Gerald Rosen

Treatment-Induced Pathologic Necrosis: A Predictor of Local Recurrence and Survival in Patients Receiving Neoadjuvant Therapy for High-Grade Extremity Soft Tissue Sarcomas

PURPOSEnTo 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.nnnPATIENTS AND METHODSnFour 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.nnnRESULTSnThe 5- and 10-year local recurrence rates for patients with > or = 95% pathologic necrosis were significantly lower (6% and 11%, respectively) than the local recurrence rates for patients with less than 95% pathologic necrosis (17% and 23%, respectively). The 5- and 10-year survival rates for the patients with > or = 95% pathologic necrosis were significantly higher (80% and 71%, respectively) than the survival rates for the patients with less than 95% pathologic necrosis (62% and 55%, respectively). Patients with less than 95% pathologic necrosis were 2.51 times more likely to develop a local recurrence and 1.86 times more likely to die of their disease as compared with patients with > or = 95% pathologic necrosis. The percentage of patients who achieved > or /= 95% pathologic necrosis increased to 48% with the addition of ifosfamide as compared with 13% of the patients in all the other protocols combined.nnnCONCLUSIONnTreatment-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 (> or = 95% pathologic necrosis) correlated with a significantly lower rate of local recurrence and improved overall survival.

High-Grade Extremity Soft Tissue Sarcomas: Factors Predictive of Local Recurrence and its Effect on Morbidity and Mortality

ObjectiveTo identify patient characteristics associated with the development of local recurrence and the effect of local recurrence on subsequent morbidity and mortality in patients with intermediate- to high-grade extremity soft tissue sarcomas. Summary Background DataNumerous studies on extremity soft tissue sarcomas have consistently shown that presentation with locally recurrent disease is associated with the development of subsequent local recurrences and that large tumor size and high histologic grade are significant factors associated with decreased survival. However, the effect of local recurrence on patient survival remains unclear. MethodsFrom 1975 to 1997, 753 patients with intermediate- to high-grade extremity soft tissue sarcomas were treated at UCLA. Treatment outcomes and patient characteristics were analyzed to identify factors associated with both local recurrence and survival. ResultsPatients with locally recurrent disease were at a significantly increased risk of developing a subsequent local recurrence. Local recurrence was a morbid event requiring amputation in 38% of the cases. The development of a local recurrence was the most significant factor associated with decreased survival. Once a patient developed a local recurrence, he or she was about three times more likely to die of disease compared to similar patients who had not developed a local recurrence. ConclusionsLocal recurrence in patients with intermediate- to high-grade extremity soft tissue sarcomas is associated with the development of subsequent local recurrences, a morbid event decreasing functional outcomes and the most significant factor associated with decreased survival. Although 85% to 90% of patients with high-grade extremity soft tissue sarcomas are treatable with a limb salvage approach, patients who develop a local recurrence need aggressive treatment and should be considered for trials of adjuvant systemic therapy.

The impact of chemotherapy on the survival of patients with high-grade primary extremity liposarcoma.

Objective:To determine if chemotherapy offers a survival benefit to patients with large, high-grade, primary extremity liposarcoma. Summary Background Data:The impact of chemotherapy on the survival of patients with primary extremity soft tissue sarcoma is controversial and its effect on individual histologic subtypes is not defined. Patient and Methods:Two prospectively collected sarcoma databases were used to identify all patients with >5 cm, high-grade, primary extremity liposarcoma that underwent surgical treatment of cure from 1975 to 2003 (n = 245). Clinical, pathologic and treatment variables were analyzed for disease-specific survival (DSS), distant recurrence-free survival (DRFS) and local recurrence-free survival (LRFS). Results:Sixty-three (26%) patients were treated with ifosfamide based chemotherapy (IF), 83 (34%) with doxorubicin based chemotherapy (DOX) and 99 (40%) received no chemotherapy (NoC). To assess the impact of DOX, a contemporary cohort analysis of patients treated from 1975 to 1990 was performed. The 5 year DSS of the DOX treated patients was 64% (53%–74%) compared with 56% (51%–79%) for the NoC patients (log-rank P value = 0.28). To assess the impact of IF, a contemporary cohort analysis of patients treated from 1990 to 2003 was performed. The 5 year DSS of the IF treated patients was 92% (84%–100%) compared with 65% (51%–79%) for the NoC patients (log-rank P value = 0.0003). Independent prognostic factors for improved DSS were smaller size (HR = 0.7, P = 0.01), myxoid/round cell histologic subtype (HR = 0.3, P = 0.03) and treatment with IF (HR = 0.3, P = 0.01). The five-year DRFS of the IF treated patients was 81% (70%–92%) compared with 63% (50%–76%) for the NoC patients (log-rank P value = 0.02). The 5 year LRFS of the IF treated patients was 86% (76%–96%) compared with 87% (77%–97%) for the NoC patients (log-rank P value = 0.99). Conclusions:In patients with large, high-grade, primary extremity liposarcoma; DOX is not associated with improved DSS and IF is associated with an improved DSS. Treatment with IF should be considered in patients with high-risk primary extremity liposarcoma.

