Intensive chemotherapy can achieve DFS for a high proportion of patients with OS. Although it is a powerful predictor of DFS, histologic response to preoperative chemotherapy cannot be assessed at diagnosis. We have not shown an ability to salvage patients with an unfavorable response. We need to increase the proportion of patients with a favorable response, identify the patients who will have an unfavorable response, and develop novel treatments to salvage poor responders.
Since June 1978, 57 patients with primary osteogenic sarcoma of an extremity were treated with high-dose methotrexate (HDMTX) and citrovorum factor rescue (CFR), Adriamycin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) given for 4-16 weeks prior to definitive surgery. Histologic examination of the resected primary tumor determined the effect of preoperative chemotherapy with many primary tumors showing greater than 90% tumor necrosis attributable to preoperative chemotherapy. A l l patients having this favorable effect of chemotherapy on the primary tumor were continued on the same chemotherapy regimen postoperatively (regimen B). However, in those patients not having a good effect of preoperative chemotherapy on the primary tumor, H D M T X with CFR was subsequently deleted from their postoperative chemotherapy and they were placed on a regimen containing cisplatinum at the dose of 120mg/M2 with mannitol diuresis combined with Adriamycin i n addition to BCD (regimen A). In the current study, 35 of the 57 patients did not demonstrate a good effect of chemotherapy on the primary tumor and were assigned to regimen A postoperatively. Of these 35 patients, 32 (91%)) have remained continuously free of recurrent or metastatic disease from 6-34 months following the start of therapy. Among the 22 remaining patients having a good histologic response and treated with regimen B postoperatively, there has been only one relapse in a patient who had a local recurrence in the area of an inadequately resected primary tumor three months after the cessation of chemotherapy. Thus, 53 of 57 patients (93%) are continuously with no evidence of recurrent or metastatic disease from 6-35 months (median, 20 months) from the start of treatment. This study demonstrates the value of thorough histologic examination in predicting survival i n responding patients and i n helping identify patients whose disease-free survival rate can be substantially increased if they are given alternative postoperative adjuvant chemotherapy after failing to have a good response to preoperative chemotherapy. This individualized chemotherapeutic strategy has yielded the highest disease free survival raw reported to date for osteogenic sarcoma.
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.
Almost a quarter of a century has passed since mesenchymal chondrosarcoma, a rare, insufficiently studied and still poorly understood cartilage neoplasm has been described. Based on 35 cases diagnosed and treated at this Cancer Center, this study found 20 males and 15 females with an average age of 26 years (range, 6–70 years). All but five of the tumors arose in the skeleton in the femur, humerus, and ilium in five cases each, while the os calcis (a rare site for any other osseous tumor) gave rise to this tumor in four instances. Pain was the cardinal symptom in 27 patients. The lesional size varied from 4 to 18 cm (average, 9.5 cm). Histologic examination revealed nine of the tumors to be of the small cell undifferentiated types while the others were of the “hemangiopericytomatoid” variant. According to this subclassification, patients with the small cell type of lesions responded to combination chemotherapy and irradiation, as usually do other small cell sarcomas. The addition of surgical resection may be of value especially in the patients with the hemangiopericytomatoid variant. Preliminary results in the treatment of five such patients with evaluable disease suggest that this combined treatment approach is encouraging. Follow‐up analysis of all patients revealed a 37.9 months median survival, and 28% to be alive at ten years.
From 1973From -1975 patients with biopsied primary osteogenic sarcoma were treated with preoperative chemotherapy followed by surgical ablation of the primary tumor. Surgery was delayed in order to obtain a custom-fitted prosthetic bone implant in an attempt to avoid amputation. Preoperative chemotherapy included high dose methotrexate (HDMTX) with citrovorum factor rescue (CFR) and adriamycin (T-5 protocol) and was administered for 3 months preoperatively and continued with the inclusion of cyclophosphamide for approximately 5 months postoperatively. At a follow-up period of 30-52 months, 23 of 31 patients (75%) are surviving (21 of 23 with no evidence of disease). Histologic examination of primary tumor removed at surgery revealed varying degrees of tumor destruction (from very little effect to no evidence of viable tumor) attributable to the effect of chemotherapy. The 2 1 patients that are disease-free survivors had a more complete effect of preoperative chemotherapy on the primary tumor. Some patients achieving favorable effects upon the primary tumor did so only after the dose of HDMTX was escalated to greater than the starting dose of 8 g/m2. Preoperative chemotherapy for all patients with osteogenic sarcoma would seem to offer the following advantages: 1) Evaluation of the effect of HDMTX with CFR on the primary tumor with escalation of the dose of HDMTX until a clinical response is observed, thus defining the dose of HDMTX effective in that patient, to be continued postoperatively as adjuvant therapy; 2) The early use of systemic therapy to eradicate distant microfoci of disease that will eventually kill the patient if not adequately treated by effective chemotherapy; 3) Allow more time for postoperative healing without the need to start adjuvant chemotherapy immediately; and 4) Provide the surgeon time to plan resection surgery. To date, 20 additional patients with biopsy proven osteogenic sarcoma have been treated with more aggressive preoperative chemotherapy (T-7) for approximately 2 $4 months prior to definitive surgery (resection or amputation).
