discretion of the radiation oncologist as a multidisciplinary recommendation without predetermined criteria. It would be difficult to comment on reexcision alone as a treatment option, as a majority of patients making up selected series received radiotherapy as part of their management. In a cohort managed similarly to ours, Giuliano and Eilber,7 demonstrated 94.5% local control at 5 years, delivering preoperative radiotherapy, followed by wound bed reexcision. Occasionally, postoperative radiotherapy alone is administered after inadvertent surgery in patients who are either medically inoperable or in whom further surgery would increase the morbidity, significantly. In a report by Kepka and colleagues, 78 patients with “small burden” disease and those who could not undergo reresection due to a variety of factors underwent radiotherapy alone to a median dose of 66 Gy (51 to 88 Gy.) The LRFS at 10 years was 86%, and the OS rate was 65%. Severe toxicity occurred in 10 patients (12.8%) resulting in neuropathy, bone fracture, and fibrosis. The severe toxicity was limited to those who received 66 Gy and above.23 In the previously mentioned study by Zagars et al,8 371 of the 666 patients were not reexcised, and received radiotherapy alone to total dose ranges of 60 to 70 Gy. The 15-year LC, DFS, causespecific survival, and DMFS were 73%, 48%, 65%, and 64%, respectively. The DFS and DMFS in the radiotherapy alone group was inferior to the group that had been reexcised before radiotherapy (48% vs. 63%, Pr0.001) and (64% vs. 75%, P = 0.004). The value of surgical reexcision is to optimize local control, and based on the findings of Zagars and colleagues, those with reexcision may also benefit in terms of DFS and DMFS. There was no patient in the current study who received radiotherapy alone without reresection. The addition of reresection likely does not impact OS, but this has not been reported in a prospective manner to our knowledge. Although cumulative morbidity may be higher after completing therapy in a patient with unplanned excision, it is doubtful that oncologic outcomes are compromised. In the Canadian randomized control trial, where preoperative radiotherapy was followed by definitive resection, local control, RFS, and OS at 5 years were reported to be 93%, 58%, 73%, respectively. Local control outcomes are similar to what we have reported. Although the patients are not directly comparable RFS and OS appears to be better in the current study. There are obvious differences between the current retrospective study and the prospective Canadian study. For example, 16% of the patients in the Canadian preoperative arm were purely superficial tumors, whereas 90.9% of ours were, possibly explaining better RFS/OS in our cohort. OS in our group was very good at 94% (95% CI, 79-99) and while this may appear better than historical reports, our group represents a highly selected cohort, with a majority having small, superficial sarcomas. Furthermore, follow-up is short, with a www.amjclinicaloncology.com |
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TABLE 3. Selected Series Reporting Outcomes of Unplanned Excision
References/ Institution Giuliano and Eilber7 Davis et al6
Patient Number, Years Studied, Follow-up Interval 90 Dates NR Median 36 mo 239 1986-1994 Median 37 mo
Zagars et al8
666 1960-1999 15 y
Kepka et al23
78 1970-1997 Median 10 y
Manoso et al20 Potter et al24 Hoshi et al11 Chandrasekar et al10
Han et al18 University of Minnesota
Patients With Reexcision (%)
RT Regiment, Dose (If Noted)
Local Control, 5 y (%)
Other Endpoints, Year (%)
100
Preoperative 82 Gy (35 Gy) PORT 3 Gy (50-60 Gy)
94.5
NR
100
Preoperative 95 Gy (50 Gy) PORT 55 Gy (60-66 Gy) Preoperative-POB 36 Gy (66 Gy total) Preoperative 121 Gy (50 Gy) PORT 174 Gy (60-70 Gy) RT alone 371 Gy (60-70 Gy)
91.6
5y DM 26.8
Reresection 85 No reresection 78
Reresection 5, 10, 15 y DFS (69/67/63) No reresection 5, 10, 15 y DFS (54/49/48) 5, 10 y OS (78/65) CSS (82/77) DMFS (80) 5y DFS 82 OS 91 NR
44
0
RT alone 78 Gy (median 66 Gy)
LRFS 88
38 1993-1999 5y 64 1989-2005 Minimum 24 mo 38 1982-2007 Mean 43 mo 363 1982-2005 Median 40 mo
