Assessment of osteopontin in early breast cancer: correlative study in a randomised clinical trial.

INTRODUCTION: Osteopontin (OPN) is a malignancy-associated glycoprotein that contributes functionally to tumor aggressiveness. In metastatic breast cancer, we previously demonstrated that elevated OPN in primary tumor and blood was associated with poor prognosis. METHODS: We measured OPN in plasma by ELISA, and in tumors by immunohistochemistry, in 624 (94%) and 462 (69%), respectively, of 667 postmenopausal women with hormone responsive early breast cancer treated by surgery followed by adjuvant treatment with tamoxifen +/- octreotide in a randomized trial (NCIC CTG MA.14; National Cancer Institute of Canada Clinical Trials Group Mammary.14). RESULTS: Plasma OPN was measured in 2,540 samples; 688 at baseline and 1,852 collected during follow-up. Mean baseline plasma OPN was 46 ng/ml (range 22.6 to 290) which did not differ from normal levels. Mean percentage OPN tumor cell positivity was 33.9 (95% CI: 30.2 to 37.9). There was no correlation between plasma and tumor OPN values. In multivariate analysis, neither was associated with event-free survival (EFS), relapse-free survival (RFS), overall survival (OS), bone RFS or non-bone RFS. An exploratory analysis in patients with recurrence showed higher mean OPN plasma levels 60.7 ng/ml (23.9 to 543) in the recurrence period compared with baseline levels. CONCLUSIONS: The hypothesis that OPN tumor expression would have independent prognostic value in early breast cancer was not supported by multivariate analysis of this study population. Plasma OPN levels in women with hormone responsive early breast cancer in the MA.14 trial were not elevated and there was no evidence for prognostic value of plasma OPN in this defined group of patients. However, our finding of elevated mean OPN plasma level around the time of recurrence warrants further study. TRIAL REGISTRATION: NCT00002864, http://clinicaltrials.gov/show/NCT00002864.

Effect of continuous statistically standardized measures of estrogen and progesterone receptors on disease-free survival in NCIC CTG MA.12 Trial and BC Cohort.

INTRODUCTION: We hypothesized improved inter-laboratory comparability of estrogen receptor (ER) and progesterone receptor (PgR) across different assay methodologies with adjunctive statistical standardization, akin to bone mineral density (BMD) z-scores. We examined statistical standardization in MA.12, a placebo-controlled pre-menopausal trial of adjuvant tamoxifen with locally assessed hormone receptor +/- tumours, and in a cohort of post-menopausal British Columbia (BC) tamoxifen-treated patients. METHODS: ER and PgR were centrally assessed for both patient groups with real time quantitative reverse transcription polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Effects on disease-free survival (DFS) were investigated separately for 345 MA.12 and 673 BC patients who had both qPCR and IHC assessments. Comparisons utilized continuous laboratory units and statistically standardized z-scores. Univariate categorization of ER/PgR was by number of standard deviations (SD) above or below the mean (z-score ≥1.0 SD below mean; z-score <1.0 SD below mean; z-score ≤1.0 SD above mean; z-score >1.0 SD above mean). Exploratory multivariate examinations utilized step-wise Cox regression. RESULTS: Median follow-up for MA.12 was 9.7 years; for BC patients, 11.8 years. For MA.12, 101 of 345 (29%) patients were IHC ER-PgR-. ER was not univariately associated with DFS (qPCR, P = 0.19; IHC, P = 0.08), while PgR was (qPCR, P = 0.09; IHC, P = 0.04). For BC patients, neither receptor was univariately associated with DFS: for ER, PCR, P = 0.36, IHC, P = 0.24; while for PgR, qPCR, P = 0.17, IHC, P = 0.31. Multivariately, MA.12 patients randomized to tamoxifen had significantly better DFS (P = 0.002 to 0.005) than placebo. Meanwhile, jointly ER and PgR were not associated with DFS whether assessed by qPCR or by IHC in all patients, or in the subgroup of patients with IHC positive stain, for pooled or separate treatment arms. Different results by type of continuous unit supported the concept of ER level being relevant for medical decision-making. For postmenopausal BC tamoxifen patients, higher qPCR PgR was weakly associated with better DFS (P = 0.06). CONCLUSIONS: MA.12 pre-menopausal patients in a placebo-controlled tamoxifen trial had similar multivariate prognostic effects with statistically standardized hormone receptors when tumours were assayed by qPCR or IHC, for hormone receptor +/- and + tumours. The BC post-menopausal tamoxifen cohort did not exhibit a significant prognostic association of ER or PgR with DFS. Adjunctive statistical standardization is currently under investigation in other NCIC CTG endocrine trials.

