Response to anti-PD1 therapy with nivolumab in metastatic sarcomas.

BACKGROUND: Manipulation 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. METHODS: We 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. RESULTS: Twenty-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. CONCLUSIONS: These data provide a rationale for further exploring the efficacy of nivolumab and other checkpoint inhibitors in soft tissue and bone sarcoma.

Attenuation-Correction Induced Artifact in F-18 FDG PET Imaging Following Total Knee Replacement.

Purpose: The clinical use of PET FDG in the work-up of patients with bone and soft tissue malignant tumors is rapidly increasing. The recognition of any source of artifact, therefore, is important to avoid interpretation pitfalls.Procedures: Two patients with complete knee joint replacement by metallic prosthesis in the course of their treatment for malignant bone and soft tissue sarcoma were evaluated by PET F-18 FDG imaging using a dual head coincidence gamma camera.Results: Both studies demonstrated in the attenuation-corrected images intense increase activity at the joint space between the metallic prosthetic surfaces at the level of the knee joint. No uptake, however, was noted in the same location on the non-attenuation-corrected images. Subsequent bone and thallium-201 scans confirmed the absence of tumor recurrence in the first patient. The second patient had multiple follow up F-18 FDG scans over a period of 16 months that show no changes from the baseline study.Conclusion: In the F-18 FDG PET images of patients with total knee metallic prosthesis, an intense activity tends to be seen in the joint space, only in the attenuation-corrected images. Such pattern of uptake is considered artifactual and should always be verified in the non-attenuated images.

Fluorine-18 fluorodeoxyglucose splenic uptake from extramedullary hematopoiesis after granulocyte colony-stimulating factor stimulation.

Two patients with sarcoma, one with recurrent osteosarcoma of the spine and the other with metastatic synovial cell sarcoma, were treated with high-dose chemotherapy that produced severe leukopenia. The patients received granulocyte colony-stimulating factor (G-CSF) to stimulate the bone marrow (480 mg given subcutaneously twice daily for 5 to 7 days); their responses were seen as a marked increase in peripheral leukocyte count with no change in the erythrocyte or platelet counts. The patients had fluorine-18 fluorodeoxyglucose (F-18 FDG) imaging 24 hours after the end of G-CSF treatment. Diffusely increased uptake of F-18 FDG was seen in the bone marrow in both patients. In addition, markedly increased uptake in the spleen was noted in both, indicating that the spleen was the site of extramedullary hematopoiesis. The patients had no evidence of splenic metastases. The first patient had a history of irradiation to the dorsal spine, which was less responsive to G-CSF administration than was the nonirradiated lumbar spine.

Primary osteogenic sarcoma of the femur: a model for the use of preoperative chemotherapy in high risk malignant tumors.

The value of adjuvant chemotherapy in primary osteogenic sarcoma (OSA) is still considered controversial by some. One reason may be that various reported series include patients with widely varying prognostic variables. To address this, the effect of chemotherapy on the continuous disease-free (CNED) survival was analyzed in 100 patients aged 21 yr or less with OSA of the femur. This classically poor prognostic group of patients represented 51% of all primary OSA seen at the Memorial Sloan-Kettering Cancer Center during the study interval. This study includes all patients aged 21 yr or less with fully malignant (Grade III-IV/IV) OSA of the femur and no metastases treated from November 1973 through November 1981. The first (T-4) protocol (31 patients) consisted of high dose methotrexate (HDMTX) with leucovorin rescue, cyclophosphamide (Cyc), and adriamycin. In the second (T-7) protocol (23 patients) the dose of HDMTX was increased to 12 g/m2 for prepubescent patients, and bleomycin, Cyc, and dactinomycin replaced Cyc. The current (T-10) protocol (46 patients) uses the same CT as T-7, but patients not having a complete response of the primary tumor to preoperative CT receive additional cisplatinum (120 mg/m2) with adriamycin (30 mg/m2/day for two consecutive days). In 31 patients treated with T-4 the CNED survival was 32% with a minimum follow up of over 7 yr. On T-7, 15/23 patients with femur primaries had a CNED survival of 65% with all of the surviving patients followed for more than 5 yr. The addition of cisplatinum in T-10 has resulted in CNED survival rate of 77% in 34/44 patients (excluding two patients that died CNED during and after treatment); the median follow-up patients who are alive CNED is 33 months, with a minimum of 2 yr follow up on the last patient entered.

Chemotherapy of malignant fibrous histiocytoma of bone. A report of five cases.

Five patients with evaluable malignant fibrous histiocytoma (MFH) of bone (three with primary tumor and two with primary tumor and metastatic disease) were treated with preoperative chemotherapy including high dose methotrexate (HDMTX) with citrovorum factor rescue (CFR) as is used for patients with osteogenic sarcoma. All five patients demonstrated a clinical response to chemotherapy. Three of four patients who underwent surgery had complete responses and one patient had greater than 90% tumor necrosis as documented by histologic examination of the resected primary tumor. All four patients who underwent surgery following preoperative chemotherapy are surviving free of disease from one to six years from the start of treatment; chemotherapy was discontinued after six to 11 months in these patients. The median disease-free survival time is 31.5 months. This study demonstrates the effectiveness of chemotherapy in MFH of bone, and in particular the effectiveness of HDMTX with CFR which caused measurable responses in all patients while receiving this therapy as a single agent.

Primary osteogenic sarcoma: eight-year experience with adjuvant chemotherapy.

Since October 1973, 185 patients 21 years of age or younger with primary osteogenic sarcoma of an extremity were treated with adjuvant chemotherapy. Twenty-five of the first fifty-two patients (48%) have remained free of disease for a median of 7 years. In the next chemotherapy protocol most patients had chemotherapy prior to amputation or resection, during which time the dose of high-dose methotrexate was escalated in many patients to that needed to shrink the primary tumor. For a median of 4 years 43 of 54 patients (80%) have remained free of disease. In the current protocol, the response of the primary tumor to chemotherapy with high-dose methotrexate was used to select postoperative adjuvant chemotherapy for the patient. With the latter approach 73 of 79 patients (92%) have remained continuously free of disease for a median of 2 years. This experience demonstrates the value of chemotherapy in increasing the cure rate in osteogenic sarcoma and that the response to preoperative chemotherapy can help select postoperative chemotherapy to produce an even higher potential cure rate for osteogenic sarcoma.

Chemical pleuritis as the cause of acute chest pain following high-dose methotrexate treatment.

This report describes the clinical and roentgenographic features of a pleuritis seen following the administration of high-dose methotrexate (HDMTX). Among 210 patients who received 3130 courses of HDMTX from 1977 through 1980, the incidence of this clinical entity was 8.5% (n = 18). The sudden onset of chest pain occurred only after the third or fourth HDMTX treatment and usually lasted between three and five days; the pain was often quite severe and led to extensive clinical examination before recognition of the benign transient nature of this syndrome. Roentgenographic examination of the chest revealed thickening of the intralobar pleura, most prominent on the right side. Our observations support the hypothesis that this adverse drug reaction occurs more frequently than assumed, but is often ignored or misinterpreted.

Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy.

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. All 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, HDMTX 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 in 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 in responding patients and in 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 rate reported to date for osteogenic sarcoma.