100
Various regiments including EBRT, brachy, both preoperative and postoperative PORT 41 Mostly PORT
95
95
PORT 9 RT alone 2
NR
87
PORT 118 RT alone 19
79 No reresection 66
104 1985-2007 Median 4.7 y 44 2004-2012 Median 36 mo
100
PORT 44 Gy (median 60 Gy)
74
100
Preoperative 44 Gy (median 50 Gy)
95
100
66
5y EFS 54.6 OS 76.3 5y OS 77 DM 24 No reresection DM 28 5, 10 y DSS 88/81 5y RFS 85 OS 94
Data are for 5 years unless otherwise stated. Brachy indicates brachytherapy implant; CSS, cause-specific survival; DFS, disease-free survival; DM, distant metastasis; DMFS, distant metastasis-free survival; LRFS, local recurrence-free survival; NR, not reported; OS, overall survival; Preoperative, preoperative RT, followed by reexcision; Preoperative-POB, preoperative RT, reexcision, followed by postoperative RT boost; PORT, reexcision followed by RT; RT alone, RT alone without reexcision; RT, regiment.
minimum of 12 months, and these patients remain at risk for failure. Preoperative radiotherapy is an acceptable alternative to postoperative radiotherapy with regards to managing soft-tissue sarcoma and limb preservation. Both methods have similar outcomes with regards to local control and OS. The main differences reside in the quality and timing of toxicity. Preoperative RT may result in higher perioperative morbidity. Postoperative RT results in greater long-term toxicity, namely fibrosis, edema, impaired functionality, and bone fracture.25 Although the referenced studies contained a significant number of patients who underwent preoperative radiotherapy, differences in outcome between patients who received preoperative and postoperative radiotherapy were not specifically stated.6–8 Eleven patients (25%) in the current study experienced significant perioperative toxicity. All 11 patients had lower extremity sarcomas. This is similar to the toxicity reported by
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O’Sullivan and colleagues who reported 35% perioperative toxicity. As in our series, patients with tumors in the lower extremity were at a higher risk for perioperative toxicity.13 Long-term toxicity is more difficult to assess, objectively. Because of limited clinical events during the follow-up period, long-term toxicity cannot be ascertained in the current study. Manoso and colleagues reported extensively on long-term functional outcomes in patients who underwent unplanned excision for sarcoma. Functional evaluation was performed using the musculoskeletal tumor society grading system. At a median of 63 months, 84% had “good to excellent” functional outcomes.20 However, it remains challenging to compare longterm outcomes of heterogeneous group of patients. The role of chemotherapy in nonmetastatic soft-tissue sarcoma is not well established. Chemotherapy either with doxorubicin-based or ifosfamide-based regimens has demonstrated mixed results.26,27 One patient in our series did receive chemotherapy before radiation therapy and reresection. To our r
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knowledge, chemotherapy has not been studied prospectively in patients with unplanned excision of sarcoma. The current study has expected limitations. It is a retrospective study analyzing a treatment policy at a single institution. The number of patients is modest and the patient characteristics are heterogeneous. However, the review represents outcomes after following a consistent treatment policy involving both radiotherapy and surgery. It remains unclear whether all patients need radiotherapy or additional reresection after inadvertent surgery. Adequate radiologic evaluation and assessment by a team with expertise in diagnostic and therapeutic aspects of sarcoma should decrease the frequency of inadvertent surgery for these neoplasms. The management of patients with unplanned excision of soft-tissue sarcomas should be carried out at institutions with interdisciplinary teams with expertise in the treatment of these tumors and should follow well-defined protocols that allow standardization of treatment and comparison of results.
9. 10. 11. 12. 13.
14. 15.
