Clinical features and outcomes of 20 patients with abdominopelvic desmoplastic small round cell tumor.

INTRODUCTION: Desmoplastic small round cell tumor (DSRCT) is a rare mesenchymal malignancy. We describe our experience with treating DSRCT at a large sarcoma referral center. METHODS: A retrospective chart review was performed on DSRCT patients referred to our institution (1998-2014). Pathology specimens were reviewed to confirm the diagnosis. Clinical and imaging were extracted and summarized with descriptive statistics. Univariate analysis was performed to evaluate the association between patient, tumor, and treatment variables and overall survival (OS). RESULTS: In this study cohort of 20 patients, median age at presentation was 29 y (range 18-43) and 90% were male. Fifty-five percent presented with metastasis. Patients underwent chemotherapy (n = 20), radiation therapy (n = 3), and cytoreductive surgery (CRS) (n = 5). Median OS was 22 m (interquartile range: 12-28 m). Five-year OS rate was 20%. Extra-abdominal metastasis was associated with a higher hazard ratio (HR) of mortality (HR: 3.1, 95% C.I. 1.0-9.4, p = 0.04), while CRS improved OS (HR: 0.1, 95% C.I. 0.03-0.7, p = 0.02). CONCLUSIONS: Despite aggressive treatment, less than half of the patients were dead of DSRCT within 2 years of presentation. Although a select group of patients who underwent CRS had improved OS, novel treatments are urgently needed.

A thematic review of scientific and family interests in Canavan Disease: where are the developmentalists?

BACKGROUND: Canavan Disease is a degenerative neurological condition resulting in a spongy deterioration of the brain. Much research has been conducted by the medical community regarding this condition, but little research can be found in the psychological literature. METHOD: A review of the scientific literature related to Canavan Disease using the Psychinfo and PubMed databases was conducted covering a 5-year span from 2006 through 2011. Concurrently, a review of parent initiated topics found on the most popular Canavan Disease Internet discussion board was conducted for comparison purposes. RESULTS: When comparing the topics discussed and information sought among parents with the themes noted in the extant scientific literature, researchers found an exceedingly small overlap between the two communities of interest. In the scientific literature, published research on Canavan Disease focused on three areas: the biochemistry of Canavan Disease, diagnosis and genetic counselling, and clinical therapeutic approaches in Canavan Disease. Of the 42 unique topics raised on a popular Internet discussion board, however, only three (7%) fell into the category of diagnosis and genetic counselling, none (0%) fell into the category of the biochemistry of Canavan Disease, and four fell into the category of clinical therapeutic approaches in Canavan Disease (10%). Of the four posts addressing clinical therapeutic approaches to Canavan Disease, only one post truly overlapped with the topics addressed by the scientific community. Worded differently, while these three categories comprise 100% of the extant scientific literature regarding Canavan Disease, they comprise only 17% of the parent-raised topics. The remaining 83% of parent-raised topics addressed concerns not currently being focusing upon by the scientific community, namely, non-medical practical issues, information regarding specific characteristics of Canavan Disease, non-medical developmental and quality of life issues, and day-to-day developmental and medical concerns. CONCLUSION: By comparing the extant literature on Canavan Disease with the topics of interest raised by parents and caregivers, it seems clear that there is a significant 'underlap' of topics raised by these two communities of interest, one that may reflect a lack of sensitivity on the part of the scientific community to meet the needs of this population of knowledge seekers. It is the suggestion of these authors that developmental psychology may be the appropriate scientific field within which to address this need and fill this gap in the current literature.

Topotecan and cyclophosphamide in adults with relapsed sarcoma.

