Secondary Logo

Journal Logo

Tumor Necrosis Has no Prognostic Value in Neoadjuvant Chemotherapy for Soft Tissue Sarcoma

Menendez, Lawrence, R*; Ahlmann, Elke, R; Savage, Kathleen; Cluck, Michael; Fedenko, Alexander, N§

Clinical Orthopaedics and Related Research: February 2007 - Volume 455 - Issue - p 219-224
doi: 10.1097/01.blo.0000238864.69486.59
SECTION II: ORIGINAL ARTICLES: Tumor
Free
SDC

Neoadjuvant chemotherapy for treatment of soft tissue sarcomas is controversial, and the correlation between local recurrence and survival is unclear. Histologic necrosis is a well-documented predictor of survival in patients with malignant bone tumors; however, the association is unknown in patients with soft tissue sarcomas. We assessed the prognostic significance of tumor necrosis for treatment of soft tissue sarcomas. We retrospectively collected data from 82 patients who received neoadjuvant chemotherapy for treatment of soft tissue sarcomas of the extremities. Patients had wide resections if tumors were high-grade, deep to the investing fascia, and had clear margins. We quantified the amount of necrosis and analyzed the relationship with local recurrence and overall survival. At an average followup of 65 months (range, 24-154 months), the 5-year local recurrence rates for patients with less than 95% and 95% or greater necrosis were 20% and 33%, respectively. The overall 5-year survivorship rates for patients with less than 95% necrosis and 95% or greater necrosis were 82% and 78%, respectively. There was no difference in recurrencefree survival or overall patient survival based on the amount of histologic necrosis. Tissue necrosis from neoadjuvant chemotherapy does not seem to predict outcome in soft tissue sarcomas.

Level of Evidence: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

From the *Department of Orthopaedic Oncology, University of Southern California Keck School of Medicine, University Hospital, Los Angeles, CA; the †Department of Orthopaedic Oncology and the ‡Department of Orthopaedic Surgery, Los Angeles County-University of Southern California Medical Center, Los Angeles, CA; and the §Department of Pathology, University of Southern California Keck School of Medicine University Hospital, Los Angeles, CA.

Received: December 8, 2005

Revised: June 7, 2006

Accepted: September 7, 2006

Each author certifies that he or she has no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article.

Each author certifies that his or her institution has approved the reporting of these cases, that all investigations were conducted in conformity with ethical principles of research, and that informed consent was obtained.

Correspondence to: Elke R. Ahlmann, MD, Department of Orthopaedic Oncology, Los Angeles County-University of Southern California Medical Center, 1200 N. State Street, GNH 3900, Los Angeles, CA 90033. Phone: 323-226-7210; Fax: 323-226-4051; E-mail: ahlmann2002@yahoo.com.

Soft tissue sarcomas represent 1% of all malignant tumors, occurring in approximately 8300 patients in the United States each year.18 Despite advances in diagnosis and treatment, more than 50% of these patients die from the disease.15,43 Large prospective databases include independent prognostic factors such as tumor grade, size, depth, location,5-7,9,10,12,20-24,30,35,37,40,45-47 microscopic margin positivity,25,38,39,42 histopathologic subtype,19 and presentation status. It has been difficult to evaluate treatment and formulate an evidence-based treatment plan because of the rarity of these tumors, the heterogeneity of their presentation, the uncertainty in responsiveness, and differing treatment strategies used between institutions. The problem arises in applying data on a spectrum of soft tissue sarcomas in varying patient populations to determine specific presentations responsive to chemotherapy. Surgery remains the mainstay of treatment, often with the addition of neoadjuvant chemotherapy or radiation. In randomized studies, radiotherapy has decreased local recurrence but without improving overall survival.46,47 Limb-sparing surgery with adjuvant radiation is equivalent to amputation in overall survival rates.1,14,36,44 The role of chemotherapy as a treatment modality is still unclear. In multiple trials, adjuvant chemotherapy improved recurrence-free survival time with a nonsignificant trend toward improved overall survival.2,3,8,11,16,31,41

Treatment-induced tissue necrosis is a well-documented predictor of survival in patients with malignant bone tumors4,27-29,32,48 and might be a predictor in soft tissue sarcomas. However, the correlation between neoadjuvant chemotherapy and survival of soft tissue sarcomas is unclear.2,11,16,41

We asked whether tissue necrosis from neoadjuvant chemotherapy correlate with local recurrence, disease progression, and overall survival in patients with high-grade soft tissue sarcomas and therefore can be used as a predictive factor in treatment.