Surgical Resection and Intraperitoneal Chemotherapy for Recurrent Abdominal Sarcomas

Background: Recurrent abdominal sarcomas have an extremely high rate of recurrence and poor overall survival. A prospective study was initiated to assess the feasibility, toxicity, and benefit of surgical resection and intraperitoneal chemotherapy for improving local control of disease and overall survival.Methods: Fifty-four patients underwent surgical excision of all gross disease and postoperative intraperitoneal chemotherapy with mitoxantrone. Thirty-five patients had peritoneal disease only (stage II), and 19 patients had peritoneal disease with hepatic metastases (stage III).Results: Nine (17%) patients remain free of disease with a mean follow-up of 37 months. The remaining 45 patients (83%) have had recurrence, with a mean interval to recurrence of 11 months. Stage (P 5.001) and grade (P 5.005) were the only two variables found to significantly affect recurrence. There was an overall peritoneal recurrence rate of 48% and an overall hepatic failure rate of 69%. Nineteen (35%) of the patients are alive, with a mean follow-up of 46 months. The overall 5-year survival was 31%. The 5-year survival for stage II patients was 46%; for stage III patients, it was only 5%. Stage (P 5.001) and grade (P 5.056) were the only two variables found to significantly affect survival. There were no treatment-related deaths, and only 5 patients (9%) developed local complications.Conclusions: Aggressive surgical resection and intraperitoneal chemotherapy for recurrent abdominal sarcomas is a feasible treatment approach with minimal toxicity. Although this treatment had little effect on the hepatic spread of this disease and thus overall survival, it appears to have significantly lowered the rate of peritoneal recurrence and may provide a survival benefit for patients with disease limited to the peritoneum.

Primary osteosarcoma of toe phalanx: first documented case. Review of osteosarcoma of short tubular bones.

A case of a sclerosing variant of osteosarcoma of a toe phalanx is reported in a 28-year-old man. This represents the first reported case of osteosarcoma of any kind at this site. This is based on a review of 4,214 cases of conventional osteosarcoma. The reason for the extraordinary rarity in toe or hand phalanges is unknown although osteosarcoma is the second most common primary tumor of bone. Since the neoplasm had minimal signs of cytologic anaplasia, it was originally mistaken for and treated as an osteoid osteoma. The lesion recurred and extended into soft tissues. Reevaluation revealed the tumor to be an osteosarcoma, sclerosing variant with normalization of nuclei. The lesions that this tumor should be distinguished from are osteoid osteoma and osteoblastoma.

Recurrent gastrointestinal stromal sarcomas

Gastrointestinal stromal sarcomas, formerly categorized as leiomyosarcomas of gastrointestinal origin, have a common pattern of intraperitoneal dissemination. Despite surgical resection with or without adjuvant systemic chemotherapy the vast majority of these patients succumb to intraperitoneal sarcomatosis and/or hepatic metastases. In an attempt to improve upon the morbidity and mortality associated with this disease we and several other centers have begun treating these patients with intraperitoneal chemotherapy. We have found that aggressive surgical resection with postoperative intraperitoneal chemotherapy has significantly lowered the peritoneal recurrence rate in patients with recurrent gastrointestinal stromal sarcomas as compared to those who have undergone surgical resection alone. However, this treatment approach has proven to be ineffective in preventing hepatic metastases, and thus has had little effect upon overall survival. With the treatment of primary rather than recurrent disease we hope to interrupt the disease process at an earlier stage further decreasing peritoneal recurrences and potentially improving survival.