CONCLUSIONS Optimal management for unplanned excision of soft-tissue sarcoma is unknown and reexcision plays an important role. There is high risk for residual disease in the tumor bed even in those who are clinically negative. It remains the goal of sarcoma treatment to minimize the chance of residual disease after local treatment. Our institution has adopted the approach of preoperative radiotherapy followed by definitive surgery with excellent local control with perioperative complications seen only in patients with lower extremity sarcomas.
16.
17. 18. 19.
REFERENCES 1. Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of softtissue 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. 1982;196:305–315. 2. Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol. 1998;16: 197–203. 3. Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop. 1980; 153:106–120. 4. Zagars G, Ballo MT, Pisters PW, et al. Prognostic factors for patients with localized soft-tissue sarcoma treated with conservation surgery and radiation therapy: an analysis of 1225 patients. Cancer. 2003;97:2530–2543. 5. Trovik CS. Local recurrence of soft tissue sarcoma. A Scandinavian Sarcoma Group Project. Acta Orthop Scand. 2001;72:1–31. 6. Davis AM, Kandel RA, Wunder JS, et al. The impact of residual disease on local recurrence in patients treated by initial unplanned resection for soft tissue sarcoma of the extremity. J Surg Oncol. 1997;66:81–87. 7. Giuliano AE, Eilber FR. The rationale for planned reoperation after unplanned total excision of soft-tissue sarcomas. J Clin Oncol. 1985;3:1344–1348. 8. Zagars G, Ballo MT, Pisters PW, et al. Surgical margins and reresection in the management of patients with soft tissue sarcoma
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20. 21. 22. 23. 24. 25.
26.
27.
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using conservative surgery and radiation therapy. Cancer. 2003; 97:2544–2553. Noria S, Davis A, Kandel R, et al. Residual disease following unplanned excision of soft-tissue sarcoma of an extremity. J Bone Joint Surg Am. 1996;78:650–655. Chandrasekar CR, Wafa H, Grimer RJ, et al. The effect of an unplanned excision of a soft-tissue sarcoma on prognosis. J Bone Joint Surg Br. 2008;90:203–208. Hoshi M, Ieguchi M, Takami M, et al. Clinical problems after initial unplanned resection of sarcoma. Jpn J Clin Oncol. 2008;38: 701–709. Arai E, Nishida Y, Tsukushi S, et al. Clinical and treatment outcomes of planned and unplanned excisions of soft tissue sarcomas. Clin Orthop. 2010;468:3028–3034. O’Sullivan B, Davis A, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet (London, England). 2002;359: 2235–2241. Coindre JM, Trojani M, Contesso G, et al. Reproducibility of a histopathologic grading system for adult soft tissue sarcoma. Cancer. 1986;58:306–309. Edge S, Byrd D, Compton C, et al. AJCC Cancer Staging Manual. 7th ed. Chicago: Springer; 2010. Trovik CS, Bauer HC, Alvega˚rd TA, et al. Surgical margins, local recurrence and metastasis in soft tissue sarcomas: 559 surgicallytreated patients from the Scandinavian Sarcoma Group Register. Eur J Cancer. 2000;36:710–716. Lewis JJ, Leung D, Espat J, et al. Effect of reresection in extremity soft tissue sarcoma. Ann Surg. 2000;231:655–663. Han I, Kang H, Kang S, et al. Does delayed reexcision affect outcome after unplanned excision for soft tissue sarcoma? Clin Orthop. 2011;469:877–883. Qureshi YA, Huddy JR, Miller JD, et al. Unplanned excision of soft tissue sarcoma results in increased rates of local recurrence despite full further oncological treatment. Ann Surg Oncol. 2012;19:871–877. Manoso M, Frassica D, Deune EG, et al. Outcomes of re-excision after unplanned excisions of soft-tissue sarcomas. J Surg Oncol. 2005;91:153–158. Rehders A, Stoecklein NH, Poremba C, et al. Reexcision of soft tissue sarcoma: sufficient local control but increased rate of metastasis. World J Surg. 2009;33:2599–2605. Fiore M, Casali P, Miceli R, et al. Prognostic effect of re-excision in adult soft tissue sarcoma of the extremity. Ann Surg Oncol. 2006;13:110–117. Kepka L, Suit H, Goldberg S, et al. Results of radiation therapy performed after unplanned surgery (without re-excision) for soft tissue sarcomas. J Surg Oncol. 2005;92:39–45. Potter B, Adams S, Pitcher JD, et al. Local recurrence of disease after unplanned excisions of high-grade soft tissue sarcomas. Clin Orthop. 2008;466:3093–3100. Davis A, O’Sullivan B, Turcotte R, et al. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol. 2005;75:48–53. Sarcoma Meta-analysis Collaboration (SMAC). Adjuvant chemotherapy for localised resectable soft tissue sarcoma in adults. Cochrane Database of Systematic Reviews. 2000(4):CD001419. DOI: 10.1002/14651858.CD001419. Woll P, Reichardt P, Le Cesne A, et al. Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected softtissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Lancet Oncol. 2012;13:1045–1054.
