Frederick R. Eilber

Impaired immunologic reactivity and recurrence following cancer surgery

One hundred patients were tested for their ability to react to 7 commonly encountered skin test antigens and to develop delayed cutaneous hypersensitivity to 2, 4‐dinitrochlorobenzene (DNCB). Following sensitization, more than 95% of normal patients, but only 60% of patients with potentially resectable neoplasms, exhibited delayed cutaneous hypersensitivity to DNCB. A correlation is suggested between the inability to react to DNCB and the incidence of either inoperability, local recurrence, or distant metastases within 6 months post‐operatively. Ninety‐three percent (27/29) of patients who failed to react to DNCB were inoperable or developed early recurrence, whereas 92% (50/54) of patients who reacted to DNCB were free of disease for 6 months; but many of these patients were nonreactive to all of the common skin test antigens. These studies suggest that there is a significant correlation between cell mediated immunologic reactivity as measured by delayed cutaneous hypersensitivity to DNCB and the course of malignant disease following definitive cancer surgery.

BCG Immunotherapy of Malignant Melanoma: Summary of a Seven-year Experience

Over the past 7 years, 151 patients with malignant melanoma have been treated with BCG immunotherapy alone or as an adjunct to surgical therapy. Direct injection of metastatic melanoma lesions limited to skin resulted in 90% regression of injected lesions and 17% regression of uninjected lesions in immunocompetent patients. Approximately 25% of these patients remained free of disease for 1 to 6 years. Direct injections of BCG into nodules of patients with subcutaneous or visceral metastases resulted in a lower incidence of local control and no long term survivors. Attempts to improve the results of immunotherapy in these patients by palliative surgical resection of large metastatic lesions to lower tumor burden followed by BCG immunotherapy significantly improved the results although many patients still developed recurrent disease. Early results of a clinical trial combining BCG immunotherapy with regional lymphadenectomy in patients with melanoma metastatic to lymph nodes have been encouraging and promising. Further controlled clinical trials are necessary to elucidate the role of BCG in immunotherapy. However, since BCG is but one of a number of potential immunologic adjuvants, even more effective immunotherapy will be possible as further knowledge of the interactions of cellular and humoral immunity is acquired.

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

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 > 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. 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 (> or = 95% pathologic necrosis) correlated with a significantly lower rate of local recurrence and improved overall survival.

Limb salvage for skeletal and soft tissue sarcomas multidisciplinary preoperative therapy

One hundred eighty‐three patients with malignant skeletal (83) or soft tissue sarcoma (100) were entered into the multimodality preoperative limb salvage protocol. Local recurrences were observed in 5 of 183 (2.7%). Six patients required amputation because of complications, and 13 patients died within 1 year from metastatic disease. There was no statistical difference in survival rates between a series of patients who had amputation and adjuvant therapy and patients treated by limb salvage and adjuvant therapy. Overall survival rates for patients with soft tissue sarcoma were 76%. Although the exact reason for the improved local control is not known, it is our belief that it is the result of the multidisciplinary therapy that destroys microscopic disease at the periphery of the primary tumor.

Is Amputation Necessary for Sarcomas? A Seven-Year Experience with Limb Salvage

The rationale for amputation for local tumor control of skeletal and soft tissue sarcomas was based on results obtained from surgical therapy alone. However, our previous results from a pilot trial of multimodality therapy of preoperative chemotherapy and radiation therapy followed by surgical resection indicated that limb salvage (without amputation) could be accomplished in most patients with little morbidity and low recurrence rate. This report summarizes our experience in a prospective trial from January 1972 to December 1979. A total of 105 consecutive patients with soft tissue sarcomas (65 patients) or bone sarcomas (40 patients) were treated with preoperative intra-arterial adriamycin, 3500 rads of rapid-fraction radiation and radical en bloc resection of primary tumor. Diseased bones were replaced with cadaver allografts (22 patients), metallic endoprostheses (10 patients) autologous bone (2 patients), or no replacement (ilium or fibula—4 patients). Salvage of a viable, neurologically intact, functional extremity was achieved in 98/105 patients (98%); 97% of limb salvage patients were free of local recurrence after a median follow-up period of 28 months. Major complication rate that required amputation was 3/105 patients (2%). Postoperative adjuvant chemotherapy with cyclical adriamycin and high-dose methotrexate was employed for all patients with osteosarcoma and 35 patients with grade III soft tissue sarcomas. The overall disease-free rate is 50% (18/35) for osteosarcomas and 65% (42/65) for soft tissue sarcomas. These results indicate that local tumor control can be achieved in 91% of patients without amputation. Their functional capabilities are excellent with a low complication rate. Since the advent of adriamycin and methotrexate has significantly improved the overall survival for patients with skeletal and soft tissue sarcomas, the quality of this survival has become even more important. Preoperative multimodality therapy is a major advance in this direction and since results of limb salvage procedures appear to be equal or superior to those achieved by amputation we believe these alternatives should be offered to all patients.

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.

Etiology and results of tumor endoprosthesis revision surgery in 64 patients.

From December 1980 to December 1995, 278 patients underwent primary custom endoprosthesis replacements for neoplastic disease at the University of California, Los Angeles and have been followed up for a minimum of 2 years or to death. The endoprosthesis reconstruction failed in 64 patients, including 10 additional patients referred for revision of their replacements. Failure was defined as the complete removal of a prosthesis for any reason. The cause of failure were aseptic loosening (44%), fatigue fracture (16%), local recurrence (14%), infection (13%), and failure of the expansion mechanism (6%). Forty-eight of 64 failed endoprostheses were managed by endoprosthesis reconstruction with most being revised using the same type of prosthesis. Nine of these patients with failed replacements experienced a second failure and four went on to require an amputation. Aseptic loosening and mechanical failure accounted for most of the failures and they were revised successfully. Sixty percent of the infected cases were salvaged satisfactorily by endoprosthetic revision, whereas, 89% of the local recurrences resulted in amputation. Based on endoprosthesis survival the 7-year failure rates were 31% and 34% for primary and revision reconstructions, respectively. The functional results for the patients with endoprosthesis revisions either were better, unchanged, or on average only slightly lower than results of patients with a surviving endoprosthesis.

