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© 2001 American Society for Clinical Oncology Treatment-Induced Pathologic Necrosis: A Predictor of Local Recurrence and Survival in Patients Receiving Neoadjuvant Therapy for High-Grade Extremity Soft Tissue SarcomasByFrom the Divisions of Surgical Oncology, Medical Oncology, Orthopedic Surgery, Surgical Pathology, Radiation Oncology, and Biostatistics, University of California Los Angeles Sarcoma Research Group, University of California Los Angeles, Los Angeles, CA. Address reprint requests to Frederick R. Eilber, MD, Division of Surgical Oncology, 54-140 CHS, University of California Los Angeles Medical Center, 10833 Le Conte Ave, Los Angeles, CA 90095-1782; email: feilber{at}surgery.medsch.ucla.edu
PURPOSE: To determine whether treatment-induced pathologic necrosis correlates with local recurrence and overall survival in patients who receive neoadjuvant therapy for high-grade extremity soft tissue sarcomas. PATIENTS AND METHODS: Four hundred ninety-six patients with intermediate- to high-grade extremity soft tissue sarcomas received protocol neoadjuvant therapy. All patients underwent surgical resection after neoadjuvant therapy and had pathologic assessment of tumor necrosis in the resected specimens.
RESULTS: The 5- and 10-year local recurrence rates for patients with
CONCLUSION: Treatment-induced pathologic necrosis is an independent predictor of both local recurrence and overall survival in patients who receive neoadjuvant therapy for high-grade extremity soft tissue sarcomas. A complete pathologic response (
NEOADJUVANT THERAPY provides several theoretical advantages in the treatment of sarcomas and solid tumors in general. Treatment-induced cytoreduction potentially facilitates a less radical surgical resection, thus decreasing the operative and postoperative morbidity. This cytoreduction is of particular importance for large soft tissue sarcomas, and it may allow patients to undergo limb salvage therapy who might otherwise have required amputation. Neoadjuvant therapy also allows for the immediate treatment of micrometastases at diagnosis. Such early treatment intervention potentially prevents the development of overt metastatic disease. Finally, neoadjuvant therapy provides an in vivo test of chemo- and radiosensitivity. This determination has many benefits, including an early indication of the effectiveness of the neoadjuvant regimen, which allows for prompt treatment modifications in the event of a poor response. Although several modalities have been used to evaluate the effectiveness of neoadjuvant therapy in sarcomas, pathologic necrosis has become the most reliable method by which an objective assessment of chemo- and radiosensitivity is made.1-9 Treatment-induced pathologic necrosis has been proven as a predictor of survival in patients with malignant bone tumors.1,10-13 However, this correlation remains unclear in patients with extremity soft tissue sarcomas.14-24 The purpose of this study was to determine whether treatment-induced pathologic necrosis correlates with local recurrence and overall survival in patients who receive neoadjuvant therapy for intermediate- to high-grade extremity soft tissue sarcomas.
From 1975 to 1998, 883 patients with nonmetastatic extremity soft tissue sarcomas were treated at University of California Los Angeles (UCLA). One hundred two patients had low-grade tumors and were excluded from this analysis. Of the 781 patients with intermediate- to high-grade sarcomas histologically, 285 received no neoadjuvant therapy. These patients were not included in the protocols for various reasons, including superficial tumors, epithelioid sarcoma, or previous radiation. The remaining 496 patients with histologic diagnoses of intermediate- to high-grade sarcoma who received the neoadjuvant therapy protocol represent the study population. The preoperative therapy protocols were performed in a nonrandomized fashion and reflect the evolution of treatment at UCLA during the past 20 years. These protocols are outlined in Fig 1 and include: intra-arterial (IA) doxorubicin 30 mg/extremity/d x 3 and 35 Gy radiation; IA doxorubicin 30 mg/extremity/d x 3 and 17.5 Gy radiation; IA doxorubicin 30 mg/extremity/d x 3 and 28 Gy radiation; intravenous (IV) doxorubicin 60 mg/m2 as a continuous infusion over 48 hours, IV cisplatin 120 mg/m2 as a 4-hour infusion, and 28 Gy radiation; and IV doxorubicin 60 mg/m2 as a continuous infusion over 48 hours, IV cisplatin 120 mg/m2 as a 4-hour infusion, IV ifosfamide 14 g/m2/d as a continuous infusion over 7 days (for patients older than 50 years) or IV ifosfamide 18 g/m2/d as a continuous infusion over 9 days (for patients younger than 50 years), and 28 Gy radiation. The mean interval from initiation of neoadjuvant therapy to surgery was 4 weeks, and no patient had a preoperative window greater than 2 months. Only three patients (0.006%) did not complete their protocol neoadjuvant therapy, two because of bleeding into their tumors that required emergent surgery and one because of chemotherapy toxicity.