Back to Top | Article Outline

MATERIALS AND METHODS

We retrospectively reviewed the database maintained by the Orthopaedic Oncology Service for all patients with soft tissue sarcomas of the extremities treated from 1991 to 2001. We identified 175 patients. Power analysis indicated the necessary sample size needed to show an increase (ie, improvement) in recurrence-free survival and overall survival from neoadjuvant chemotherapy would be 532 patients. The inclusion criteria consisted of all patients treated with neoadjuvant chemotherapy for a non-metastatic high-grade soft tissue sarcoma of the extremity, located deep to the fascia and resected with clear margins, with a minimum 24-month followup. Patients with retroperitoneal or visceral primary sarcomas were excluded. Sixty-eight patients with either low-grade tumors or superficial tumors of smaller than 5 cm did not receive neoadjuvant chemotherapy and were excluded as were nine patients who received neoadjuvant radiation therapy in addition to chemotherapy. Sixteen more patients were excluded because they did not have a minimum of 24 months followup. This left 82 patients available for review, of whom 35 were men and 47 were women. The average age was 48.4 years (range, 21-76 years). The average time to followup or end point was 65 months (range, 24-154 months).

We reviewed patients' charts regarding demographics (age, gender, duration of symptoms), neoadjuvant therapy, histology, and surgical management. We performed plain radiographs, magnetic resonance imaging (MRI) of the extremity, and computed tomography (CT) of the chest before doing a biopsy. All patients were staged according to the American Joint Committee on Cancer (AJCC) system.13 Twenty-eight patients were classified as having AJCC Stage IIB disease, 17 were classified as having Stage IIC disease, and 37 were classified as having Stage III disease.

Seventy-three patients completed three cycles of neoadjuvant chemotherapy in 3-week intervals with each cycle consisting of doxorubicin (continuous intravenous infusion of 75 mg/m2 over 72 hours), ifosphamide (2 g/m2/day given as a 2-3 hour intravenous bolus for 4 days), and cisplatin (120 mg/m2 intravenous infusion over 4 hours). Nine patients received four cycles of the chemotherapy regimen. All patients had surgical resections consisting of limb salvage with wide excision by the senior author (LRM) within 3 weeks after completing chemotherapy. After wound healing was completed, all patients received four cycles of adjuvant chemotherapy in 3-week intervals of the same regimen as before surgery.

Patients were followed every 3 months for the first 2 years, and then every 6 months for 3 years thereafter. Patients had a physical examination, MRI of the involved extremity, and a CT scan of the chest to evaluate for local recurrence and metastatic disease.

All gross specimens were assessed and measured for tumor dimensions during resection. Tissue specimens were processed according to previously described methods for bone sarcomas,26,33 with the goal of obtaining representative samples from all areas of the specimen to find viable residual tumor. These methods were adapted for soft tissue sarcoma processing by first inking and cutting each tumor along the long axis, resulting in slab sections of opposing hemispheres. The slab sections then were cut parallel and perpendicular into small cubes from end-to-end in a grid-like fashion, and the location of the segments was labeled sequentially for mapping. Histologic analyses were performed for each mapped segment and random samples to obtain representative sections from all areas of the tumor. Slides were prepared on a standard microtome and cut 4 μm thick. We obtained an average of 30 histologic sections from each tumor. Two pathologists (ANF, AC) specializing in musculoskeletal neoplasms retrospectively reexamined the permanent histologic specimens individually to minimize interobserver error in the grading of response. Both pathologists were in agreement with grading of all specimens. Microscopically, the tumor was classified as high-grade based on established criteria including the degree of nuclear pleomorphism, degree of differentiation, and number of mitoses per high power field. We reviewed multiple morphologic parameters including the presence or absence of tumor, anatomic distribution of residual tumor when present, qualitative and quantitative analysis of tumor necrosis, qualitative and quantitative analysis of viable tumor when present, and resection margin status. A clear margin was defined as a minimum of 5 mm between the surgical margin and evidence of tumor. The extent of necrosis was determined relative to the percentage of residual viable tumor seen on each slide. Quantitative analysis was performed by reviewing data in a slide-by-slide fashion, then totaling and averaging the values for extent of necrosis and residual tumors. The percentage of histologic necrosis attributable to chemotherapy was reached by semiquantitative estimation. This technique is analogous to that used in the evaluation of tumor necrosis after neoadjuvant chemotherapy for osteosarcoma. In addition to actual percent necrosis, each specimen was evaluated qualitatively for response to chemotherapy according to the grading system of Huvos et al17 for necrosis.

