CHS 828 is a new guanidino-containing drug. The aim of this study was to determine the maximum tolerated dose (MTD), the recommended dose and the toxicity of CHS 828. CHS 828 was given orally once ...every 3
weeks. The starting dose was 50
mg, which was escalated to 500
mg. A total of 107 courses was administered to 37 patients. At the 500-mg dose level, two of three patients experienced dose-limiting toxicities (DLT) (grade 3 mucositis and grade 4 thrombocytopenia), establishing this as the MTD. One of seven patients treated at 420
mg dose experienced DLT (grade 4 leucopenia, grade 4 mucositis and grade 4 diarrhoea), and this was considered the recommended dose for phase II studies. Vomiting, haematuria, leucopenia and thrombocytopenia were other significant toxicities. The pharmacokinetics of CHS 828 showed large variations both between and within patients. No objective responses were seen. A dose of 420
mg of CHS 828 administered every 3
weeks is the recommended dose, while 500
mg is the MTD.
Forty-four samples from 25 cases of retroperitoneal sarcoma initially diagnosed as malignant fibrous histiocytoma were histologically reviewed. Immunohistochemistry for mdm2 and cdk4 was performed on ...20 cases. Comparative genomic hybridization was performed on 18 samples from 13 patients. Seventeen cases were reclassified as dedifferentiated liposarcoma. Twenty-one of 32 samples from these patients showed areas of well-differentiated liposarcoma, allowing the diagnosis of dedifferentiated liposarcoma. Immunohistochemistry performed in 15 of these cases showed positivity for mdm2 and cdk4. Comparative genomic hybridization analysis performed on 15 samples from 11 of these patients showed an amplification of the 12q13–15 region. Eight cases were reclassified as poorly differentiated sarcoma. Twelve samples from these patients showed no area of well-differentiated liposarcoma. Immunohistochemistry showed positivity for mdm2 and cdk4 in one of six of these patients and showed positivity for CD34 in another one. Comparative genomic hybridization analysis performed on three samples from two of these patients showed no amplification of the 12q13–15 region but showed complex profiles. This study shows that most so-called malignant fibrous histiocytomas developed in the retroperitoneum are dedifferentiated liposarcoma and that a poorly differentiated sarcoma in this area should prompt extensive sampling to demonstrate a well-differentiated liposarcoma component, immunohistochemistry for mdm2 and cdk4, and if possible, a cytogenetic or a molecular biology analysis.
Summary
Multidrug chemotherapy increases responses in advanced soft tissues sarcoma. Can a 20% increase of relative dose intensity of the MAID regimen, more improve responses? From 1994 to 1997, 162 ...patients were randomized in a phase III study to the conventional drug combination (6 cycles of MAID: 60, 7,500, 900 mg/m
2
for doxorubicin, ifosfamide and dacarbazine respectively), or at doses 20–33% higher per cycle (5 cycles of intensified MAID for similar cumulative doses) with systematic G-CSF. Primary endpoint was response rate; secondary were toxicity, event-free and overall survival. The objective response rate in assessable patients was 38% with intensified MAID and 35% with MAID (
p
= 0.72). Event-free and overall survivals were similar in both arms. Only grade 3–4 thrombocytopenia and anemia were significantly higher in intensified arm. Treatment with intensified MAID did not improve response rate neither survival and cannot be recommended for advanced or metastatic soft tissue sarcoma.
MDM2 and CDK4 immunostaining can be useful adjuncts in diagnosing liposarcoma among soft tissue neoplasms. We examined the reproducibility of MDM2 and CDK4 staining between 2 laboratories and between ...tissue microarrays and whole tissue sections. Sixty-two soft tissue tumors were immunostained at the Bergonié Institute, Bordeaux, France, and the Curie Institute, Paris, France. We also examined 203 soft tissue neoplasms on standard tissue sections and tissue microarrays. There was high concordance of results obtained from the 2 laboratories (with 2 different pathologists) for MDM2 (kappa, 0.93) and CDK4 (kappa, 0.8) staining. There also was excellent concordance between results on tissue microarray and on whole tissue sections for MDM2 (kappa, 0.80) and CDK4 (kappa, 0.93). Immunostaining for MDM2 and CDK4 is a reproducible technique that may be exported to different laboratories for routine use. Tissue microarray is indicated for studying large series.