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Management of Unplanned Excision for Soft-Tissue Sarcoma With Preoperative Radiotherapy Followed by Definitive Resection Daniel A. Jones, MD,* Charles Shideman, MD, PhD,* Jianling Yuan, MD, PhD,* Kathryn Dusenbery, MD,* J. Carlos Manivel, MD,wz Christian Ogilvie, MD,y Denis R. Clohisy, MD,y Edward Y. Cheng, MD,y Ryan Shanley, MS,8 and L. Chinsoo Cho, MD*
Background and Objectives: The purpose of this study was to review the outcomes after preoperative radiotherapy and definitive surgery for patients who initially had inadvertent excision for sarcoma. Materials and Methods: Treatment records of 44 consecutive patients, who initially underwent unplanned excision of soft-tissue sarcoma between January 2004 and January 2012, were reviewed. All patients had clinically localized disease before treatment and received preoperative external-beam radiotherapy followed by definitive oncologic surgery at our institution. Results: The median follow-up was 36 months. Residual tumor after preoperative radiotherapy and wound bed excision was identified in 39% (17/44) of the cases. Kaplan-Meier estimates for 5-year local control, recurrence-free survival, and overall survival are 95% (95% confidence interval [CI], 80-99), 86% (95% CI, 69-94), and 94% (95% CI, 79-99) respectively. Perioperative morbidity occurred in 25% of patients (11/44.) All patients with perioperative wound complications had lower extremity sarcomas. Conclusions: Optimal management for unplanned excision of softtissue sarcoma is unknown. Our institution has adopted the approach of preoperative radiotherapy, followed by definitive surgery. In our series of 44 patients, local control was excellent at 95%, with perioperative complications seen only in patients with lower extremity sarcomas, suggesting that this is a reasonable approach to manage inadvertently resected sarcoma. Key Words: sarcoma, preoperative radiotherapy, unplanned excision
(Am J Clin Oncol 2014;00:000–000)
I
n the management of peripheral soft-tissue sarcomas, limbsparing surgery and adjuvant radiotherapy has been standard of care since the landmark NCI study.1 Compared with surgery alone, radiotherapy improves local control, without impacting overall survival (OS).2 Wide local excision with clear margins remains the goal of treatment for soft-tissue sarcoma. Surgical margins have been defined as intralesional, marginal, wide, or radical.3 Uncontrolled or positive surgical margins may result in higher rates of local failure, despite the administration of adjuvant radiotherapy.4–6 Inadvertent surgery is performed when an attempt is made to excise a mass mistakenly believed to be benign. It usually indicates a gross surgical removal of tumor without preoperative staging or oncologic removal of normal tissue around the tumor. Reoperation is often required because of the high likelihood of residual disease.7 Inadvertent simple excision of sarcoma presents a challenge for management. Rates of unplanned excision range from 18% to 54% in selected series.8–10 In 1 report, 47% of patients presented with gross residual disease.9 Reresection and reconstruction may be more difficult after unplanned resection.11,12 Postoperative radiation therapy fields are implicitly larger to include disturbed skin, fascial planes, compartments, and previous drain sites. Since 2004, it has been the policy at the University of Minnesota Medical Center to irradiate all cases of inadvertent surgery before definitive oncologic resection by the orthopedic oncology services. The purpose of this study was to review the outcomes of patients in this cohort.