We used the Kaplan-Meier method to generate survivorship curves with corresponding 95% confidence intervals (CIs) for implant and patient survival using GraphPad Prism® software (San Diego, CA). Time zero was defined as the date of surgical resection. The end point of evaluation for recurrence-free survival was defined as the time of local recurrence. The end point for disease-free survival was defined as the time to development of local recurrence or distant metastases. The end point for overall survival was tumor-related death. All other deaths unrelated to the neoplasm were censored. The log-rank test and Cox proportional hazards regression model were used to analyze the association between percent necrosis and recurrence or overall survival. A p value less than 0.05 was considered significant.

Back to Top | Article Outline

RESULTS

Percent tumor necrosis following chemotherapy averaged 64% (range, 10-100%). Thirty two of the 82 patients (39%) had an estimated percent tumor necrosis of 95% or greater. The majority (50 of 82; 61%) had less than 95% necrosis. Of the patients with the three most common histologic subtypes, approximately ⅓ to ½ of patients had 95% or greater % necrosis, whereas ⅔ to ½ of patients had less than 95% necrosis. Given the subtle differences in responsiveness to chemotherapy, we additionally classified each tumor specimen according to the grading system of Huvos et al for necrosis. The majority of specimens had a good response (Grade III or IV) based on this system. We saw no bias toward a certain subtype of tumor having an entirely favorable or unfavorable amount of tumorrelated necrosis (Table 1).

TABLE 1

TABLE 1

Histologic necrosis did not relate to survival. Patients with 95% or greater necrosis had a 93% survival rate at 2 years and an 82% survival rate at 5 years, while those for patients with less than 95% necrosis were 87% at 2 years and 78% at 5 years (Fig 1). We also found no difference in patient survival based on amount of tumor necrosis using the qualitative classification system. The mean time to death was 29 months (range, 12-48 months) for patients who died of the disease. Fourteen patients had metastatic disease develop and died of their disease. The average time from surgery to the detection of lung metastases was 18 months (range, 15-28 months). Tumors resulting in metastatic disease included seven malignant fibrous histiocytomas, three synovial sarcomas, two liposarcomas, one fibrosarcoma, and one malignant peripheral nerve sheath tumor.

Fig 1

Fig 1

We found no difference in disease-free survival based on percent of tumor necrosis or on classification of tumor necrosis. Disease-free survival rates for patients with 95% or greater necrosis were 87% at 2 years and 82% at 5 years. For patients with less than 95% necrosis, disease-free survival rates were 86% at 2 years and 79% at 5 years (Fig 2).

Fig 2

Fig 2

With a mean followup of approximately 5 years, the recurrence rate in patients with evidence of 95% or greater necrosis was similar to the rate in patients with less than 95% necrosis. The local recurrence rates at 2 and 5 years were 6% and 20%, respectively for patients with 95% or greater necrosis and 12% and 23%, respectively, for patients with less than 95% necrosis based on Kaplan-Meier survivorship analysis (Fig 3). There were no differences in recurrence rates based on the classification of Huvos et al. Local tumors recurred in patients an average of 22 months (range, 14-37 months) after surgical resection. These patients had wide reresections followed by external beam radiation.