UNLABELLED: Background. The combination of topotecan and cyclophosphamide (TC) has activity in pediatric patients with recurrent sarcoma, especially Ewing's sarcoma (EWS). We sought to determine the toxicity of and response to TC in adults with recurrent sarcoma. Patients and Methods. Adults treated with TC from 2005 to 2010 were reviewed who received T = topotecan at 0.75 mg/m(2)/day (days 1-5) and C = cyclophosphamide at 250 mg/m(2)/day (days 1-5) every 21 days. Results. Fifteen patients, median age 31 years (range 17.5-56) had nonpleomorphic rhabdomyosarcoma (RMS, n = 6), EWS, n = 5, synovial sarcoma (SS, n = 2) leiomyosarcoma (LMS, n = 1), and desmoplastic small round cell tumour (DSRCT, n = 1). Median time to progression was 2.5 months (range 1.6-13.0). Partial responses were seen in 2/6 RMS and 1/2 SS. Stable disease was seen in 2/5 EWS, 1/2 SS and 1 DSRCT. The most common reason for stopping treatment was progressive disease 12/15, (80%). Hematologic toxicity was common; 7 (47%) patients required blood product transfusion, 5 (33%) patients had fever/neutropenia. At median follow-up time of 7.7 months, all but 1 patient had died of disease. CONCLUSION: TC combination is tolerable but has only modest activity in adults with recurrent sarcoma. Other regimens deserve exploration for this high-risk group of patients.

Clinical features, treatment, and outcome in 102 adult and pediatric patients with localized high-grade synovial sarcoma.

Background. There remains controversy on the routine use of chemotherapy in localized SS. Methods. The records of 87 adult (AP) and 15 pediatric (PP) patients with localized SS diagnosed between 1986 and 2007 at 2 centres in Toronto were reviewed. Results. Median age for AP and PP was 37.6 (range 15-76) and 14 (range 0.4-18) years, respectively. 65 (64%) patients had large tumours (>5 cm). All patients underwent en bloc surgical resection resulting in 94 (92.2%) negative and 8 (7.8%) microscopically positive surgical margins. 72 (82.8%) AP and 8 (53%) PP received radiotherapy. Chemotherapy was administered to 12 (13.8%) AP and 13 (87%) PP. 10 AP and 5 PP were evaluable for response to neoadjuvant chemotherapy, with response rate of 10% and 40%, respectively. 5-year EFS and OS was 69.3 ± 4.8% and 80.3 ± 4.3%, respectively, and was similar for AP and PP, In patients with tumors >5 cm, in whom chemotherapy might be considered most appropriate, relapse occurred in 9/19 (47%) with chemotherapy, compared to 17/46 (37%) In those without. Conclusions. Patients with localized SS have a good chance of cure with surgery and RT. Evidence for a well-defined role of chemotherapy to improve survival In localized SS remains elusive.

Osteosarcoma in adolescents and adults: survival analysis with and without lung metastases.

BACKGROUND: Survival data are still limited and controversial about adult patients with osteosarcoma as older group of patients has mostly been excluded from the historical trials. PATIENTS AND METHODS: Patients with osteosarcoma, from 1986 to 2003, in a single center, were reviewed. Survival according to a cutoff age of 40 was studied. Patients with lung metastases were identified. Variables at first lung involvement including time to first lung metastases, multiplicity and size of the metastatic lesions and use of chemotherapy were all analyzed. RESULTS: A total of 247 patients, with age range of 14-77 years, were reviewed. Five-year survival is 66% with no difference between patients <40 or >or=40 years. Eighty-five patients, with either synchronous or metachronous lung involvement, have 3-year postlung metastases survival (PLMS) of 30%. Forty-seven patients (55.3%) underwent lung resection with 3-year PLMS of 38% compared with 16% for nonoperated patients (P = 0.00023). Patients who developed lung metastases within a year and have fewer than four lung lesions have better PLMS (P < 0.0001 for both). CONCLUSIONS: Older patients have identical survival to pediatric population and should have a similar management approach. Complete metastectomy is the key issue for prolonged survival. Time to lung metastases and number of lung lesions are the most important prognostic factors.

Dose-intensive chemotherapy with growth factor or autologous bone marrow or stem-cell transplant support in first-line treatment of advanced or metastatic adult soft tissue sarcoma: a clinical practice guideline.