To identify most significant and therapeutically relevant prognostic factors in adults with localized primary synovial sarcomas (SS) and to confirm the usefulness of the French Federation of Cancer ...Centers (FNCLCC) grading system, the prognostic impact of which has been already proven in soft tissue sarcomas.
Data on 128 patients with nonmetastatic SS collected from a cooperative database by the FNCLCC Sarcoma Group between 1980 and 1994 were studied retrospectively. Immunohistochemistry was performed at diagnosis in 77 cases (61%). The tumors were classified as biphasic (n = 45), monophasic fibrous (n = 72), and poorly differentiated (n = 10) subtypes. Histologic grade was determined according to the FNCLCC method, and vascular invasion was assessed in every case.
The 5-year disease-specific survival (DSS) rate for this series of patients with localized SS was 62.9% (+/- 9.6% SD) with a median follow-up time of 37 months (range, 8 to 141 months). In multivariate analysis, the adverse risk factors associated with decreased DSS were International Union Against Cancer/American Joint Committee on Cancer stage III/IVA disease, male sex, and truncal tumor locations. For metastasis-free survival (MFS), disease stage III/IVA, tumor necrosis, and monophasic subtypes were the major factors associated with a less favorable prognosis. Separately, when not using disease stage, tumor necrosis, and mitotic activity, histologic grade became the most significant prognostic factor for both DSS and MFS. In addition, larger tumors and older patients become associated with a significantly worse prognosis. Independent adverse risk factors for local recurrence-free survival included histologic grade 3 and truncal tumor location.
These data confirm that not all SS present the same severe outcome. High-risk patients identified on the basis of these parameters may qualify for an aggressive treatment approach.
Identification of the alveolar subtype of rhabdomyosarcoma (ARMS) is important, because the poor prognosis associated with this subtype necessitates a modified therapeutic regimen. At present, ARMS ...diagnoses are made on the basis of histologic findings and the extent of myogenin immunopositivity. Nonetheless, the absence of an alveolar pattern in the solid variant, the low degree of differentiation in certain embryonal rhabdomyosarcomas (ERMS), and the increasing use of microbiopsy samples make the diagnosis of ARMS somewhat difficult. Two specific translocations have been found in ARMS, and fusion transcripts can be detected by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of paraffin-embedded tissue (PET).
To assess the value of myogenin staining and molecular testing in the diagnosis of rhabdomyosarcoma, the authors examined 109 rhabdomyosarcoma samples (45 ARMS samples and 64 ERMS samples). Real-time RT-PCR analysis of PET was performed in all 109 rhabdomyosarcomas, and RT-PCR analysis of frozen material was performed in 24 cases.
PAX fusion transcripts were present in 44 cases (39 ARMS and 5 ERMS) and absent in 52 cases (2 ARMS and 50 ERMS). In 13 cases (4 ARMS and 9 ERMS), the results were not interpretable. Results were concordant between paired frozen and fixed tumor samples. All 35 interpretable ERMS samples that contained < 50% myogenin-positive cells failed to yield detectable PAX fusion transcripts. Of the 61 interpretable tumor samples (41 ARMS and 20 ERMS) that contained > 50% myogenin-positive cells, 44 (39 ARMS and 5 ERMS) yielded detectable PAX fusion transcripts.
The current study demonstrates that molecular detection of PAX fusion transcripts via real-time RT-PCR analysis of PET is a sensitive and specific method for the diagnosis of ARMS and that immunohistochemical analysis of myogenin expression can be used to select cases for such molecular testing. Although RT-PCR analysis appears not to possess diagnostic value in tumors with < 50% tumor cell immunopositivity, it is strongly recommended for the diagnosis of tumors containing > 50% myogenin-positive cells.
To assess the outcome and the prognosis of adults with a neoplasm related to the Ewing's sarcoma family of tumors.
The outcomes of 182 consecutive patients older than 15 years with Ewing's sarcoma or ...related neoplasms managed from 1982 to 1992 were reviewed, without any selection according to primary tumor site or disease extension.