MATERIALS AND METHODS From the Departments of *Radiation Oncology; wLaboratory Medicine and Pathology; yOrthopedic Surgery, University of Minnesota Affiliated Hospitals; 8Biostatistics and Bioinformatics Core, Masonic Cancer Center, University of Minnesota; and zDepartment of Laboratory Medicine and Pathology, Veterans Administration Medical Center, Minneapolis, MN. D.A.J., C.S., J.Y., K.D., L.C.C., J.C.M., C.O., D.C., E.C., and R.S.: manuscript writing; D.A.J.: data collection; D.A.J., K.D., L.C.C., C.O., D.C., E.C.: management of patients; J.C.M.: interpretation of pathologic specimens; RS: statistical analysis. Presented in poster format, ASTRO, American Society for Radiation Oncology 2013, Atlanta, GA, September 22-25, 2013. The authors declare no conflicts of interest. Reprints: Daniel A. Jones, MD, Masonic Memorial Building, 424 Harvard St. SE, Room M26, Minneapolis, MN 55455. E-mail: [email protected]. Copyright r 2014 by Lippincott Williams & Wilkins ISSN: 0277-3732/14/000-000 DOI: 10.1097/COC.0000000000000095
American Journal of Clinical Oncology
The retrospective study was approved by the University of Minnesota IRB. The treatment records of patients who presented after having undergone an inadvertent excision for soft-tissue sarcoma between the years of January of 2004 and January of 2012 were included. Nearly all patients were referred from outside of the University of Minnesota Medical Center. All patients were evaluated in a multidisciplinary manner before definitive treatment. Preoperative tumor imaging was usually not available. Further workup included physical examination, imaging of the primary site, and soft-tissue compartment with a contrast-enhanced magnetic resonance imaging (MRI), and staging of the chest, usually with computed tomography (CT). Patients with evidence of metastatic disease on presentation or with histologies such as rhabdomyosarcoma, Ewing sarcoma, medullary osteosarcoma, and desmoid tumors were excluded from the analysis. Since 2004,
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patients presenting with inadvertent excision of sarcoma were managed in a consistent manner of preoperative radiotherapy followed by surgery regardless of the anatomic site, size, or grade of the sarcoma. Treatment records of 44 consecutive patients met the above stated inclusion criteria. For the purpose of this study, the lower extremity is defined the thigh, buttock, leg, and foot. The upper extremity is defined as the supraclavicular fossa, shoulder, arm, forearm, and hand. Preoperative imaging, when available and gross description from the pathology reports were used to estimate the tumor size. The prior inadvertent surgical resection was defined as, as intralesional, marginal, or wide.3 Intralesional or subtotal resection encompassed resection by a piecemeal or intracapsular fashion. Marginal or gross total resection included an attempted simple excisional biopsy. None of the patients had initial resection considered to be oncologically adequate for sarcoma. All patients received preoperative radiotherapy with 3D conformal technique or in some cases with en face electrons. No patient received boost radiotherapy, postoperatively. The preoperative gross tumor volume was reconstructed to the best of our ability based on preoperative clinical and pathologic information. Field sizes varied based on tumor location and extent of the original surgery. Typically, 3 cm was added in craniocaudal directions to both preoperative gross tumor volume and the operative bed, and 1 to 2 cm was added in all directions in the axial plane to create a treatment clinical treatment volume (CTV). The CTV also included the previous surgical scar, changes visible on CT or MRI scan after the inadvertent surgery, and drainage sites. Additional margin of 1 cm was added to the block edge to account for daily set up variability. The prescription dose covered the CTV. Patients were immobilized in a treatment position that allowed optimal gantry angles. Bolus was not routinely added to the skin unless the skin was known to be involved. When possible, the entire circumference of a weight-bearing bone was spared with full dose, such as the femur or the tibia. A portion of skin and soft tissues were spared to facilitate rechanneling of lymphatics in all patients. Generally, at least 1/3 of the circumference received 5 cm) tumors, and those with multiple factors such as deep location, high grade, and large size predict for residual tumor after