Fig 3

Fig 3

Back to Top | Article Outline

DISCUSSION

Neoadjuvant chemotherapy has numerous theoretical advantages for treatment of high- grade soft tissue sarcomas. Cytoreduction could reduce the extent of excision and reduce the morbidity of the surgical procedure, making limb salvage an option for patients with tumors that otherwise could be treated only with amputation. Treatment-induced tissue necrosis is a well-documented predictor of survival in patients with malignant bone tumors4,27-29,32,48 and might be a predictor in soft tissue sarcomas. Additionally, the primary tumor acts as an in vivo test for the effectiveness of a specific chemotherapy regimen. Postoperative chemotherapy agents may be altered if the amount of histologic necrosis shows a poor response to the neoadjuvant regimen.4,29,32,48 Because the efficacy of chemotherapy is still debated, it would be beneficial to show a correlation between neoadjuvant chemotherapy and necrosis to determine which tumor may be more likely to respond to chemotherapy, and if there ultimately is an association with prognosis and survival.

As with most studies evaluating the effectiveness of chemotherapy in improving patient survival, our study is limited by inadequate patient numbers. These are relatively rare tumors and one institution cannot accumulate the large numbers of patients required to detect significant differences. An attempt at a multicenter randomized trial was performed by the Intergroup Sarcoma Study Group (ISSG) with a goal of 450 patients. However, this trial was closed after 18 months because of insufficient patient accrual. Therefore, the likelihood of a definitive trial ever being conducted is questionable. Even with a relatively large group of 82 patients in our study, we were unable to show a difference in survival based on tumor necrosis. This may be because of insufficient power, however until large multicenter studies are performed results should be interpreted with this in mind.

The most important independent variables in predicting outcome of soft tissue sarcomas are grade, size, and depth.5-7,9,10,12,20-24,30,35,37,40,45-47 The amount of tumor necrosis also may predict outcome as shown in the treatment of osteogenic sarcoma and Ewing's sarcoma.4,27-29,32,48 A previous study11 showed neoadjuvant therapy induced necrosis and independently predicted survival and recurrence in patients with soft tissue sarcomas. The initial data in that study showed an increase in the local recurrence rate when the dose of radiation was reduced, but a reduction in the recurrence rate was seen when cisplatinum was added to the chemotherapy regimen. An even greater benefit was seen with high-dose ifosfamide. This is similar to the chemotherapy regimen we used; however, direct comparison cannot be made as the study by Eilber et al11 was confounded by the use of neoadjuvant radiation therapy in addition to chemotherapy. Therefore, it is difficult to interpret these data when evaluating the effects of chemotherapy alone.

Tumor necrosis may reflect the response to chemotherapy, however it also can occur as a spontaneous natural phenomenon.26,29 Previous studies17,34 have shown as much as 40% of tumor necrosis may be unrelated to the effects of chemotherapy. Others who evaluated the treatment of osteosarcoma treated by surgery alone reported tumor necrosis as much as 30% may occur spontaneously, in the absence of neoadjuvant chemotherapy.33 To avoid interpreting spontaneous necrosis of the tumor as a response to chemotherapy and the precedent set for excellent responsiveness to chemotherapy in the treatment of bone tumors, we used 95% as the cut-off for amount of necrosis. In the treatment of osteogenic sarcoma, necrosis of 95% or greater correlates with an excellent response to chemotherapy and improved prognosis.4,29,32,48 With a mean followup of approximately 5 years, our recurrence rate in patients with 95% or greater necrosis was the same as the rate for patients with less than 95% necrosis. To detect more subtle differences in survivorship based on histologic response to chemotherapy, we additionally assessed survival in all patients according to the classification system of Huvos et al.17 However, the overall patient survivorship at the 3-year and 5-year followups also did not differ between the groups. Although we were able to obtain an excellent overall survival rate comparable to those reported in other studies10-12 investigating the role of chemotherapy in soft tissue sarcomas, we were unable to obtain consistently high histologic necrosis values achieved in those studies.10-12 Our data suggest that the percent of necrosis as a result of neoadjuvant chemotherapy can be variable and should not be used as an independent predictor of local recurrence or overall patient survival.

Despite the addition of adjuvant therapy, the prognosis of patients with soft tissue sarcomas has not improved during the past 20 years.43 This may indicate our current therapy has reached the limits of efficacy. Several questions remain regarding the treatment of soft tissue sarcomas, with the use of neoadjuvant chemotherapy being one of the most debated. Future treatment strategies must be developed to take into account various prognostic factors. Our data suggest the amount of necrosis as a result of chemotherapy alone may not be an independent prognostic indicator of local recurrence or overall survival. Since 2001, we have added neoadjuvant radiation to our treatment protocol for deep high-grade soft tissue sarcomas greater than 5 cm in diameter in addition to neoadjuvant chemotherapy, as several studies have shown improvement in local recurrence rates.10-12 This is followed by wide resection and adjuvant chemotherapy. Further long-term studies of this regimen are being done to evaluate if this protocol improves histologic necrosis rates, outcome, and survival.

