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Increased doses of doxorubicin may not improve the survival of non-Hodgkin's lymphoma patients. Non-Hodgkin's lymphoma is a cancer of the lymph tissue accompanied by lymph node enlargement. Of 238 patients with non-Hodgkin's lymphoma, 119 were assigned to receive increased doses of doxorubicin and 119 were assigned to receive standard doses. Because of severe white blood cell depletion, only 56 patients received escalated doses. The two groups did not differ in their response to treatment. The overall response rate was 88% in the escalated therapy group and 84% in the standard therapy group. Forty-eight percent of those in the escalated therapy group survived five years, compared to 60% in the standard therapy group. The five-year survival rates without disease progression were 51% in the escalated therapy group and 53% in the standard therapy group. More deaths in the escalated therapygroup were a result of treatment complications or drug toxicity than in the standard therapy group.

Purpose. To determine intrinsic breast cancer subtypes represented within categories defined by quantitative hormone receptor (HR) and HER2 expression. Methods. We merged 1,557 cases from three randomized phase III trials into a single data set. These breast tumors were centrally reviewed in each trial for quantitative ER, PR, and HER2 expression by immunohistochemistry (IHC) stain and by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), within trinsic subtyping by research-based PAM50RT-qPCR assay. Results. Among 283 HER2-negative tumors with,1% HR expression by IHC, 207 (73%) were basal-like; other subtypes, particularly HER2-enriched (48, 17%),were present. Among the 1,298 HER2-negative tumors, borderline HR (1%-9% staining) was uncommon (n = 39), and these tumors were heterogeneous: 17 (44%) luminal A/B, 12 (31%) HER2-enriched, and only 7 (18%) basal-like. Including them in the definition of triple-negative breast cancer significantly diminished enrichment for basal-like cancer (p, .05). Among 106 HER2-positive tumors with,1% HR expression by IHC, the HER2-enriched subtype was the most frequent (87, 82%), whereas among 127 HER2-positive tumors with strong HR (.10%) expression, only 69 (54%) were HER2-enriched and 55 (43%) were luminal (39 luminal B, 16 luminal A). Quantitative HR expression by RT-qPCR gave similar results. Regardless of methodology, basal-like cases seldom expressed ER/ESR1 or PR/PGR and were associated with the lowest expression level of HER2/ERBB2 relative to other subtypes. Conclusion. Significant discordance remains between clinical assay-defined subsets and intrinsic subtype. For identifying basal-like breast cancer, the optimal HRIHC cut pointwas,1%, matching the American Society of Clinical Oncology and College of American Pathologists guidelines. Tumors with borderline HR staining are molecularly diverse and may require additional assays to clarify underlying biology. [ABSTRACT FROM AUTHOR]

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 tumor 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). 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 - 290) which did not differ from normal levels. Mean percentage OPN tumor cell positivity was 33.9 (95% CI 30.2 - 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 - 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 [ABSTRACT FROM AUTHOR]

Information about several symposiums related to adjuvant/neoadjuvant therapy for adult soft tissue sarcoma were discussed including the International Coalition Against Sarcomas, and European Organization for Research and Treatment of Cancer (EORTC). The potential benefits of adjuvant/neoadjuvant therapy includes on the delay in local recurrence, possible improvement of overall survival, and the potential to increase operability for large tumors and proportion of limb salvage operations.

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/m2 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 survival 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. [ABSTRACT FROM AUTHOR]

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 auto transplant, 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 140mg/m² 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. [ABSTRACT FROM AUTHOR]

Focuses on the rare incidence and heterogeneous nature of soft tissue sarcomas (STS) which are barriers to the conduct of large randomized controlled trials. Basis for the recommended management of advanced STS; Definition and epidemiology of advanced sarcoma.

Presents the case of a 40-year-old man with secondary fibrosarcoma of bone, arising from a non-ossifying fibroma. Development of metastastic disease that responded to four successive chemotherapy courses; Association of an eventual rapid progression of a huge intra-abdominal mass with the syndrome of extrapancreatic tumor hypoglycemia.