Of 182 patients, 53 had evidence of metastases at presentation (29%). Tumor size was greater than 10 cm in 70 patients (41%). With a median follow-up duration of 66 months, the 5-year overall survival (OS) rate was 41%. In patients with localized disease, 5-year OS rate was 54% and 5-year progression-free survival (PFS) rate, 43%. Late relapses after 5 years accounted for 9% of relapses. Metastasis at presentation (P = .00001), pelvic primary lesion (P = .0025), and tumor size greater than 10 cm (P = .004) were independent prognostic factors for survival. Five-year OS was 67% in patients with nonpelvic tumors < or = 10 cm, 52% in those with pelvic tumors less than 10 cm or extrapelvic tumors > or = 10 cm, 16% in those with pelvic tumors greater than 10 cm, and 9% in those with metastasis (P = .00001).
Based on our experience and a review of the literature, we concluded that the natural history and the prognosis of the Ewing's family of tumors in adults are not different from that found in children. A greater tumor bulk in adults may explain the less favorable prognosis previously reported by others. Outcome could be adequately monitored by a simple prognostic index.
To describe chemotherapy treatment patterns and clinical outcomes in metastatic soft tissue sarcoma (mSTS) patients with favorable response to chemotherapy.
Multicenter (25) multi-country (9) ...retrospective chart review of mSTS patients with favorable response to chemotherapy, defined as stable disease or better following four cycles.
Two hundred and thirteen patients (58% female; mean age 54.7 years) received a mean of 2.7 lines of chemotherapy and 5.2 cycles per line. The most common first-line regimens were doxorubicin (34%) and anthracycline plus ifosfamide (30%). Favorable response was achieved by 83% to first-line and 42% and 38% in second- and third-line chemotherapy. The most common reason for chemotherapy discontinuation in lines with a favorable response was reaching a predefined number of cycles in first line (64% of 213) and disease progression in second or later lines (41% of 138). The mean time off chemotherapy was 38.0 weeks after first line, falling to 2.7–6.4 weeks in second or later lines. Median overall and progression-free survival were 23.5 (95% confidence interval 20.5–28.1) and 8.3 (7.4–9.9) months from first favorable response to chemotherapy.
mSTS patients achieving favorable response to chemotherapy have poor outcomes. Additional treatment options are needed.
Abstract only
10057
Background: There are no data regarding the management and the outcome of elderly patients (pts) diagnosed with advanced soft-tissue sarcoma (STS). Methods: The charts of pts aged ...≥ 75 years and diagnosed with metastatic and/or unresectable STS between 1990 and 2011 at Memorial Sloan Kettering (New York) and Institut Bergonié (Bordeaux, France) were reviewed. Results: 189pts were included.Median age was 79 years (range 75-93).160 pts (84.5%) had metastatic disease. The most frequent histological subtype was leiomyosarcoma (n=57, 30%). The median age-adjusted Charlson comorbidity score was 10 (range 5-17). 120 pts (63.5%) received systemic therapy whereas 69 pts (36.5%) were managed with best supportive care (BSC) only. Pts who received BSC only were more likely ≥ 80 years old (58% versus 38%, p=0.01) and with performance status (PS) ≥ 2 (35% versus 14%, p=0.01). Single agent and combination therapy were delivered in 87 (72.5%) and 33 (27.5%) cases respectively. 67 pts (56%) received a 1
st
-line anthracycline-containing regimen. The median progression-free survival of pts treated with systemic therapy was 4 months (95% CI: 2.5-5.5). 21 pts (17.5%) had to stop 1
st
line treatment because of toxicity. On multivariate analysis, age ≥ 80 years, PS ≥ 2, and single-agent therapy were significantly associated with poor PFS. 51 pts received one or more further lines of therapies. At the time of analysis, 170 pts (90%) had died. 96% of deaths were related to the disease. The median OS for the entire cohort of pts was 9.6 months (95% CI: 7.3-12). The 1-year and 2-year OS rates were 43% (95% CI: 36–50), and 22% (95% CI: 16–28), respectively. The median OS of pts managed with systemic therapy and BSC were 12.5 months (95% CI: 8.4-16.6) and 5.1 months (95% CI: 3.7-6.5), respectively (p=0.02). However, on multivariate analysis, PS ≥ 2 and age-adjusted Charlson score ≥ 10 were the sole independent factors significantly associated with OS. Conclusions: A high proportion of elderly pts with advanced STS were considered unfit for chemotherapy. The OS of STS pts ≥ 75 years who were managed with systemic therapy seems similar to that of younger pts. Further efforts are needed to better define the optimal care for fit and unfit elderly pts with advanced STS.
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