Back to Top | Article Outline

Acknowledgment

We thank Dr. Adrian Correa for assistance with this study.

Back to Top | Article Outline

References

1. Alektiar KM, Leung D, Zelefsky MJ, Brennan MF. Adjuvant radiation for stage II-B soft tissue sarcoma of the extremity. J Clin Oncol. 2002;20:1643-1650.
2. Alvegard TA, Berg NO, Ranstam J, Rydholm A, Rooser B. Prognosis in high-grade soft tissue sarcomas: the Scandinavian Sarcoma Group experience in a randomized adjuvant chemotherapy trial. Acta Orthop Scand. 1989;60:517-521.
3. Anonymous. Adjuvant chemotherapy for localized resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet. 1997;350:1647-1654.
4. Bacci G, Mercuri M, Longhi A, Ferrari S, Bertoni F, Versari M, Picci P. Grade of chemotherapy-induced necrosis as a predictor of local and systemic control in 881 patients with non-metastatic os-teosarcoma of the extremities treated with neoadjuvant chemotherapy in a single institution. Eur J Cancer. 2005;41:2079-2085.
5. Coindre JM, Terrier P, Bui NB, Bonichon F, Collin F, Le Doussal V, Mandard AM, Vilain MO, Jacquemier J, Duplay H, Sastre X, Barlier C, Henry-Amar M, Mace-Lesech J, Contesso G. Prognostic factors in adult patients with locally controlled soft tissue sarcoma: a study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol. 1996;14:869-877.
6. Collin C, Godbold J, Hajdu S, Brennan M. Localized extremity soft tissue sarcoma: an analysis of factors affecting survival. J Clin Oncol. 1987;5:601-612.
7. Collin CF, Friedrich C, Godbold J, Hajdu S, Brennan MF. Prognostic factors for local recurrence and survival in patients with localized extremity soft-tissue sarcoma. Semin Surg Oncol. 1988;4:30-37.
8. Cormier JN, Huang X, Xing Y, Thall PF, Wang X, Benjamin RS, Pollock RE, Antonescu CR, Maki RG, Brennan MF, Pisters PW. Cohort analysis of patients with localized, high-risk, extremity soft tissue sarcoma treated at two cancer centers: chemotherapy-associated outcomes. J Clin Oncol. 2004;22:4567-4574.
9. Deshmukh R, Mankin HJ, Singer S. Synovial sarcoma: the importance of size and location for survival. Clin Orthop Relat Res. 2004;419:155-161.
10. Eilber FC, Brennan MF, Riedel E, Alektiar KM, Antonescu CR, Singer S. Prognostic factors for survival in patients with locally recurrent extremity soft tissue sarcomas. Ann Surg Oncol. 2005;12:228-236.
11. Eilber FC, Eilber FR, Eckardt J, Rosen G, Riedel E, Maki RG, Brennan MF, Singer S. The impact of chemotherapy on the survival of patients with high-grade primary extremity liposarcoma. Ann Surg. 2004;240:686-695.
12. Eilber FC, Rosen G, Nelson SD, Selch M, Dorey F, Eckardt J, Eilber FR. High-grade extremity soft tissue sarcomas: factors predictive of local recurrence and its effect on morbidity and mortality. Ann Surg. 2003;237:218-226.
13. Fleming ID, Cooper JS, Henson DE. American Joint Committee on Cancer Staging Manual. 5th ed. Philadelphia, PA: Lippincott-Raven; 1997.
14. Ghert MA, Abudu A, Driver N, Davis AM, Griffin AM, Pearce D, White L, O'Sullivan B, Catton CN, Bell RS, Wunder JS. The indications for and the prognostic significance of amputation as the primary surgical procedure for localized soft tissue sarcoma of the extremity. Ann Surg Oncol. 2005;12:10-17.
15. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin. 2001;51:15-36.
16. Grobmyer SR, Maki RG, Demetri GD, Mazumdar M, Riedel E, Brennan MF, Singer S. Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma. Ann Oncol. 2004;15:1667-1672.