Prognostic factors in adolescents and young adults (AYA) with high risk soft tissue sarcoma (STS) treated by adjuvant chemotherapy: a study based on pooled European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62771 and 62931.

BACKGROUND: We conducted a retrospective study, pooling data from two clinical trials in high risk soft tissue sarcoma (STS) patients, with the objective of comparing two different age groups: 15-29 years (adolescents and young adults (AYA) population) and ≥ 30 years. The aim was to determine prognostic factors for the AYA population. METHODS: Patients selected for analysis were treated in two randomised trials of adjuvant chemotherapy in STS (European Organisation for Research and Treatment of Cancer (EORTC) 62771 and 62931). A total of 793 patients were included with a median follow-up (FU) of 8.74 years (AYA population: n=161, median FU 9.46 years; patients ≥ 30 years: n=632, median FU 8.62 years). Study endpoints were overall survival (OS) and relapse-free survival (RFS). The variables of the multivariate analysis were gender, subtype and grade, tumour size and localisation (limb versus other), absence or presence of local recurrence and treatment (control arm versus adjuvant chemotherapy). RESULTS: Patients' characteristics were globally similar with two exceptions, histological subtype (p=0.0043) and tumour size (p<.0001). The commonest sarcoma subtype in the AYA population was synovial sarcoma (29%), whereas leiomyosarcoma (18%), malignant fibrous histiocytoma (MFH, presently being termed undifferentiated pleomorphic sarcoma (UPS), 16%) and liposarcoma (15%) were more frequent in patients ≥ 30 years. For OS, independent favourable prognostic factors were low grade and small tumour size for both groups; radical resection and MFH or liposarcoma subtype were favourable factors for patients ≥ 30 years only. For RFS, favourable prognostic factors were small tumour size and low grade for both groups; tumour location in the extremities was a favourable factor for the AYA population only, whereas radical resection and adjuvant chemotherapy treatment were favourable factors for patients ≥ 30y ears only. CONCLUSIONS: Significant differences could be found concerning prognostic factors between the AYA population and older patients. Interestingly, adjuvant chemotherapy was associated with improved RFS only in patients ≥ 30 years. The results may have further implications for the treatment of STS patients in different age groups, as well as the design of future clinical trials.

Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial.