After neoadjuvant therapy, all 496 patients underwent surgical resection. Surgery was performed by one of two surgeons for the duration of the study. Surgical resection was performed through grossly normal tissue planes. If the tumor abutted a neural or vascular structure, the adventitia of the artery and vein or perineurium was removed in continuity. No attempts at compartmental resection were made. During the study interval, three different pathologists who specialize in sarcomas prospectively evaluated all specimens in a standard fashion. Each specimen was bisected along its greatest diameter, and the perimeter of the tumor was defined grossly. The entire area of the bisected tumor was partitioned into 2.0 cm2 (average) blocks of tissue en face and processed for histologic examination. The extent of necrosis was assessed relative to the percentage of residual viable tumor in each case and in an identical manner to that established for bone tumors.11,25 Although the percentage of necrosis ranged from 0% to 100%, for this study we grouped the results into three categories: 95% or greater pathologic necrosis, less than 95% pathologic necrosis, and no residual tumor. Tumor grade was classified as either high, intermediate, or low on the basis of established criteria, including degree of differentiation, nuclear pleomorphism, and number of mitoses per high-powered field.26 The resected specimens also were assessed for distance of clearance in millimeters or centimeters. A positive margin was defined as microscopic tumor present at the surgical margin. A tumor was considered primary if it was untreated previously or only a biopsy (incisional or excisional) had been performed at the time of presentation. Locally recurrent disease was defined as tumor recurrence at the site of previous surgery. Tumor size was defined as maximum diameter at pathologic analysis. Tumors were grouped into three size ranges: less than 5 cm, 5 to 10 cm, and greater than 10 cm. Tumors were staged in accordance with the American Joint Committee on Cancer staging system. All tumors in this study were below the superficial fascia and as such were either stage IIB or III. Upper extremity was defined as a tumor at or distal to the shoulder. Upper extremity proximal refers to patients with tumors within the shoulder region, including the axilla. Upper extremity medial refers to patients with a tumor located in the region from the shoulder to the forearm. Upper extremity distal refers to patients with tumors distal to the forearm. Lower extremity was defined as a tumor at or distal to the groin or gluteal area. Lower extremity proximal refers to patients with tumors within the groin or gluteal region. Lower extremity medial refers to patients with tumors located in the region from the groin to the calf. Lower extremity distal refers to patients with tumors beyond the calf. Postoperative follow-up included physical examination, chest radiograph, and computed tomography of the primary site at 6-month intervals for the first 2 years and yearly thereafter. End points for evaluation included date of local recurrence, date of death, and date of last follow-up. The interval to recurrence was measured from the date of surgery at UCLA to the date of recurrence. Survival was measured from the date of surgery at UCLA to the date of last follow-up or death. Follow-up in this group of patients was 100%. All patient data, including percentage of pathologic necrosis, were collected prospectively. However, because the correlation between pathologic necrosis and both local recurrence and survival was not questioned before data collection, this should be viewed as a retrospective study. Actuarial survival curves were determined by the Kaplan-Meier method and compared by the log-rank test. Multivariate analyses were performed with the Cox proportional hazards model.
Patient and Tumor Characteristics Fifty-four percent of the 496 patients evaluated were 50 years of age or younger (mean, 48 years; range, 8 to 90 years). There were 275 males (55%) and 221 females (45%). The most common anatomic site of the primary tumor was lower extremity medial (60%), followed by upper extremity medial (16%) and lower extremity proximal (11%) (Table 1).
Eighty-three percent of the patients presented with primary tumors and 17% presented with locally recurrent tumors. Fifty percent of the tumors were in the 5- to 10-cm range, and 30% were larger than 10 cm. Twenty percent of the tumors were stage IIB and 80% were stage III. Liposarcoma (27%) was the most common histologic finding, followed by malignant fibrous histiocytoma (25%) and synovial cell sarcoma (16%). Seventy-nine percent of the tumors were high grade and 21% were intermediate grade. Fourteen percent of the patients had 95% or greater pathologic necrosis, and 48% had less than 95% pathologic necrosis. The remaining 38% had no residual tumor. Three percent of the patients had microscopically positive surgical margins, and 97% had microscopically negative surgical margins (Table 1). The mean follow-up for all 496 patients was 87 months (median, 73 months; range, 12 to 240 months). The mean follow-up for surviving patients was 114 months (median, 113 months; range, 12 to 240 months).