17. Huvos AG, Rosen G, Marcove RC. Primary osteogenic sarcoma: pathologic aspect in 20 patients treated with chemotherapy, en bloc resection, and prosthetic bone replacement. Arch Pathol Lab Med. 1977;101:14-18.
18. Khatri VP, Goodnight JE Jr. Extremity soft tissue sarcoma: controversial management issues. Surg Oncol. 2005;14:1-9.
19. Koea JB, Leung D, Lewis JJ, Brennan MF. Histopathologic type: an independent prognostic factor in primary soft tissue sarcoma of the extremity? Ann Surg Oncol. 2003;10:432-440.
20. LeDoussal V, Coindre JM, Leroux A, Hacene K, Terrier P, Bui NB, Bonichon F, Collin F, Mandard AM, Contesso G. Prognostic factors for patients with localized primary malignant fibrous histiocytoma: a multicenter study of 216 patients with multivariate analysis. Cancer. 1996;77:1823-1830.
21. LeVay J, O'Sullivan B, Catton C, Bell R, Fornasier V, Cummings B, Hao Y, Warr D, Quirt I. Outcome and prognostic factors in soft tissue sarcoma in the adult. Int J Radiat Oncol Biol Phys. 1993;27:1091-1099.
22. Lewis JJ, Antonescu CR, Leung DH, Blumberg D, Healey JH, Woodruff JM, Brennan MF. Synovial sarcoma: a multivariate analysis of prognostic factors in 112 patients with primary localized tumors of the extremity. J Clin Oncol. 2000;18:2087-2094.
23. Lewis JJ, Leung D, Casper ES, Woodruff J, Hajdu SI, Brennan MF. Multifactorial analysis of long-term follow-up (more than 5 years) of primary extremity sarcoma. Arch Surg. 1999;134:190-194.
24. Massi D, Beltrami G, Mela MM, Pertici M, Capanna R, Franchi A. Prognostic factors in soft tissue leiomyosarcoma of the extremities: a retrospective analysis of 42 cases. Eur J Surg Oncol. 2004;30:565-572.
25. McKee MD, Liu DF, Brooks JJ, Gibbs JF, Driscoll DL, Kraybill WG. The prognostic significance of margin width for extremity and trunk sarcoma. J Surg Oncol. 2004;85:68-76.
26. Picci P, Bacci G, Campanacci M, Gasparini M, Pilotti S, Cerasoli S, Bertoni F, Guerra A, Capanna R, Albisinni U. Histologic evaluation of necrosis in osteosarcoma induced by chemotherapy: regional mapping of viable and nonviable tumor. Cancer. 1985;56:1515-1521.
27. Picci P, Bohling T, Bacci G, Sangiorgi L, Mercuri M, Ruggieri P, Manfrini M, Ferraro A, Casadei R, Benassi MS, Mancini AF, Rosito P, Cazzola A, Barbieri E, Tienghi A, Brach del Prever A, Coman-done A, Bacchini P, Bertoni F. Chemotherapy-induced tumor necrosis as a prognostic factor in localized Ewing's sarcoma of the extremities. J Clin Oncol. 1997;15:1553-1559.
28. Picci P, Rougraff BT, Bacci G, Neff JR, Sangiorgi L, Cazzola A, Baldini N, Ferrari S, Mercuri M, Ruggieri P. Prognostic significance of histopathologic response to chemotherapy in nonmetastatic Ewing's sarcoma of the extremities. J Clin Oncol. 1993;11:1763-1769.
29. Picci P, Sangiorgi L, Rougraff BT, Neff JR, Casadei R, Campanacci M. Relationship of chemotherapy-induced necrosis and surgical margins to local recurrence in osteosarcoma. J Clin Oncol. 1994;12:2699-2705.
30. Pisters PW, Leung DH, Woodruff J, Shi W, Brennan MF. Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol. 1996;14:1679-1689.
31. Pisters PW, Patel SR, Varma DG, Cheng SC, Chen NP, Nguyen HT, Feig BW, Pollack A, Pollock RE, Benjamin RS. Preoperative chemotherapy for stage IIIB extremity soft tissue sarcoma: long-term results from a single institution. J Clin Oncol. 1997;15:3481-3487.
