Primary extremity soft tissue sarcomas: outcome improvement over time at a single institution.

BACKGROUND: To assess changes in survival over time of extremity soft tissue sarcoma (ESTS) patients treated at a single reference institution. PATIENTS AND METHODS: Patients with primary localized adult-type ESTS surgically treated at our institution between 1987 and 2007 were retrospectively reviewed. Patients were categorized into four 5-year groups according to the timing of their first operation. Crude cumulative incidence (CCI) of sarcoma-specific mortality (SSM), local recurrence (LR), and distant metastases (DMs) were calculated for each time period. RESULTS: A total of 1094 patients were identified. Median follow-up was 81 months. CCI of SSM and LR were significantly better in period 4 in comparison to periods 1-3 (P < 0.001 for both end points), dropping, respectively, from 15% to 6% and from 23% to 9%. An overall improvement of DMs-free survival at 5 years could be detected in the latter period, as well as a better postmetastasis survival. CONCLUSIONS: Reference institutions for sarcomas may have improved their outcome in the last years. Although biases of retrospective analyses as well as the effect of institutional learning curves need to be discounted, it is possible that optimal exploitation of a series of subtle improvements in sarcoma treatment may make a difference in results currently achievable.

Oncogenic and ligand-dependent activation of KIT/PDGFRA in surgical samples of imatinib-treated gastrointestinal stromal tumours (GISTs).

As the range of receptor tyrosine kinase (RTK) inhibitors widens, a detailed understanding of the activating mechanisms of KIT/platelet-derived growth factor receptor (PDGFR)A and the related downstream pathways involved in the development and maintenance of GISTs is becoming increasingly important. We analysed areas with different histological response ratios in surgical specimens taken from imatinib-treated and untreated GIST patients in order to investigate KIT and PDGFRA expression/activation, the presence of their cognate ligands and the activation of downstream signalling, by means of biochemistry, immunohistochemistry and flow cytometry. All of the cases showed KIT and PDGFRA co-expression. In addition to the oncogenic activation of mutated receptors, activation of wild-type KIT and wild-type PDGFRA, sustained by heterodimerization and an autocrine-paracrine loop, was demonstrated by the presence of their specific ligands, stem cell factor (SCF) and PDGFA. To confirm RTK activation further, all of the samples (including those with the highest regression ratios) were investigated for downstream effectors, and all proved to have activated downstream signalling. The results show that after the mutated receptors are switched off, heterologous wild-type receptors become important in imatinib-treated GISTs as a means of maintaining signalling activation. Taken together, our findings suggest that drugs targeting wild-type receptors should be tested in imatinib-treated GIST patients.

Steroid premedication markedly reduces liver and bone marrow toxicity of trabectedin in advanced sarcoma.

Trabectedin is a marine-derived cytoxic alkaloid which has shown promising antitumour activity in a variety of human malignancies including sarcoma. Fifty-four patients with advanced sarcoma (age 43 yrs, range 18-70), all pretreated with prior chemotherapy, were enrolled on a named individual basis for treatment with trabectedin. Diagnosis was adult soft tissue sarcoma (STS) in 46 patients, Ewing's family tumour (EFT) in 4, and osteosarcoma (OS) in 4. The initial 23 patients (total number of courses administered: 68) did not receive premedication prior to trabectedin, while the other 31 patients (total number of courses administered: 134) received premedication with dexamethasone 4 mg po bid 24 hours before therapy. Incidence of toxicity (grade 3-4), expressed as percentage of courses, was as follows: in patients without dexamethasone, elevation of transaminases 34%, neutropenia 24% and thrombocytopenia 25%; in patients with prior dexamethasone, elevation of transaminases 2%, neutropenia 2% and no thrombocytopenia. The median received dose intensity of trabectedin was superimposable in the two groups (404 microg and 400 microg per week, respectively), as well as progression-free survival (19% at 6 months). Among STS patients, 9% had objective responses. In this unselected patient series, premedication with dexamethasone strongly reduced drug-induced hepatotoxicity and myelosuppression.

Status of surgical margins and prognosis in adult soft tissue sarcomas of the extremities: a series of patients treated at a single institution.

PURPOSE: To explore the prognostic effect of microscopic marginal status after surgery for extremity soft tissue sarcomas. PATIENTS AND METHODS: We analyzed 911 consecutive patients surgically treated throughout a 20-year span at a single referral center. Six hundred forty-two were first seen with a primary tumor, and 269, with a locally recurrent tumor. All patients underwent macroscopically complete resection. Microscopic marginal status was negative (tumor size > 1 mm) in 748 patients and positive (

Some lessons learned from imatinib mesylate clinical development in gastrointestinal stromal tumors.