BACKGROUND: The effect of adjuvant chemotherapy on survival for resected soft-tissue sarcoma remains unknown. We investigated the effect of intensive adjuvant chemotherapy on survival in patients after resection of high-risk soft-tissue sarcomas. METHODS: In this multicentre randomised trial, patients with macroscopically resected, Trojani grade II-III soft-tissue sarcomas at any site, no metastases, performance status lower than 2 and aged between 16 and 70 years were eligible within 4 weeks of definitive surgery. Patients were randomly assigned to receive adjuvant chemotherapy or no chemotherapy (control group). Randomisation was done with a minimisation technique, stratified by hospital, site of primary tumour, tumour size, planned radiotherapy, and isolated limb perfusion therapy. Chemotherapy consisted of five cycles of doxorubicin 75 mg/m(2), ifosfamide 5 g/m(2), and lenograstim every 3 weeks. Patients in both groups received radiotherapy if the resection was marginal or the tumour recurrent. The primary endpoint was overall survival and analyses were done by intention to treat. The final results are presented. This trial is registered with ClinicalTrials.gov, NCT00002641. FINDINGS: Between February, 1995, and December, 2003, 351 patients were randomly assigned to the adjuvant chemotherapy group (175 patients) or to the control group (176). 258 (73%) of 351 patients received radiotherapy, 129 in each group. Overall survival did not differ significantly between groups (hazard ratio [HR] 0·94 [95% CI 0·68-1·31], p=0·72) nor did relapse-free survival (HR 0·91 [0·67-1·22], p=0·51). 5-year overall survival rate was 66·5% (58·8-73·0) in the chemotherapy group and 67·8% (60·3-74·2) in the control group. Chemotherapy was well tolerated, with 130 (80%) of 163 patients who started it completing all five cycles. 16 (10%) patients had grade 3 or 4 fever or infection, but no deaths due to toxic effects were recorded. INTERPRETATION: Adjuvant chemotherapy with doxorubicin and ifosfamide in resected soft-tissue sarcoma showed no benefit in relapse-free survival or overall survival. Future studies should focus on patients with larger, grade III, and extremity sarcomas.

Survival after recurrent osteosarcoma: data from 3 European Osteosarcoma Intergroup (EOI) randomized controlled trials.

BACKGROUND: Recurrence after osteosarcoma usually leads to death; thus prognostic factors for survival are of great importance. METHODS: Between 1983 and 2002, the European Osteosarcoma Intergroup accrued 1067 patients to 3 randomized controlled trials of pre- and post-operative chemotherapy for patients with resectable non-metastatic high-grade osteosarcoma of the extremity. Control treatment in all trials was doxorubicin 75 mg/m² and cisplatin 100mg/m². The comparators were additional high-dose methotrexate (BO02), T10-based multi-drug regimen (BO03) and G-CSF intensified-DC (BO06). Post-recurrence survival (PRS) was investigated on combined data with standard survival analysis methods. RESULTS: Median recurrence-free survival was 31 months; 8 recurrences were reported more than 5 years after the diagnosis. In 564 patients with a recurrence (median 13 months post-randomisation), there was no difference in post-relapse survival between treatment arms. Patients whose disease recurred within 2 years after randomization had a worse prognosis than those recurring after 2 years. Patients with good initial histological response to pre-operative chemotherapy had a better overall survival after recurrence than poor responders. Local relapse was more often reported after limb-saving procedures (2 versus 8%; amputation versus limb-saving), independent of the primary tumour site. Site of first recurrence (local 20%, lung 62%, "other" 19%) affected survival, as patients recurring with non-lung distant metastases only or any combination of local relapse, lung metastases and non-lung metastases (=group "other") had significantly worse overall survival (local 39%, lung 19%, "other" 9% at 5 years). CONCLUSIONS: These data describing a large series of patients with recurrent extremity osteosarcoma confirm the relationship between early recurrence and poor survival. There was better PRS in patients after good histological response to pre-operative chemotherapy, or with local-only recurrence.

Changes over time of extracellular domain of HER2 (ECD/HER2) serum levels have prognostic value in metastatic breast cancer.

BACKGROUND: Blood levels of the extracellular domain of HER-2/neu (ECD/HER2) have been suggested to have potential as a tumor marker in breast cancer. Our aim was to assess the prognostic value of baseline levels of ECD/HER2, but more importantly changes in levels over time, in women with metastatic breast cancer. METHODS: Baseline and serial levels of ECD/HER2 were measured in 158 women with newly-diagnosed metastatic breast cancer, in whom we previously performed serial measurement of plasma osteopontin. ECD/HER2 was measured in 1,282 serum samples using a validated ELISA at baseline and every 3-12 weeks during and after therapy until death (median, n=8 samples per patient). Multivariate time-dependent survival analyses were conducted using models that right-censored patient outcomes 3, 6 and 12 months after last known ECD/HER2 measurement. RESULTS: Thirty-four patients (22%) had elevated baseline ECD/HER2 (median 10.2 ng/ml: range 4.1-40.4 ng/ml). In univariate analysis, elevated baseline ECD/HER2 was associated with short survival (P=0.001). In a multivariate model incorporating standard clinical prognostic factors, baseline ECD/HER2 was significantly associated with survival duration (RR 1.029; P=0.020). Presence of visceral metastases and ECOG status 2-4 also retained significance. In a multivariate model incorporating standard prognostic factors and changes in sequential ECD/HER2 levels, an ECD/HER2 increase of >12 ng/ml at any time was the variable with most prognostic value for poor survival (RR 6.10; P=0.0003); poor ECOG status also retained significance. CONCLUSION: Increases over time of ECD/HER2 levels were strongly associated with poor survival in this cohort of women with metastatic breast cancer.

Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033.

PURPOSE: To assess potential differences in progression-free or overall survival when imatinib mesylate is administered to patients with incurable gastrointestinal stromal tumors (GIST) at a standard dose (400 mg daily) versus a high dose (400 mg twice daily). PATIENTS AND METHODS: Patients with metastatic or surgically unresectable GIST were eligible for this phase III open-label clinical trial. At registration, patients were randomly assigned to either standard or high-dose imatinib, with close interval follow-up. If objective progression occurred by Response Evaluation Criteria in Solid Tumors, patients on the standard-dose arm could reregister to the trial and receive the high-dose imatinib regimen. RESULTS: Seven hundred forty-six patients with advanced GIST from 148 centers across the United States and Canada were enrolled onto this trial in 9 months. With a median follow-up of 4.5 years, median progression-free survival was 18 months for patients on the standard-dose arm, and 20 months for those receiving high-dose imatinib. Median overall survival was 55 and 51 months, respectively. There were no statistically significant differences in objective response rates, progression-free survival, or overall survival. After progression on standard-dose imatinib, 33% of patients who crossed over to the high-dose imatinib regimen achieved either an objective response or stable disease. There were more grade 3, 4, and 5 toxicities noted on the high-dose imatinib arm. CONCLUSION: This trial confirms the effectiveness of imatinib as primary systemic therapy for patients with incurable GIST but did not show any advantage to higher dose treatment. It appears reasonable to initiate therapy with 400 mg daily and to consider dose escalation on progression of disease.

Serial plasma osteopontin levels have prognostic value in metastatic breast cancer.

PURPOSE: Osteopontin is a malignancy-associated protein measurable in blood and tumor tissue. To evaluate its prognostic value in advanced disease, we conducted a prospective clinical study measuring serial osteopontin plasma levels in women with metastatic breast cancer throughout the course of their disease. EXPERIMENTAL DESIGN: One hundred fifty-eight women with newly diagnosed metastatic breast cancer were enrolled in the study. Plasma osteopontin was measured using our validated ELISA, at baseline and every 3 to 12 weeks during and after therapy until death. Multivariate time-dependent survival analyses were conducted using models that right censored patient outcomes 3, 6, and 12 months after the last known osteopontin measurement. RESULTS: Osteopontin was measured in 1,378 samples (median, 9 per patient). Ninety-nine patients had elevated baseline osteopontin (median, 177 ng/mL; range, 1-2,648 ng/mL). In univariate analysis, elevated baseline osteopontin was associated with short survival (P = 0.02). In a multivariate model incorporating standard prognostic factors, baseline osteopontin was significantly associated with survival duration (relative risk, 1.001; P = 0.038). Metastasis-free interval, visceral metastases, and Eastern Cooperative Oncology Group status 2 to 4 also retained significance. In a multivariate model incorporating standard prognostic factors and changes in sequential osteopontin levels, an osteopontin increase of >250 ng/mL at any time was the variable with the most prognostic value for poor survival (relative risk, 3.26; P = 0.0003), and poor Eastern Cooperative Oncology Group status also retained significance. CONCLUSIONS: This is the first study to show that in women with metastatic breast cancer, increases in osteopontin levels over time are strongly associated with poor survival. Sequential monitoring of osteopontin may have use in making treatment decisions for these patients.