Two hundred seventy‐nine consecutive patients with Stage II osteogenic sarcoma of the appendicular skeleton treated between 1976 and 1986 were studied to identify predictors of long‐term survival. Survival was 77% and 73% at 5 and 10 years, respectively, with continuously disease‐free survival being 70% and 69%. On univariate analysis, the most significant predictors of survival were the location of the primary lesion, local control of the tumor, and the degree of necrosis in the primary tumor after intravenous neoadjuvant chemotherapy (histologic response). On initial multivariate analysis, similarly, only location and histologic response to chemotherapy predicted disease‐free outcome. After statistical control for local recurrence, only histologic response to chemotherapy was retained as an independent predictor, suggesting that in this data set, the location of primary lesion exerted its effect only secondarily through its association with the ability to provide local control. The risk of local recurrence was almost fivefold higher in tumors of the femur than in tumors of other locations (relative risk, 4.6) and, within the femur, was more than threefold higher in the proximal femur than in the distal femur (relative risk, 3.4). None of the other primary tumor or patient characteristics studied yielded independent predictive significance for survival. The rate of failure was almost fivefold as high in those with an incomplete response to chemotherapy compared with those with a complete response to chemotherapy (relative risk, 4.9; 95% confidence interval, 2.2 to 11). Even in those patients with minimal or no necrosis in the primary tumor, ultimately 62% and 54% were disease‐free at 5 and 10 years, respectively.
BackgroundManipulation of immune checkpoints such as CTLA4 or PD-1 with targeted antibodies has recently emerged as an effective anticancer strategy in multiple malignancies. Sarcomas are a heterogeneous group of diseases in need of more effective treatments. Different subtypes of soft tissue and bone sarcomas have been shown to express PD-1 ligand.MethodsWe retrospectively analyzed a cohort of patients (pts) with relapsed metastatic/unresectable sarcomas, who were treated with nivolumab provided under a patient assistance program from the manufacturer. Pts underwent CT or PET/CT imaging at baseline and after at least four doses of nivolumab; RECIST 1.1 criteria were used for response assessment.ResultsTwenty-eight pts with soft tissue (STS, N = 24) or bone sarcoma (N = 4), received IV nivolumab 3 mg/kg every 2 weeks from July 2015. Median age was 57 (24–78), male:female ratio was 14:14; the median number of nivolumab cycles was eight. Eighteen pts concomitantly received pazopanib at 400–800 mg daily. The most common side effect was grade 1–2 LFT elevations; grade 3–4 toxicity occurred in five patients (colitis, LFT elevations, pneumonitis). Twenty-four pts received at least four cycles. We observed three partial responses: one dedifferentiated chondrosarcoma, one epithelioid sarcoma and one maxillary osteosarcoma (last two patients on pazopanib); nine patients had stable disease including three leiomyosarcomas; 12 patients had progression of disease including 4 leiomyosarcoma. Clinical benefit (response + stability) was observed in 50% of the evaluable patients.ConclusionsThese data provide a rationale for further exploring the efficacy of nivolumab and other checkpoint inhibitors in soft tissue and bone sarcoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s13569-016-0064-0) contains supplementary material, which is available to authorized users.
Background. This report describes the unusually high response rate of metastatic synovial sarcoma to high dose ifosfamide (14–18 g/m2) when that drug was used to treat 13 consecutive patients with recurrent metastatic synovial sarcoma before surgery (or thoracotomies) to provide optimal salvage therapy for these patients. Patients and Methods. Thirteen patients with recurrent or pulmonary metastatic synovial sarcoma seen at the Cedars‐Sinai Comprehensive Cancer Center (Los Angeles, CA) from April, 1989 through January, 1993 were treated with high dose ifosfamide (14–18 g/m2). Ifosfamide was infused at the dose of 2 g/m2 over a 4‐hour bolus infusion, followed by 2‐g/m2 24‐hour continuous infusions of ifosfamide, for a total of 14 or 18 g/m2 (6–8 days). Mesna (Mesnex, Bristol‐Myers Oncology, Princeton, NJ) was infused with the ifosfamide at equimolar doses. Supplemental sodium bicarbonate (180 mEq) was given daily to prevent severe acidosis. Nine of the thirteen patients were treated with prior chemotherapy for their primary tumors. Prior chemotherapy consisted of doxorubicin (Adriamycin, Adria Labs, Dublin, OH) in all patients and doxorubicin combined with cisplatin in eight of them. Results. All 13 patients had objective responses to high dose ifosfamide chemotherapy. There were nine partial responses and four complete responses. Five of the patients died of disease at 20–40 months (median, 27 months) from initial therapy. Eight patients have survived from 2 to 43 months (median, 20 months) from initial therapy, and three of these patients are disease free. Those patients surviving disease free had successful surgical removal of their residual metastatic disease after chemotherapy. Conclusion. Metastatic synovial sarcoma appears to be particularly sensitive to high dose ifosfamide chemotherapy. This experience suggests that there is a role for high dose ifosfamide chemotherapy in preoperative and postoperative adjuvant chemotherapy for primary synovial sarcoma, which is usually always a high grade malignant lesion with a poor prognosis after surgery alone.
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