Imatinib mesylate is a molecular-targeted agent, shown to be effective in chronic myeloid leukemia and gastrointestinal stromal tumors (GIST). The latter may currently serve as a model on which speculating how the future of molecular-targeted therapy in solid tumors will be. So far, some lessons have been learnt. 1) Molecular-targeted therapy can be effective in the advanced disease setting, resulting in major tumor responses. 2) Patterns of tumor responses may be peculiar, radiologically and pathologically. 3) Anti-tumor activity may be highly predictable by assessing tumor molecular biology. 4) The methodology of clinical development of molecular-targeted agents may differ from standard chemotherapy in some respects, because, say, the preclinical rationale may be stronger, thus increasing the Bayesian prior probability of efficacy, or the optimal dose cannot be determined separately from the assessment of activity and efficacy. 5) Molecular-targeted agents will hardly remain "orphan drugs", if effective. 6) While an obvious impact on survival in the advanced disease setting has been clearly demonstrated, the biologic and clinical impact of molecular-targeted therapy still needs to be elucidated. Its eradicating capabilities, as well as the implications of secondary resistance, are to be understood. 7) Integrated, multimodality approaches, including surgery, may still be of value in the molecular-targeted therapy era.

Quality of surgery and outcome in extra-abdominal aggressive fibromatosis: a series of patients surgically treated at a single institution.

PURPOSE: To explore prognostic factors in surgically treated aggressive fibromatosis (extra-abdominal desmoid tumor). PATIENTS AND METHODS: A total of 203 consecutive patients treated with surgery over a 35-year period at a single referral center were retrospectively reviewed. One hundred twenty-eight were first seen at our institution with primary disease, whereas 75 had a recurrent tumor. All patients underwent macroscopically complete resection. Margins were rated as negative in 146 (97 with primary tumors, 49 with recurrences) and positive in 57 (31 in primary, 26 in recurrences) patients. Median follow-up was 135 months. RESULTS: Patients with primary disease had a better disease-free survival rate than those with recurrence (76% v 59% at 10 years). Presenting with a recurrence was also the strongest predictor of local failure in the multivariate analysis. In patients first treated for primary disease, size and site had prognostic significance, whereas microscopically positive surgical margins did not. In contrast, in patients with recurrence, there was a trend toward better prognosis if margins were negative (although this was not significant at multivariate analysis). CONCLUSION: Presence of microscopic disease does not necessarily affect long-term disease-free survival in patients with primary presentation of extra-abdominal desmoid tumors. Thus, function-sparing surgery may be a reasonable choice when feasible without leaving macroscopic residual disease. In patients with recurrences, positive margins may more clearly affect prognosis, potentially necessitating adjuvant radiation in selected cases.

Low-dose chemotherapy with methotrexate and vinblastine for patients with advanced aggressive fibromatosis.

BACKGROUND: This Phase II study was undertaken to assess the activity of methotrexate plus vinblastine in the treatment of patients with inoperable aggressive fibromatosis (AF) and to observe the evolution of the disease after such low-dose chemotherapy. METHODS: Thirty patients with a median age of 27 years who were affected by primary (20%) or recurrent (80%), advanced, inoperable AF were treated with weekly methotrexate at a dose of 30 mg/m(2) plus vinblastine at a dose of 6 mg/m(2) for a median interval of 1 year. Patients with recurrent disease had received surgery, radiotherapy, tamoxifen, and antracycline-based chemotherapy. Tumor response was assessed in all patients as well as time to disease progression. RESULTS: Eighteen patients (60%) showed stable disease or minor tumor shrinkage along with symptom relief. A partial response was detected in 12 patients (40%). No complete responses were observed, and no patients had tumor progression during treatment. Four patients received fewer than 15 cycles of chemotherapy, mainly because of severe myelotoxicity. One of these patients died of local disease progression 33 months later, and the other three patients were stable. After a median follow-up of 75 months, the 10-year actuarial progression free interval is 67%. CONCLUSIONS: Methotrexate plus vinblastine given every 7-10 days for several months is associated with prolonged stable disease in a substantial subset of patients with advanced (inoperable) aggressive fibromatosis.

Combined epirubicin and interleukin-2 regimen in the treatment of malignant mesothelioma: a multicenter phase II study of the Italian Group on Rare Tumors.