A Phase II Study of Flavopiridol in Patients With Previously Untreated Advanced Soft Tissue Sarcoma.

Purpose. Flavopiridol is a potent cyclin-dependent kinase (CDK) inhibitor that has preclinical activity in many tumours. This synthetic flavonoid was tested in a phase II nonrandomized, nonblinded multicentre clinical trial to determine its activity and toxicity in patients with previously untreated metastatic or locally advanced soft tissue sarcoma. Methods. A total of 18 patients with histologically confirmed nonoperable soft tissue was treated with flavopiridol administered at a dose of 50 mg/m(2) IV over 1 hour daily x3 days every 3 weeks. Results. Eighteen patients were accrued to the study over a period of 6 months. No objective responses were noted in the seventeen evaluable patients. Eight patients (47%) exhibited stable disease after 2 cycles (median duration of 4.3 months (range 1.4-6.9 months). Kaplan-Meier estimates for 3- and 6-month progression-free survivial rates were 44 percent and 22 percent, respectively. The only grade 3 toxicities were diarrhea (N = 2), nausea (N = 2), gastritis (N = 1), and fatigue (N = 1). Ninety-four percent of patients received >/= 90% of the planned dose intensity, during 55 treatment cycles. Conclusions. Flavopiridol was well tolerated at the dose and schedule used in this study, however, no objective treatment responses were seen and thus our results do not support further exploration of flavopiridol as a monotherapy at this dose and schedule in soft tissue sarcomas.

Expression of osteopontin and HGF/met in adult soft tissue tumors.

There is a need for molecular markers that predict biological behavior of adult soft tissue tumors. Elevated levels of osteopontin (OPN) a transformation-linked protein, have been associated with poor survival in many cancers. OPN induces cell migration in cancer cells, in part through activation of the hepatocyte growth factor (HGF) receptor (Met) and its signaling pathway. Met expression has been associated with a poor prognosis in some sarcomas. In a series of 15 patients with adult soft tissue tumors, we found that mRNA levels of OPN (p=0.015), Met (p=0.03) and HGF (p<0.001) were significantly higher in tumor tissues relative to paired normal tissues. By immunohistochemistry, in tumor tissue from 33 patients, we demonstrated that increased expression of OPN, but not Met protein, was associated with higher stage (p=0.025) and grade (p=0.005). We found that increased expression of OPN, but not Met protein, was associated with decreased overall survival (p=0.008) at five years. This study, which is the first to examine coexpression of these two markers, suggests that OPN may have potential as a prognostic marker in adult soft tissue sarcomas, and further that OPN+/-Met signaling pathways may contribute to their biological behavior.

Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5.

PURPOSE: Certain anthracycline-containing adjuvant chemotherapy regimens are associated with improved relapse-free survival (RFS) and overall survival (OS) compared with the classic regimen of cyclophosphamide, methotrexate, and fluorouracil in women with early-stage breast cancer. PATIENTS AND METHODS: Between 1989 and 1993, 710 pre- and perimenopausal women with axillary node-positive breast cancer were randomly assigned to either cyclophosphamide 75 mg/m(2) orally days 1 through 14, epirubicin 60 mg/m(2) intravenously days 1 and 8, and fluorouracil 500 mg/m(2) intravenously days 1 and 8 (CEF) or CMF (cyclophosphamide 100 mg/m(2) orally days 1 through 14, methotrexate 40 mg/m(2) intravenously days 1 and 8, and fluorouracil 600 mg/m(2) intravenously days 1 and 8). On the basis of follow-up to May 1997 (median follow-up time, 59 months), there was a statistically significant improvement in RFS and OS for CEF compared with CMF. RESULTS: The trial results are now updated, with a median follow-up of 10 years for live patients. The 10-year RFS is 52% for patients who received CEF compared with 45% for CMF patients (hazard ratio [HR] for CMF v CEF = 1.31; stratified log-rank, P = .007). The 10-year OS for patients who received CEF and CMF are 62% and 58%, respectively (HR for CMF v CEF = 1.18; stratified log-rank, P = .085). The rates of acute leukemia have not changed since the original report, whereas the rates of congestive heart failure are slightly higher but acceptable (four patients [1.1%] in the CEF group v one patient [0.3%] in the CMF group). CONCLUSION: The previously demonstrated benefit of CEF compared with CMF adjuvant chemotherapy is maintained with longer follow-up in the MA5 trial.