unplanned excision.10 In addition to the final surgical margin, the evidence of residual disease may be a poor risk factor. Patients with residual disease after definitive surgery are at higher risk for LR which may contribute to a higher rate of distant metastasis and worse survival. Davis et al6 reported that recurrence rates were 16.6% of the patients with residual disease and only 1.6% for patients without residual disease. Similarly, Rehders and colleagues reported superior outcomes in those without residual disease. With a median follow-up of 98 months, those without residual disease had significantly better RFS (P = 0.0002), distant metastasis-free survival (P = 0.0024), and OS (P = 0.0007).21 In a separate report, even patients with evidence of only microscopic residual disease had higher incidence of distant metastasis on multivariate analysis (P = 0.002).22 In the current study, 18 of 44 (40.9%) had residual disease, but ultimately too few events of recurrences occurred to analyze this endpoint. Interestingly, others found no difference and possibly an improvement in outcome for those undergoing unplanned surgery compared with those with standard primary sarcoma treatment. Lewis and colleagues reviewed 1092 patients who underwent both primary management of sarcoma and those who underwent additional surgery after inadvertent excision. The 5-year disease-free survival (DFS) and distant metastasisfree survival (DMFS) rates in those with reresection versus primary resection was (88% vs. 70%, P = 0.001) and (83% vs. 63%, P = 0.0001), respectively. After controlling for patient factors, the DFS difference remained significant. The author credited retrospective bias to the unexpected findings.17 Fiore et al22 found no difference in clinical outcomes between those who underwent reexcision after inadvertent surgery and patients who underwent primary sarcoma management. One of the potential benefits of avoiding an unplanned excision is to reduce treatment related morbidity. After inadvertent excision, many patients present with transverse excisions, remote placement of drains, and other potential sites of contamination. In addition, preoperative imaging studies are often unavailable. Reresection and reconstruction may be more difficult and complex after unplanned excision due to the need to resect a greater amount of tissues.11,12 Furthermore, radiotherapy fields must include greater areas of possible contamination which may increase the possibility of radiotherapy induced acute and chronic complications. Outcomes of patients after unplanned excision are highly variable. Select series have been highlighted in Table 3. It must be understood that this is a heterogeneous group of patients and results are not directly comparable. Differences exist in location, size, and grade of sarcoma. Most reports incorporate reexcision, with adjuvant radiotherapy as part of the regimen. Patients without residual tumor in the operative bed are reported to have good prognosis. After reresection, a study r
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Unplanned Excision
reported a local control rate of 90% in this favorable population.10 Zagars et al8 also reported an estimated local control of 93% at 15 years in 129 patients with negative surgical margin given radiotherapy without reresection. In the current series of 44 patients, 5 patients presented after a marginal excision with a negative margin originally, and thus would have been predicted to do well. However, all 5 either had a high-grade or large ( > 5 cm) tumor and would have required adjuvant radiotherapy. Therefore, the patients in the current study would not have received unnecessary courses of radiotherapy. Most series have used at least selective adjuvant radiotherapy after reexcision for high-risk factors (Table 3). Authors often commented that radiotherapy was given at the discretion of the radiation oncologist as a multidisciplinary recommendation without predetermined criteria. It would be difficult to comment on reexcision alone as a treatment option, as a majority of patients making up selected series received radiotherapy as part of their management. In a cohort managed similarly to ours, Giuliano and Eilber,7 demonstrated 94.5% local control at 5 years, delivering preoperative radiotherapy, followed by wound bed reexcision. Occasionally, postoperative radiotherapy alone is administered after inadvertent surgery in patients who are either medically inoperable or in whom further