Local Recurrence
A multivariate analysis of factors related to local recurrence was performed for the 309 patients with pathologically assessable tumors. In order of relative risk, malignant peripheral nerve sheath tumors, less than 95% pathologic necrosis, high histologic grade, and age greater than 50 years were all independent predictors of local recurrence (Table 2). When the 187 patients with no residual tumor were included in the analysis (N = 496), an identical order of relative risk was found.
Survival The overall survival for all 496 patients was 71% (SE, ± 2.1%) at 5 years and 66% (SE, ± 2.4%) at 10 years. Of the patients who died of their disease, the time to death ranged from 2 to 173 months, with a mean time to death of 36 months (median, 26 months). The 5- and 10-year survival rates for the patients with less than 95% pathologic necrosis were 62% and 55%, respectively. In comparison, the 5- and 10-year survival rates for the patients with 95% or greater pathologic necrosis were 80% and 71%, respectively. This result also was similar to the group with no residual tumor, which had 5- and 10-year survival rates of 81% and 78%, respectively (Fig 3).
A multivariate analysis of factors related to survival was performed for the 309 patients with assessable tumors. In order of relative risk, high histologic grade, less than 95% pathologic necrosis, initial presentation with locally recurrent disease, and size larger than 5 cm were all independent predictors of reduced survival (Table 3). A similar order of significance with similar relative risk was found when data for all 496 patients were analyzed in a multivariate manner.
Protocol Comparison Among the 309 patients with assessable tumors, 48% (39 of 81) of the patients who received the ifosfamide-containing protocol (ifosfamide, cisplatin, doxorubicin, and 28 Gy) achieved  95% pathologic necrosis. Mean follow-up for these 81 patients was 53 months (median, 45 months; range, 12 to 127 months). In comparison, only 13% (30 of 228) of the patients in all the other protocols combined achieved a pathologic response of 95% or greater pathologic necrosis. Mean follow-up for these 228 patients was 96 months (median, 91 months; range, 14 to 275 months) (Fig 4). This corresponded to significantly different 5- and 10-year survival rates for each group. The 5- and 10-year survival rates for patients who received the ifosfamide-containing protocol were 77% and 71%, respectively. In contrast, the 5- and 10-year survival rates for patients who received all other protocols combined were 64% and 58%, respectively (Fig 5).
Treatment-induced pathologic necrosis has been proven a predictor of survival in patients who receive neoadjuvant therapy for osteogenic and Ewing’s sarcomas.1,10-13 The correlation between pathologic necrosis and either local recurrence or survival in patients with soft tissue sarcomas remains unproved. Although such a correlation has been suggested, as yet there has been no study with an adequate number of patients or a sufficiently long follow-up period to make any definitive statements.14-24 In an attempt to resolve this issue, we looked at whether treatment-induced pathologic necrosis correlates with local recurrence and survival in 496 patients who received protocol neoadjuvant therapy. The patient and tumor characteristics of this study population are similar to those found in other large studies of soft tissue sarcomas for age, histology, and tumor location.27-31 In addition, these patients were ideal candidates for neoadjuvant therapy because the majority of the tumors were larger than 5 cm (80%), primary (83%), and high grade (79%). Histologic evaluation of tumor necrosis in the resected specimen remains the accepted standard for assessment of response to neoadjuvant therapy. No satisfactory clinical method exists, and decreases in volume do not accurately reflect the extent of tumor necrosis. Multiple imaging modalities have been used in attempts to assess response to preoperative treatment, including angiography, computed tomography, dynamic contrast-enhanced magnetic resonance imaging, thallium-201 scintigraphy, and (18F)-fluorodeoxyglucose proton emission tomography. Although several of these modalities show promise, none can provide a reliable and objective quantitation of tumor viability.1-9
We grouped the degree of pathologic necrosis into three response categories for several reasons. We regarded 95% or greater pathologic necrosis as a complete response, less than 95% pathologic necrosis as less than a complete response, and no residual tumor as an unassessable response. Although there is an unavoidable interobserver variation as to the exact percentage of necrosis, we minimized this variable by grouping necrosis into these three distinct ranges. In addition, high-grade soft tissue sarcomas have some degree of spontaneous necrosis. To avoid interpreting any spontaneous necrosis as a pathologic response, we set a high cutoff ( With a mean follow-up of approximately 10 years for surviving patients, the 5- and 10-year local recurrence rates for patients with 95% or greater pathologic necrosis were only 6% and 11%, respectively. This