High-Dose Chemotherapy Followed by Peripheral and/or Bone Marrow Stem Cell Transplant in Patients With Advanced Sarcoma: Experience of a Canadian Centre.

PURPOSE: Few reports have been published on the evaluation of stem cell auto transplantation for chemosensitive sarcomas. Some suggest benefit, others do not. We present results of 24 patients with sarcoma undergoing autotransplantation at a Canadian institution. PATIENTS AND METHODS: Twenty-four patients were treated between 1988 and 1998: 23 were >/=18 years (median 27; range 12-56); genders were equal; 12 patients had Ewing's sarcoma. At diagnosis, 12 (50%) had metastatic disease. Prior to autotransplant, all had >/=1 chemotherapy regimen. Fourteen (58%) were in complete remission (CR) and seven (29%) had minimal residual disease. All received etoposide 60 mg/kg (Day -4), melphalan 140 mg/malpha(2) on (Day -3) and a stem cell reinfusion (Day 0). RESULTS: Three patients (12.5%) were alive and disease-free with median follow-up of 92 months (80-142); one was alive with disease 32 months post-autotransplant. Twenty had died (disease, 17; transplant-related, 2; unknown, 1). Of the four alive, three had Ewing's sarcoma, one alveolar rhabdomyosarcoma, and all were in CR at transplant. Median time to relapse was 6 months (2-59). Sixteen of 18 (89%) relapsed within 1 year. Median overall survival was 10 months (0-137). A trend towards improved survival (P=0.07) was evident for patients in CR prior to autotransplant. CONCLUSIONS: Stem cell autotransplantation does not benefit most patients with sarcoma. A subgroup of high-risk patients in CR may fare better and warrant further study.

Metastatic secondary fibrosarcoma of bone responsive to repeated courses of Ifosfamide and associated with hypoglycemia.

We present a case of a 40-year-old man with secondary fibrosarcoma of bone, arising from a non-ossifying fibroma. He subsequently developed metastatic disease that responded to four successive chemotherapy courses, the last three using the same dose/schedule of single agent ifosfamide. Eventual rapid progression of a huge intra-abdominal mass was associated with the syndrome of extrapancreatic tumour hypoglycemia (EPTH). The clinicopathological behaviour of fibrosarcoma of bone, and the mechanism of EPTH are discussed.

Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases.

Breast cancer is noted for long periods of tumor dormancy and metastases can occur many years after treatment. Adjuvant chemotherapy is used to prevent metastatic recurrence but is not always successful. As a model for studying mechanisms of dormancy, we have used two murine mammary carcinoma cell lines: D2.0R/R cells, which are poorly metastatic but form metastases in some mice after long latency times, and D2A1/R cells, which form more numerous metastases much earlier. Previously we identified a surprisingly large population of dormant but viable solitary cells, which persisted in an undivided state for up to 11 weeks after injection of D2.0R/R cells. Dormant cells were also detected for D2A1/R cells, in a background of growing metastases. Here we used this model to test the hypothesis that dormant tumor cells would not be killed by cytotoxic chemotherapy that targets actively dividing cells, and that the late development of metastases from D2.0R/R cells would not be inhibited by chemotherapy that effectively inhibited D2A1/R metastases. We injected mice with D2A1/R or D2.0R/R cells via a mesenteric vein to target liver. We developed a doxorubicin (DXR) treatment protocol that effectively reduced the metastatic tumor burden from D2A1/R cells at 3 weeks. However, this treatment did not reduce the numbers of solitary dormant cells in mice injected with either D2A1/R or D2.0R/R cells. Furthermore, DXR did not reduce the metastatic tumor burden after an 11-week latency period in mice injected with D2.0R/R cells. Thus, apparently effective chemotherapy may spare non-dividing cancer cells, and these cells may give rise to metastases at a later date. This study has important clinical implications for patients being treated with cytotoxic chemotherapy.

