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