The Italian Group on Rare Tumors undertook a phase II study of a combination of epirubicin and interleukin-2 in 21 chemotherapy-naive patients with malignant mesothelioma. All patients had bidimensionally measurable disease at CT scan. Treatment included Intravenous administration of epirubicin at a dose of 110 mg/m2 i.v. on day 1, and interleukin-2 at a dose of 9 MU subcutaneously from day 8 to day 12 and from day 15 to day 19. Cycles were repeated every three weeks, up to six times in the absence of progressive disease. Treatment response was evaluated after two cycles of therapy. Only one patient achieved a partial response, resulting in an overall response rate of 5% (1/21) with a median progression-free and overall survival of 5 and 10 months, respectively. Toxicity was relevant and caused treatment discontinuation in many patients. These results do not support the use of such a combination in the management of malignant mesothelioma.

Combined modality treatment for primary gastrointestinal non-Hodgkin's lymphoma: the Milan Cancer Institute experience.

BACKGROUND: The study analyzes clinical-pathologic features, treatment and outcome of all patients with primary lymphoma of the gastrointestinal tract (GI-NHL) seen during the past two decades at the Milan Cancer Institute. SUBJECTS AND METHODS: Clinical and histopathological data from 135 patients presenting with GI-NHL and disease localized within the abdomen were reviewed. Of these, 114 (84%) presented with limited disease (stage I and II), while 21 patients were found to have disease involvement of other abdominal organs (i.e., liver, pancreas, peritoneum) or more than one gastrointestinal site and were therefore classified as stage IV. Seventy-three percent presented with lymphoma in the stomach, 15% in the small intestine and 9% in the large bowel, while in 5 cases multiple localizations of the gastrointestinal tract were documented. Median age was 50 years, with one-fourth of patients older than 60 years. According to the revised Kiel classification for GI-NHL, 61% of patients presented with pure high-grade lymphoma, 9% high-grade NHL associated with residual low-grade lymphoma, and 30% had low-grade NHL. Nine percent presented with bulky disease, 5% with elevated LDH and 21% with a Karnofsky performance status (PS) < or = 80. RESULTS: Laparotomy with radical (108 patients) or palliative (15 patients) intent was performed in all patients who were not deemed at high risk of complication from major surgery. Complete removal of all measurable tumor was feasible in 101 patients, with no difference relative to primary site. Surgical morbidity and mortality were 11% and 2%, respectively. Overall, 83% of patients were treated with chemotherapy. Patients who did not receive systemic chemotherapy included 12 managed with surgery alone and 10 who received only postoperative irradiation mainly because of low-grade lymphoma with superficial disease. Of patients with limited disease, 99% achieved complete tumor remission. After a median follow-up of 73 months, 13 of 113 patients have relapsed, mostly (70%) outside the gastrointestinal tract. The actuarial 10-yr. freedom from progression (FFP) and overall survival (OS) were 84% and 86%, respectively. Aside from age, no other factor revealed a statistically significant impact on outcome. There was only a trend in favor of low-grade histology (FFP 97% vs. 79%), that failed to reach statistical significance. Of patients with advanced abdominal disease, 48% achieved complete remission with chemotherapy with or without prior surgical debulking. Actuarial 10-yr. FFP and OS were 44% and 42%, respectively. In this subset, tumor burden and LDH levels represented the most important prognostic factors affecting outcome. CONCLUSIONS: This retrospective study underscores the good results obtained in a wide and unselected population of patients with limited-stage primary GI-NHL following a combined-modality approach that included surgical debulking and systemic chemotherapy for most patients. Surgery alone can be considered adequate treatment for patients with low-grade NHL disease that does not infiltrate beyond the submucosa. Patients with advanced GI-NHL show a long-term outcome similar to that of patients with advanced NHL arising outside the gastrointestinal tract.

Perspectives on anthracyclines plus ifosfamide in advanced soft tissue sarcomas.

Doxorubicin and ifosfamide are currently the two main drugs for the treatment of soft tissue sarcomas in adults. Given in combination at full doses, with or without dacarbazine, these agents have induced higher response rates than were obtained with single-agent therapy. Because they involve considerable myelotoxicity, however, full-dose regimens should be reserved for patients with good performance status and without potential septic foci. Obviously, higher response rates do not automatically translate into improved survival. In soft tissue sarcomas, full-dose polychemotherapy will most probably provide a survival benefit only in selected patients in whom surgery can be performed in combination with chemotherapy. Prospective trials in such patients, although difficult to carry out, would be highly desirable. The information they would provide might help the clinician tailor treatment in a more rational way and improve chances of cure or long-term survival in at least some patient subgroups.