Safety and efficacy of the multidrug-resistance inhibitor biricodar (VX-710) with concurrent doxorubicin in patients with anthracycline-resistant advanced soft tissue sarcoma.

PURPOSE: Incel (biricodar, VX-710) restores drug sensitivity to P-glycoprotein and multidrug resistance-associated protein-1-expressing cells. This Phase I/II study evaluated the safety/tolerability, pharmacokinetics, and efficacy of VX-710 plus doxorubicin in patients with inoperable, locally advanced or metastatic, anthracycline-resistant/refractory, soft tissue sarcoma. EXPERIMENTAL DESIGN: In Phase I, i.v. bolus doxorubicin at 60, 75, or 67.5 mg/m(2) was administered 8 h after initiation of a 72-h continuous i.v. (CIV) infusion of VX-710 (120 mg/m(2)/h) to cohorts of patients to establish a maximum tolerated dose. For efficacy evaluations in Phase II, eligible patients had inoperable, locally advanced or metastatic, anthracycline-resistant/refractory soft tissue sarcoma; < or =225 mg/m(2) cumulative prior doxorubicin; and adequate hematological, liver, and kidney function. Cycles were repeated every 3 weeks. RESULTS: Fourteen patients were enrolled in Phase I. Myelosuppression was the dose-limiting toxicity with 75 and then 67.5 mg/m(2) doxorubicin, and the maximum tolerated dose was established at 60 mg/m(2) with VX-710, 120 mg/m(2)/h, 72-h CIV. VX-710 had no apparent effect on doxorubicin pharmacokinetics. Twenty-nine patients enrolled in Phase II were treated with VX-710, 120 mg/m(2)/h 72-h CIV, and 60 mg/m(2) doxorubicin. Among 26 evaluable patients, minimal activity was noted among 11 patients with gastrointestinal stromal tumors (GISTs); however, in 15 patients with anthracycline-resistant sarcomas of other histologies, 2 achieved partial responses and 7 patients had disease stabilization with an overall median progression-free interval of 3.4 months. CONCLUSION: Anthracycline resistance in GISTs appears to be independent of P-glycoprotein or multidrug resistance-associated protein-1 resistance mechanisms. However, the combination of VX-710 and doxorubicin resulted in objective responses or disease stabilization in patients with strictly defined anthracycline-refractory non-GIST sarcomas, which warrants further evaluation.

Adjuvant chemotherapy following complete resection of soft tissue sarcoma in adults: a clinical practice guideline.

Purpose. To review the literature and make recommendations for the use of anthracycline-based adjuvant chemotherapy in adult patients with soft tissue sarcoma (STS).Patients. The recommendations apply to patients >15 years old with completely resected STS.Methods. A systematic overview of the published literature was combined with a consensus process around the interpretation of the evidence in the context of conventional practice to develop an evidence-based practice guideline.Results. Four meta-analyses and 17 randomized clinical trials comparing anthracycline-based adjuvant chemotherapy versus observation were reviewed. The Sarcoma Meta-Analysis Collaboration (SMAC) was the best analysis because it assessed individual patient data and had the longest follow-up. The results of the SMAC meta-analysis together with data from more recently published randomized trials, as well as our analysis of the toxicity and compliance data, are incorporated in this systematic review.Discussion. It is reasonable to consider anthracycline-based adjuvant chemotherapy in patients who have had removal of a sarcoma with features predicting a high likelihood of relapse (deep location, size >5 cm, high histological grade). Although the benefits of adjuvant chemotherapy are most apparent in patients with extremity sarcomas, patients with high-risk tumours at other sites should also be considered for such therapy.