QUESTIONS: In patients with inoperable locally advanced or metastatic soft tissue sarcoma, does first-line dose-intensive chemotherapy supported by growth factor or autologous bone marrow or stem-cell transplantation improve response rate, time to disease progression, or survival as compared with standard-dose chemotherapy? What are the effects of first-line dose-intensive chemotherapy supported by growth factor or autologous bone marrow or stem-cell transplantation on toxicity and quality of life? PERSPECTIVES: Because therapeutic options for adult patients with advanced or metastatic soft tissue sarcoma are scarce and the possibility of cure for these patients is extremely limited, the Sarcoma Disease Site Group (dsg) felt that a review of the available literature on dose-intensive chemotherapy for adult patients with locally advanced or metastatic soft tissue sarcoma and subsequent development of a clinical practice guideline based on the evidence were important. METHODOLOGY: A systematic review was developed and clinical recommendations relevant to patients in Ontario were drafted. The practice guideline report was reviewed and approved by the Sarcoma dsg, which comprises medical oncologists, radiation oncologists, surgeons, a pathologist, a methodologist, and community representatives. External review by Ontario practitioners was obtained through a mailed survey, the results of which were incorporated into the practice guideline. Final review and approval of the practice guideline was obtained from the Report Approval Panel. PRACTICE GUIDELINE: Based on the systematic review, consensus, and external review, the Sarcoma dsg makes these recommendations: Dose-intensive chemotherapy with growth factor support is not recommended in the first-line treatment of patients with inoperable locally advanced or metastatic soft tissue sarcoma. The data are insufficient to support the use of high-dose chemotherapy with autologous bone marrow or stem-cell transplantation as first-line treatment in this group of patients. Eligible patients should be encouraged to enter clinical trials assessing novel approaches or compounds. QUALIFYING STATEMENTS: High-dose chemotherapy with growth factor or autologous bone marrow or stem-cell transplantation has adverse effects similar to those seen with standard-dose chemotherapy. With high-dose regimens, the incidence of grades 3 and 4 thrombocytopenia is significantly higher, and neutropenic fever and febrile neutropenia occur more frequently. Compared with standard treatment, the rate of treatment-related death is also higher with high-dose regimens.

A dose escalation trial of adjuvant cyclophosphamide and epirubicin in combination with 5-fluorouracil using G-CSF support for premenopausal women with breast cancer involving four or more positive nodes.

BACKGROUND: Dose-dense and dose-intensive regimens have improved the outcome of breast cancer in high-risk women with operable disease. PATIENTS AND METHODS: Sixty-three premenopausal women with Stage 2, 3 breast cancer and > or =4 positive axillary nodes were treated in three successive cohorts with 70 mg/m(2) of epirubicin, 500 mg/m(2) of 5-fluorouracil and G-CSF every 14 days for 12 cycles. Cyclophosphamide (C) was given at 700 mg/m(2), 900 mg/m(2), and 1100 mg/m(2) doses. Patients were evaluated for dose-limiting toxicities (DLTs) in the first four cycles, the primary endpoint of the trial. RESULTS: No DLTs were seen at C 700 mg/m(2); at C 900 mg/m(2) two of 16 patients experienced febrile neutropenia and poor performance status; at C 1100 mg/m(2), 1 of 31 patients experienced poor performance status. Over 6 months, febrile neutropenia, grade 4 thrombocytopenia, grade 3 anemia and severe fatigue were observed. Clinical congestive heart failure occurred in three patients over 4 years. CONCLUSION: A dose-intense and dose-dense regimen of cyclophosphamide, epirubicin and 5-fluorouracil was delivered with G-CSF without apparent increase in acute toxicity. Cyclophosphamide could be increased to more than twice the standard dose at the cost of more anemia and fatigue.

Ifosfamide-based combination chemotherapy in advanced soft-tissue sarcoma: a practice guideline.