surgery would increase the morbidity, significantly. In a report by Kepka and colleagues, 78 patients with “small burden” disease and those who could not undergo reresection due to a variety of factors underwent radiotherapy alone to a median dose of 66 Gy (51 to 88 Gy.) The LRFS at 10 years was 86%, and the OS rate was 65%. Severe toxicity occurred in 10 patients (12.8%) resulting in neuropathy, bone fracture, and fibrosis. The severe toxicity was limited to those who received 66 Gy and above.23 In the previously mentioned study by Zagars et al,8 371 of the 666 patients were not reexcised, and received radiotherapy alone to total dose ranges of 60 to 70 Gy. The 15-year LC, DFS, causespecific survival, and DMFS were 73%, 48%, 65%, and 64%, respectively. The DFS and DMFS in the radiotherapy alone group was inferior to the group that had been reexcised before radiotherapy (48% vs. 63%, Pr0.001) and (64% vs. 75%, P = 0.004). The value of surgical reexcision is to optimize local control, and based on the findings of Zagars and colleagues, those with reexcision may also benefit in terms of DFS and DMFS. There was no patient in the current study who received radiotherapy alone without reresection. The addition of reresection likely does not impact OS, but this has not been reported in a prospective manner to our knowledge. Although cumulative morbidity may be higher after completing therapy in a patient with unplanned excision, it is doubtful that oncologic outcomes are compromised. In the Canadian randomized control trial, where preoperative radiotherapy was followed by definitive resection, local control, RFS, and OS at 5 years were reported to be 93%, 58%, 73%, respectively. Local control outcomes are similar to what we have reported. Although the patients are not directly comparable RFS and OS appears to be better in the current study. There are obvious differences between the current retrospective study and the prospective Canadian study. For example, 16% of the patients in the Canadian preoperative arm were purely superficial tumors, whereas 90.9% of ours were, possibly explaining better RFS/OS in our cohort. OS in our group was very good at 94% (95% CI, 79-99) and while this may appear better than historical reports, our group represents a highly selected cohort, with a majority having small, superficial sarcomas. Furthermore, follow-up is short, with a www.amjclinicaloncology.com |
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Jones et al
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TABLE 3. Selected Series Reporting Outcomes of Unplanned Excision
References/ Institution Giuliano and Eilber7 Davis et al6
Patient Number, Years Studied, Follow-up Interval 90 Dates NR Median 36 mo 239 1986-1994 Median 37 mo
Zagars et al8
666 1960-1999 15 y
Kepka et al23
78 1970-1997 Median 10 y
Manoso et al20 Potter et al24 Hoshi et al11 Chandrasekar et al10
Han et al18 University of Minnesota
Patients With Reexcision (%)
RT Regiment, Dose (If Noted)
Local Control, 5 y (%)
Other Endpoints, Year (%)
100
Preoperative 82 Gy (35 Gy) PORT 3 Gy (50-60 Gy)
94.5
NR
100
Preoperative 95 Gy (50 Gy) PORT 55 Gy (60-66 Gy) Preoperative-POB 36 Gy (66 Gy total) Preoperative 121 Gy (50 Gy) PORT 174 Gy (60-70 Gy) RT alone 371 Gy (60-70 Gy)
91.6
5y DM 26.8
Reresection 85 No reresection 78
Reresection 5, 10, 15 y DFS (69/67/63) No reresection 5, 10, 15 y DFS (54/49/48) 5, 10 y OS (78/65) CSS (82/77) DMFS (80) 5y DFS 82 OS 91 NR
44
0
RT alone 78 Gy (median 66 Gy)
LRFS 88
38 1993-1999 5y 64 1989-2005 Minimum 24 mo 38 1982-2007 Mean 43 mo 363 1982-2005 Median 40 mo
100
Various regiments including EBRT, brachy, both preoperative and postoperative PORT 41 Mostly PORT
95
95
PORT 9 RT alone 2
NR
87
PORT 118 RT alone 19
79 No reresection 66
104 1985-2007 Median 4.7 y 44 2004-2012 Median 36 mo
100
PORT 44 Gy (median 60 Gy)
74
100
Preoperative 44 Gy (median 50 Gy)
95
100
66
5y EFS 54.6 OS 76.3 5y OS 77 DM 24 No reresection DM 28 5, 10 y DSS 88/81 5y RFS 85 OS 94
Data are for 5 years unless otherwise stated. Brachy indicates brachytherapy implant; CSS, cause-specific survival; DFS, disease-free survival; DM, distant metastasis; DMFS, distant metastasis-free survival; LRFS, local recurrence-free survival; NR, not reported; OS, overall survival; Preoperative, preoperative RT, followed by reexcision; Preoperative-POB, preoperative RT, reexcision, followed by postoperative RT boost; PORT, reexcision followed by RT; RT alone, RT alone without reexcision; RT, regiment.