Purpose: Histological grading is currently one of the best predictors of tumor behavior and outcome in soft tissue sarcoma. However, occasionally there is significant disagreement even among expert pathologists. An alternative method that gives more reliable and non-subjective diagnostic information is needed. The potential use of proton magnetic resonance spectroscopy in combination with an appropriate statistical classification strategy was tested here in differentiating normal mesenchymal tissue from soft tissue sarcoma. Methods: Fifty-four normal and soft tissue sarcoma specimens of various histological types were obtained from 15 patients. One-dimensional proton magnetic resonance spectra were acquired at 360 MHz. Spectral data were analyzed by using both the conventional peak area ratios and a specific statistical classification strategy. Results: The statistical classification strategy gave much better results than the conventional analysis.The overall classification accuracy (based on the histopathology of the MRS specimens) in differentiating normal mesenchymal from soft tissue sarcoma was 93%, with a sensitivity of 100% and specificity of 88%.The results in the test set were 83, 92 and 76%, respectively. Our optimal region selection algorithm identified six spectral regions with discriminating potential, including those assigned to choline, creatine, glutamine, glutamic acid and lipid. Conclusion: Proton magnetic resonance spectroscopy combined with a statistical classification strategy gave good results in differentiating normal mesenchymal tissue from soft tissue sarcoma specimens ex vivo. Such an approach may also differentiate benign tumors from malignant ones and this will be explored in future studies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: A population-based cohort study of soft tissue sarcoma of the extremities (STSE) in Ontario, Canada was conducted using linked administrative databases. Methods and materials: Electronic administrative databases were linked from the Ontario Cancer Registry, the Canadian Institute for Health Information, and Radiation Oncology Research Unit database of radiation therapy (RT) records. Results: The definitive surgery was amputation for 6.0%, resection for 60.9%, biopsy for 7.5%; the remainder had no surgical record. Adjuvant RT was administered to 40.2% of cases. Among cases initially treated by surgical resection, 2.0% later underwent amputation and 9.5% underwent further resection during follow-up. The adjusted odds ratio (OR) for amputation as definitive surgery was 2.3 (1.19, 4.45) in eastern Ontario relative to Toronto. The likelihood of adjuvant RT among those not registered at a cancer centre within 3 months of diagnosis was decreased (OR = 0.20 (95% CI (0.13, 0.30)) relative to those registered. The adjusted relative risk of amputation at any time following diagnosis was 3.48 (95% CI (1.63, 7.46)) among cases not attending a cancer centre. The adjusted relative risk of death was 1.4; 95% CI (1.1, 1.7) among those not attending a cancer centre. Conclusions: Cases not seen at a multidisciplinary cancer centre within 3 months following diagnosis of STSE have an increased relative risk for amputation at any time, and for death due to any cause. Many hypotheses for further study are suggested by the results of this analysis. [ABSTRACT FROM AUTHOR]

Purpose. To make recommendations for the use of doxorubicin-based chemotherapy in patients with soft-tissue sarcoma. Patients. The recommendations apply to patients with symptomatic unresectable locally advanced or metastatic soft-tissue sarcoma who are candidates for palliative chemotherapy. Methods. A systematic review 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. Eight randomized trials comparing doxorubicin-based combination versus doxorubicin single-agent chemotherapy were reviewed. Response rates and overall survival were evaluated using pooled statistical analysis. The pooled response data in 2281 patients showed a slight trend favouring the combination therapy, although this did not reach statistical significance (odds ratio (OR), 0.79; 95% confidence interval (CI), 0.60-1.05; p=0.10). Survival data could only be abstracted from six studies involving 2097 patients, and showed no significant advantage for combination therapy (OR, 0.84; 95% CI, 0.67-1.06; p=0.13). Data on adverse effects could not be combined in a meta-analysis; however nausea, vomiting and myelosuppression were consistently more severe with combination chemotherapy than with single-agent chemotherapy. Discussion. Single-agent doxorubicin is an appropriate first-line chemotherapy option for advanced or metastatic soft-tissue sarcoma. Some doxorubicin-based combination chemotherapy regimens, given in conventional doses, produce only marginal increases in response rates, at the expense of increased adverse effects, and with no improvements in overall survival. Future randomized clinical trials should compare new regimens, whose activity has been established in single-arm studies, with single-agent doxorubicin, and include quality of life as an outcome measure. [ABSTRACT FROM AUTHOR]

Reports on the outcome of 37 patients with metastatic osteosarcoma who entered into a large randomized trial comparing two different regimens of chemotherapy. Drugs used in the randomized trial; Absence of major differences of outcome in the types of drugs used.