QUESTIONS: In adult patients with inoperable locally advanced or metastatic soft-tissue sarcoma, do combination chemotherapy regimens containing ifosfamide have an advantage in terms of response rate, time to progression, or survival, as compared with similar regimens without ifosfamide when used as first-line therapy? What are the adverse effects and effects on quality of life of ifosfamide-containing combination chemotherapy as compared with similar regimens without ifosfamide? PERSPECTIVES: The prognosis for patients with inoperable or meta-static soft-tissue sarcoma (sts) remains grim. Although the surgical resection of pulmonary metastases may be curative in 15%-30% of patients with isolated slow-growing metastases, most patients receive chemotherapy for palliative purposes. Ifosfamide has documented activity in patients who have received prior treatment with, or who have progressed on, doxorubicin. A number of studies have suggested a schedule and a dose-response relationship for ifosfamide in metastatic sts. Ifosfamide has also been assessed in combination with other drugs such as doxorubicin and dacarbazine (dtic); results of such studies have led some authors to suggest that polychemotherapy using "appropriate doses" of ifosfamide and doxorubicin may represent the "most effective systemic treatment" in this population. Given the limited effective therapeutic options available for patients with metastatic sts, the Sarcoma Disease Site Group (dsg) felt that a need existed to more specifically evaluate the potential benefits of ifosfamide-containing combination chemotherapy in that setting. The Sarcoma dsg developed an evidence-based series report through systematic review, evidence synthesis, and input from practitioners across Ontario. OUTCOMES: Outcomes of interest included survival, response rate, adverse events, and quality of life. METHODOLOGY: A systematic review and meta-analysis served as the evidentiary base for this clinical practice guideline. The report was reviewed and approved by the Sarcoma dsg, which comprises medical oncologists, radiation oncologists, surgeons, methodologists, and patient representatives. The results of an external review by Ontario practitioners, obtained through a mailed survey, were incorporated into this report. Final approval of the evidence-based series report was obtained from the Report Approval Panel of Cancer Care Ontario's Program in Evidence-Based Care (pebc). RESULTS: The current practice guideline reflects a combination of the draft recommendations (based on the evidence identified in a systematic review and meta-analysis) and the external feedback from Ontario practitioners and the pebc's Report Approval Panel. PRACTICE GUIDELINE: In patients with metastatic sts, the addition of ifosfamide to standard first-line doxorubicin-containing regimens is not recommended over single-agent doxorubicin. However, in patients with symptomatic, locally advanced, or inoperable sts, in whom tumour response might potentially result in reduced symptomatology or render a tumour resectable, use of ifosfamide in combination with doxorubicin is reasonable. QUALIFYING STATEMENT: In combination with a doxorubicin-containing regimen, the dose of ifosfamide should not exceed 7.5 g/m(2), given as either a split bolus or a continuous infusion.

A phase II study of perifosine (D-21226) in patients with previously untreated metastatic or locally advanced soft tissue sarcoma: A National Cancer Institute of Canada Clinical Trials Group trial.

UNLABELLED: BACKGROUND/PATIENTS AND METHODS: 16 adult patients with untreated measurable locally advanced or metastatic inoperable soft tissue sarcoma were treated with oral perifosine, a synthetic alkylphospholipid, believed to inhibit MAP kinase (MAP-K), protein kinase C (PKC), Akt and other regulatory proteins. Perifosine was administered orally in cycles for 21 days out of 28. Loading doses were given day 1 each cycle (900 mg cycle 1, 300 mg cycle 2+) and 150 mg daily was given days 2-21 of each cycle. Cycles were repeated until disease progression, unacceptable toxicity or patient refusal. RESULTS: Seventeen patients were enrolled; 16 and 15 were evaluable for toxicity and response, respectively. A total of 30 cycles of perifosine were administered. Most toxic effects were grade 1 or 2 and commonly included nausea, vomiting, diarrhea, and fatigue (> or =40%). Hematologic toxicity was generally mild. There were no significant biochemical abnormalities due to the drug reported. There were 4 serious adverse events (SAE)-none of which was related to perifosine. No objective responses were seen; 4 patients had stable disease for 1.3 to 8.2 months and the remainder of the patients had progressive disease. CONCLUSIONS: Perifosine when given according to this dosing schedule does not show evidence of activity in a mixed population of adult soft tissue sarcoma patients.