32. Raymond AK, Chawla SP, Carrasco CH, Ayala AG, Fanning CV, Grice B, Armen T, Plager C, Papadopoulos NE, Edeiken J. Osteo-sarcoma chemotherapy effect: a prognostic factor. Semin Diagn Pathol. 1987;4:212-236.
33. Raymond AK, Simms W, Ayala AG. Osteosarcoma: specimen management following primary chemotherapy. Hematol Oncol Clin North Am. 1995;9:841-867.
34. Rosen G, Caparros B, Huvos AD, Kosloff C, Nirenberg A, Cacavio A, Marcove RC, Lane JM, Mehta B, Urban C. Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer. 1982;49:1221-1240.
35. Singer S, Corson JM, Gonin R, Labow B, Eberlein TJ. Prognostic factors predictive of survival and local recurrence for extremity soft tissue sarcoma. Ann Surg. 1994;219:165-173.
36. Stojadinovic A, Jaques DP, Leung DH, Healey JH, Brennan MF. Amputation for recurrent soft tissue sarcoma of the extremity: indications and outcome. Ann Surg Oncol. 2001;8:509-518.
37. Stojadinovic A, Leung DH, Allen P, Lewis JJ, Jaques DP, Brennan MF. Primary adult soft tissue sarcoma: time-dependent influence of prognostic variables. J Clin Oncol. 2002;20:4344-4352.
38. Stojadinovic A, Leung DH, Hoos A, Jaques DP, Lewis JJ, Brennan MF. Analysis of the prognostic significance of microscopic margins in 2,084 localized primary adult soft tissue sarcomas. Ann Surg. 2002;235:424-434.
39. Tanabe KK, Pollock RE, Ellis LM, Murphy A, Sherman N, Roms-dahl MM. Influence of surgical margins on outcome in patients with preoperatively irradiated extremity soft tissue sarcomas. Cancer. 1994;73:1652-1659.
40. Ueda T, Aozasa K, Tsujimoto M, Hamada H, Hayashi H, Ono K, Matsumoto K. Multivariate analysis for clinical prognostic factors in 163 patients with soft tissue sarcoma. Cancer. 1988;62:1444-1450.
41. Van Glabbeke M, van Oosterom AT, Oosterhuis JW, Mouridsen H, Crowther D, Somers R, Verweij J, Santoro A, Buesa J, Tursz T. Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2,185 patients treated with an-thracycline-containing first-line regimens: a European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 1999;17:150-157.
42. Vraa S, Keller J, Nielsen OS, Jurik AG, Jensen OM. Soft-tissue sarcoma of the thigh: surgical margin influences local recurrence but not survival in 152 patients. Acta Orthop Scand. 2001;72:72-77.
43. Weitz J, Antonescu CR, Brennan MF. Localized extremity soft tissue sarcoma: improved knowledge with unchanged survival over time. J Clin Oncol. 2003;21:2719-2725.
44. Williard WC, Hajdu SI, Casper ES, Brennan MF. Comparison of amputation with limb-sparing operations for adult soft tissue sarcoma of the extremity. Ann Surg. 1992;215:269-275.
45. Wilson RB, Crowe PJ, Fisher R, Hook C, Donnellan MJ. Extremity soft tissue sarcoma: factors predictive of local recurrence and survival. Aust N Z J Surg. 1999;69:344-349.
46. Zagars GK, Ballo MT, Pisters PW, Pollock RE, Patel SR, Benjamin RS, Evans HL. Prognostic factors for patients with localized soft-tissue sarcoma treated with conservation surgery and radiation therapy: an analysis of 225 patients. Cancer. 2003;97:2530-2543.
47. Zagars GK, Mullen JR, Pollack A. Malignant fibrous histiocytoma: outcome and prognostic factors following conservation surgery and radiotherapy. Int J Radiat Oncol Biol Phys. 1996;34:983-994.
48. Zunino JH, Johnston JO. Prognostic value of histologic tumor necrosis assessment in osteogenic sarcoma of bone. Am J Orthop. 2000;29:369-372.
© 2007 Lippincott Williams & Wilkins, Inc.