Abstract Purpose : To determine the efficacy and toxicity of docetaxel as first-line chemotherapy in adult patients with locally advanced and/or metastatic soft tissue sarcoma (STS). Patients/methods . Thirty eligible patients, with histologically proven STS, Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and bidimensionally measurable disease, entered this study. None had received previous chemotherapy. Docetaxel 100 mg m- 2 was given as a 1-h intravenous infusion every 3 weeks. Patients were evaluable for response, evaluated by WHO criteria, after one cycle of chemotherapy and toxicity was graded by NCIC-CTG common toxicity criteria. Results . One hundred and thirty two cycles were aldministered, with a range per patient of 1-9. The median delivered dose intensity was 32.2 mg m- 2 week- 1 (planned 33.3 mg m- 2 week- 1 ) and 67% of patients received 90% planned dose intensity. There were three partial responses (10.7%; 95% confidence interval 2.3-28.2) with a median duration of 7 months (range 6.4-8.3 months). Thirty patients were evaluable for non-haematological toxicity and 28 for haematological toxicity (repeat counts were not available in two patients). Haematological toxicity was moderately severe, with 18 (64%) patients experiencing at least one episode of grade 4 neutropenia, and 7 (25%) patients experiencing febrile neutropenia. Conclusions . In this study, activity of docetaxel in adult chemotherapy-naive patients with advanced STS was modest. [ABSTRACT FROM AUTHOR]

Analyzes articles and abstracts on sarcoma published between the January 1991 and January 1997 issues of the periodical 'Sarcoma'. Outcome of intensive multi-agent chemotherapy; Response to new agents evaluated better in patients who received no previous chemotherapy.

Two cases are reported of recurrent fallopian tube carcinoma treated with CHIP (cis-dichloro-transdihydroxy-bis-isopropylamine platinum IV), a new cis-platinum analogue, resulting in one complete (though transient) and one good partial remission. [ABSTRACT FROM AUTHOR]

Most women with estrogen receptor expressing breast cancers receiving anti-estrogens such as tamoxifen may not need or benefit from them. Besides the estrogen receptor, there are no predictive biomarkers to help select breast cancer patients for tamoxifen treatment. CCND1 (cyclin D1) gene amplification is a putative candidate tamoxifen predictive biomarker. The RSF1 (remodeling and spacing factor 1) gene is frequently co-amplified with CCND1 on chromosome 11q. We validated the predictive value of these biomarkers in the MA.12 randomized study of adjuvant tamoxifen vs. placebo in high-risk premenopausal early breast cancer. Premenopausal women with node-positive/high-risk node-negative early breast cancer received standard adjuvant chemotherapy and then were randomized to tamoxifen (20 mg/day) or placebo for 5 yrs. Overall survival (OS) and relapse-free survival (RFS) were evaluated. Fluorescent in-situ hybridization was performed on a tissue microarray of 495 breast tumors (74% of patients) to measure CCND1 and RSF1 copy number. A multivariate Cox model to obtain hazard ratios (HR) adjusting for clinico-pathologic factors was used to assess the effect of these biomarkers on Os and RFS. 672 women were followed for a median of 8.4 years. We were able to measure the DNA copy number of CCND1 in 442 patients and RSF1 in 413 patients. CCND1 gene amplification was observed in 8.7% and RSF1 in 6.8% of these patients, preferentially in estrogen receptor-positive breast cancers. No statistically significant interaction with treatment was observed for either CCND1 or RSF1 amplification, although patients with high RSF1 copy number did not show benefit from adjuvant tamoxifen (HR = 1.11, interaction p = 0.09). Unlike CCND1 amplification, RSF1 amplification may predict for outcome in high-risk premenopausal breast cancer patients treated with adjuvant tamoxifen. [ABSTRACT FROM AUTHOR]

Abstract: 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: 15–29years (adolescents and young adults (AYA) population) and ⩾30years. 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 8.74years (AYA population: n =161, median FU 9.46years; patients ⩾30years: n =632, median FU 8.62years). 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 ⩾30years. 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 ⩾30years 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 ⩾30years 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 ⩾30years. 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. [Copyright &y& Elsevier]

Abstract: 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 75mg/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 31months; 8 recurrences were reported more than 5years after the diagnosis. In 564 patients with a recurrence (median 13months post-randomisation), there was no difference in post-relapse survival between treatment arms. Patients whose disease recurred within 2years after randomization had a worse prognosis than those recurring after 2years. 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 5years). 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. [Copyright &y& Elsevier]