minimum of 12 months, and these patients remain at risk for failure. Preoperative radiotherapy is an acceptable alternative to postoperative radiotherapy with regards to managing soft-tissue sarcoma and limb preservation. Both methods have similar outcomes with regards to local control and OS. The main differences reside in the quality and timing of toxicity. Preoperative RT may result in higher perioperative morbidity. Postoperative RT results in greater long-term toxicity, namely fibrosis, edema, impaired functionality, and bone fracture.25 Although the referenced studies contained a significant number of patients who underwent preoperative radiotherapy, differences in outcome between patients who received preoperative and postoperative radiotherapy were not specifically stated.6–8 Eleven patients (25%) in the current study experienced significant perioperative toxicity. All 11 patients had lower extremity sarcomas. This is similar to the toxicity reported by
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O’Sullivan and colleagues who reported 35% perioperative toxicity. As in our series, patients with tumors in the lower extremity were at a higher risk for perioperative toxicity.13 Long-term toxicity is more difficult to assess, objectively. Because of limited clinical events during the follow-up period, long-term toxicity cannot be ascertained in the current study. Manoso and colleagues reported extensively on long-term functional outcomes in patients who underwent unplanned excision for sarcoma. Functional evaluation was performed using the musculoskeletal tumor society grading system. At a median of 63 months, 84% had “good to excellent” functional outcomes.20 However, it remains challenging to compare longterm outcomes of heterogeneous group of patients. The role of chemotherapy in nonmetastatic soft-tissue sarcoma is not well established. Chemotherapy either with doxorubicin-based or ifosfamide-based regimens has demonstrated mixed results.26,27 One patient in our series did receive chemotherapy before radiation therapy and reresection. To our r
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Volume 00, Number 00, ’’ 2014
knowledge, chemotherapy has not been studied prospectively in patients with unplanned excision of sarcoma. The current study has expected limitations. It is a retrospective study analyzing a treatment policy at a single institution. The number of patients is modest and the patient characteristics are heterogeneous. However, the review represents outcomes after following a consistent treatment policy involving both radiotherapy and surgery. It remains unclear whether all patients need radiotherapy or additional reresection after inadvertent surgery. Adequate radiologic evaluation and assessment by a team with expertise in diagnostic and therapeutic aspects of sarcoma should decrease the frequency of inadvertent surgery for these neoplasms. The management of patients with unplanned excision of soft-tissue sarcomas should be carried out at institutions with interdisciplinary teams with expertise in the treatment of these tumors and should follow well-defined protocols that allow standardization of treatment and comparison of results.
9. 10. 11. 12. 13.
14. 15.
CONCLUSIONS Optimal management for unplanned excision of soft-tissue sarcoma is unknown and reexcision plays an important role. There is high risk for residual disease in the tumor bed even in those who are clinically negative. It remains the goal of sarcoma treatment to minimize the chance of residual disease after local treatment. Our institution has adopted the approach of preoperative radiotherapy followed by definitive surgery with excellent local control with perioperative complications seen only in patients with lower extremity sarcomas.
16.
17. 18. 19.
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