Chemotherapy Is Associated With Improved Survival in Adult Patients With Primary Extremity Synovial Sarcoma

Purpose:To determine if ifosfamide-based chemotherapy (IF) offers a survival benefit to adult patients with primary extremity synovial sarcoma. Patients and Methods:Prospectively collected patient data from 2 institutions was used to identify all adult patients (≥16 years) with ≥5 cm, deep, primary, extremity, synovial sarcoma that underwent surgical treatment of cure from 1990 to 2002. A total of 101 patients were identified and the median follow-up for survivors was 58 months. 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-eight (67%) patients were treated with IF and 33 (33%) patients received no chemotherapy (NoC) for the primary tumor. The characteristics of the IF-treated patients [median tumor size = 7.2 cm; monophasic n = 46 (68%)] were similar to NoC patients [median tumor size = 7 cm; monophasic n = 23 (70%)]. The 4-year DSS of the IF-treated patients was 88% compared with 67% for the NoC patients (P = 0.01). Smaller size (HR = 0.3 per 5-cm decrease, P < 0.0001) and treatment with IF (HR = 0.3 compared with NoC, P = 0.007) were independently associated with an improved DSS. Treatment with IF was independently associated with an improved DRFS (HR = 0.4, P = 0.03) but not associated with an improved LRFS (P = 0.39). Conclusion:Ifosfamide-based chemotherapy was associated with an improved DSS in adult patients with high-risk, primary, extremity, synovial sarcoma and should be considered in the treatment of such patients.

Outcome Prediction in Primary Resected Retroperitoneal Soft Tissue Sarcoma: Histology-Specific Overall Survival and Disease-Free Survival Nomograms Built on Major Sarcoma Center Data Sets

PURPOSE Integration of numerous prognostic variables not included in the conventional staging of retroperitoneal soft tissue sarcomas (RPS) is essential in providing effective treatment. The purpose of this study was to build a specific nomogram for predicting postoperative overall survival (OS) and disease-free survival (DFS) in patients with primary RPS. PATIENTS AND METHODS Data registered in three institutional prospective sarcoma databases were used. We included patients with primary localized RPS resected between 1999 and 2009. Univariate (Kaplan and Meier plots) and multivariate (Cox model) analyses were carried out. The a priori chosen prognostic covariates were age, tumor size, grade, histologic subtype, multifocality, quality of surgery, and radiation therapy. External validation was performed by applying the nomograms to the patients of an external cohort. The models discriminative ability was estimated by means of the bootstrap-corrected Harrell C statistic. RESULTS In all, 523 patients were identified at the three institutions (developing set). At a median follow-up of 45 months (interquartile range, 22 to 72 months), 171 deaths were recorded. Five- and 7-year OS rates were 56.8% (95% CI, 51.4% to 62.6%) and 46.7% (95% CI, 39.9% to 54.6%. Two hundred twenty-one patients had disease recurrence. Five- and 7-year DFS rates were 39.4% (95% CI, 34.5% to 45.0%) and 35.7% (95% CI, 30.3% to 42.1%). The validation set consisted of 135 patients who were identified at the fourth institution for external validation. The bootstrap-corrected Harrell C statistics for OS and DFS were 0.74 and 0.71 in the developing set and 0.68 and 0.69 in the validating set. CONCLUSION These nomograms accurately predict OS and DFS. They should be used for patient counseling in clinical practice and stratification in clinical trials.

Pulmonary metastases of stage IIB extremity osteosarcoma and subsequent pulmonary metastases.

PURPOSE This study investigated prognostic factors in nonmetastatic high-grade extremity osteosarcoma and the prognosis following resection of subsequent pulmonary metastases, with emphasis on the effect of chemotherapy-induced tumor necrosis. PATIENTS AND METHODS We reviewed 111 consecutive patients with high-grade nonmetastatic extremity osteosarcoma treated with preoperative chemotherapy and surgical resection, with additional review of 36 patients who had subsequent pulmonary metastases resected. RESULTS The overall 5-year survival rate was 53%. In resected primary tumors, tumor-free resection margin (P < .001) and increasing chemotherapy-induced tumor necrosis (> 90% threshold, P < .003) correlated with increased metastasis-free survival. Relative risk factors for metastases were as follows: tumor-containing resection margin (most likely to metastasize); poor response to preoperative chemotherapy and/or lack of postoperative chemotherapy (next worse prognosis); and excellent response to preoperative chemotherapy (> or = 90% necrosis) combined with postoperative chemotherapy (best prognosis). The 5-year survival rate following pulmonary metastasis resection was 23%, whereas a 0% 4-year survival rate followed development of bony metastases (P < .001). The extent of tumor necrosis in resected pulmonary metastases did not affect prognosis. Survival was best in patients with three or fewer pulmonary nodules (P < .048), four or fewer recurrent pulmonary nodules (P < .047), unilateral pulmonary metastases (P < .037), or longer intervals between primary tumor resection and metastases (P < .082). CONCLUSION Intensive preoperative and postoperative chemotherapy combined with complete resection of both primary and metastatic pulmonary osteosarcomas is justified, with a goal of 100% tumor necrosis and excision. Although current treatment regimens allow effective salvage therapy for a few patients with pulmonary metastases, more effective systemic treatment is needed.