Large, deep, high-grade extremity sarcomas: treating tumors of the flexor fossae

Limb salvage is now possible for the majority of patients with extremity sarcomas. Although overall prognosis is primarily based on tumor size and histologic grade, complete surgical excision and local control is essential for cure. There are, however, certain anatomic locations such as the flexor fossae in which a complete surgical margin is difficult to attain, and surgery without adjuvant therapy has a high local failure and amputation rate. We have found that preoperative adjuvant therapy consisting of chemotherapy and radiation followed by surgical excision with tumor-free margins has been successful in treating flexor fossa sarcomas with high limb salvage (96%), local control (89%) and overall survival rates (70%). These results are comparable to patients with similar large, high-grade extremity tumors in other compartmental locations.

Mitoxantrone for malignant pleural effusion due to metastatic sarcoma

Malignant pleural effusion due to metastatic sarcoma is a difficult problem to treat. Mitoxantrone hydrochloride is an anthracenodione that has been reported to be useful when used intracavitary for malignant effusion due to gynaecological malignancies. We reviewed 15 cases of malignant pleural effusion due to pleural involvement by metastatic sarcoma that were treated with intrapleural mitoxantrone. None of the patients had previous pleurodesis. A standard dose of 20 mg per square metre in 50 cc of saline solution was instilled by chest tube after drainage of the effusion. All patients were initially evaluated by chest CAT scans and chest films, control films were done immediately and 6 weeks after treatment. Thirteen cases were evaluated. Three patients presented with fever, two patients had local pain and one patient developed neutropenia. Three patients did not respond to the treatment. Complete resolution of the effusion was achieved in 76% of the patients: such an effect could be due to the local antineoplastic activity of the drug. We believe that mitoxantrone is effective in the treatment of malignant pleural effusion due to pleural involvement with sarcoma without causing significant local or systemic toxicity.

Expandable Endoprostheses for the Skeletally Immature: The Initial UCLA Experience

Until the concept of an expandable endoprosthesis was introduced in 1986 by Lewis [1] the only local control options for the skeletally immature patient with a primary malignant bone tumor were amputation or rotationplasty as has been recently advocated by Kotz and Salzer [2]. Since January of 1985, 15 expandable endoprostheses were implanted into skeletally immature patients following resection of a primary malignant bone tumor as part of the UCLA Limb Salvage Program. This paper reviews the survival and functional results of the first ten who have a minimum follow-up of 2 years. All patients were followed until prosthesis revision, extremity amputation, or patient death.

Limb Salvage Versus Amputation for Malignant Tumors Other Than Osteogenic Sarcoma

Seventy-seven patients with malignant tumors other than osteosarcoma were treated at UCLA between 1973 and 1987. Chondrosarcoma (39 cases), Ewing’s sarcoma (19 cases), and a third group composed primarily of fibrosarcoma and MFH were identified. Amputation was used as the surgical means of local control in only 6% (5/77) of the patients. Limb sparing surgery was performed in 94% (72/77), generally in conjunction with adjuvant protocols. Of the limb salvage patients, 32% experienced some sort of complication, of whom only 15 required additional surgery. Only one limb salvage patient went on to have an amputation and no deaths were associated with the limb salvage procedures. Local recurrence was observed in 4.2% (3/72) of patients undergoing limb salvage and 20% (1/5) of those undergoing primary amputation. The Musculoskeletal Tumor Society’s functional analysis revealed a 50% good to excellent rating in the limb salvage group, with the best results seen in intercalary and partial resection-reconstructions. Endoprosthetic reconstructions generally resulted in improved function when compared with their amputation counterparts who receive an obligatory “poor” by this schema. Kaplan-Meier survivor analysis for the 72 limb salvage patients revealed a 1- and 2-year survival for Ewing’s patients of 78% and 32%, respectively; for chondrosarcoma, it was 97% at 1 year and 69% at 5 years, and for the FS/MFH group it was 70% at 1 year and 40% at 5 years. Chemotherapy as applied in this present chondrosarcoma group did not give any survival advantage and has been deleted from present chondrosarcoma protocols. Careful longitudinal follow-up of both the oncological outcome and reconstruction techniques will be important to determine where each limb salvage technique should be utilized.