was significantly better than the 17% 5-year and 23% 10-year local recurrence rates for patients with less than 95% pathologic necrosis (Fig 2). When analyzed in a multivariate manner, pathologic necrosis was found to be an independent predictor of local recurrence. Patients with less than 95% pathologic necrosis were 2.51 times more likely to develop a local recurrence as compared with those who had 95% or greater pathologic necrosis. In addition, there was no change in the order of relative risk with the inclusion of the group with no residual tumor (Table 2). The 5- and 10-year survival rates for patients with 95% or greater pathologic necrosis were 80% and 71%, respectively. This was significantly better than the 62% 5-year and 55% 10-year survival rates for patients with less than 95% pathologic necrosis (Fig 3). When analyzed in a multivariate manner, pathologic necrosis is an independent predictor of survival regardless of whether the group with no residual tumor is included in the analysis. Patients with less than 95% pathologic necrosis were 1.86 times more likely to die of their disease as compared with patients with 95% or greater pathologic necrosis. The efficacy of doxorubicin-based adjuvant therapy in the treatment of soft tissue sarcomas has been variable. The majority of studies have investigated postoperative chemotherapy and have demonstrated a clear benefit only when several trials are grouped in meta-analysis.32,33 This is consistent with our findings, in which all of the primarily doxorubicin-based protocols achieved only a 13% complete pathologic response rate. In comparison, 48% of the patients who received the ifosfamide-containing protocol achieved a complete pathologic response (Fig 4). Although the mean follow-up for the patients who received the ifosfamide-containing protocol was 41/2 years, as compared with 8 years for the doxorubicin-based protocols, this increase in the percentage of patients who achieved 95% or greater pathologic necrosis translated into a statistically significant improved survival (Fig 5). The addition of cisplatin to doxorubicin did not increase the percentage of patients who achieved a complete response as compared with the patients who received doxorubicin alone. Cisplatin was included in the most recent ifosfamide-containing protocol to maintain continuity, but its effectiveness in combination with doxorubicin or doxorubicin and ifosfamide is unclear. For our current protocol, we are accruing patients treated with doxorubicin, ifosfamide, and 28 Gy radiation to determine whether the elimination of cisplatin effects the percentage of patients who achieve a complete response. Radiation therapy was included in all protocols, and its exact contribution to the percentage of tumor necrosis in this study is unknown. Although the dose ranged from 17.5 to 35 Gy in the earlier protocols, no change was observed in the percentage of patients who achieved a complete response. In addition, this variable has remained constant (28 Gy) during the past three protocols, and only the addition of ifosfamide significantly increased the percentage of patients who achieved a complete pathologic response. Finally, the effect of neoadjuvant therapy on surgical margins was not assessable in a statistically significant manner, because only 16 patients (3%) had a positive resection margin. In addition, we were unable to correlate positive surgical margins with a particular protocol because treatment of these 16 patients was distributed throughout the duration of the study. The strategy to increase the percentage of patients who achieve a complete pathologic response has been effective for improved patient survival in osteogenic and Ewing’s sarcoma. We think this also is true for patients with high-grade extremity soft tissue sarcomas. In addition, neoadjuvant therapy not only allows for a rapid assessment of the effectiveness of a particular treatment on an individual basis, it is also a potentially powerful tool to test new treatment strategies in a timely manner. Such benefits are not possible with postoperative therapy, for which long-term follow-up is required to assess the effectiveness of a particular therapy or any changes made to a current treatment regimen.
Treatment-induced pathologic necrosis is an independent predictor of both local recurrence and overall survival in patients who receive neoadjuvant therapy for high-grade extremity soft tissue sarcoma. A complete pathologic response ( The percentage of patients who achieve a complete pathologic response increased to 48% with the addition of ifosfamide. An increase in the percentage of patients who achieve a complete pathologic response correlated with a significantly improved 5- and 10-year survival rate. Further efforts to increase the percentage of patients who achieve complete pathologic response are warranted. In addition, assessment of the percentage of pathologic necrosis is a valid and timely end point by which new protocols can be evaluated.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
, 
, < 95% pathologic necrosis).
, < 95% pathologic necrosis; 
, all other protocols [n = 228]).