Gemcitabine as first-line therapy in patients with metastatic breast cancer: a phase II trial.

OBJECTIVES: This phase II study was conducted to evaluate the efficacy and safety of gemcitabine in patients with metastatic breast cancer (MBC). METHODS: Women with histologically or cytologically confirmed bidimensionally measurable MBC not amendable to curative surgery or radiation were eligible. Prior chemotherapy for metastatic disease was not permitted. Patients received gemcitabine 1,200 mg/m(2) on days 1, 8 and 15 for 3 weeks every 28 days for a maximum of 8 cycles. RESULTS: Thirty-nine patients, with a median age of 58 years, were enrolled. The overall response rate for the 35 evaluable patients was 37.1% (95% confidence interval [CI], 21.5-55.1%), with 2 complete responses and 11 partial responses. Median time to progression and survival were 5.1 months (95% CI, 3.5-8.8 months) and 21.1 months (95% CI, 11.0-26.9 months), respectively. Chemotherapy was well tolerated, with a median of 4 cycles completed. Grade 4 toxicities were 1 infection and 1 abnormal pulmonary function. Grade 3 neutropenia and thrombocytopenia occurred in 30.3% and 6.3% of patients, respectively. The most common grade 3 non-hematologic toxicity was nausea/vomiting (10.3%). Five of 21 patients had improved Karnofsky performance status (KPS) scores. CONCLUSION: Single-agent gemcitabine is active and well tolerated as first-line treatment in patients with MBC.

Extended follow-up of patients treated with cytotoxic chemotherapy for intra-abdominal desmoid tumors.

BACKGROUND: Cytotoxic chemotherapy can achieve a good initial response in inoperable desmoid tumors that have caused progressive obstruction of the gastrointestinal and urinary tracts and have caused unrelenting pain. METHODS: We have reviewed 8 patients (3 male) with desmoid tumors and familial adenomatous polyposis who underwent cytotoxic chemotherapy for inoperable gastrointestinal obstruction and/or uncontrolled pain. They were treated with doxorubicin and dacarbazine followed by carboplatin and dacarbazine. RESULTS: Follow-up after cytotoxic chemotherapy in the 7 patients for whom it was available was a mean of 42 (range 24-54) months. Two patients achieved complete remission after therapy. Four patients achieved a partial remission after completing all or some of the chemotherapy regimen; of these, three remained in stable remission, whereas the other was lost to follow-up. There were two recurrences that required further therapy; one of these patients was treated with further chemotherapy, which induced a second remission, and the other was treated with pelvic exenteration and has subsequently died. CONCLUSIONS: Most patients had a substantial response to cytotoxic chemotherapy; however, two patients required additional therapy 24 and 30 months after cytotoxic chemotherapy, respectively. Cytotoxic chemotherapy is effective in producing short-term and long-term remission in these difficult patients.

Comparison of HER2/neu status assessed by quantitative polymerase chain reaction and immunohistochemistry.

We prospectively evaluated a series of 254 breast cancers by quantitative polymerase chain reaction (PCR) and immunohistochemistry using 3 antibodies: HercepTest, CB11, and TAB250. DNA was extracted from a 10-micron tumor section for PCR, and 4-micron serial sections were taken from the same block for immunohistochemistry. The immunohistochemical results were scored using a semiquantitative immunohistochemical system. A positive tumor by immunohistochemistry had a score of 5 or more. The manufacturer's recommended scoring system was used for the HercepTest. Tumors were positive for gene amplification if the ratio of the HER2/neu gene to control gene after normalization was 2 or more. Of 254 cases, 61 showed gene amplification. For immunohistochemistry, 23% of tumors were positive with CB11, 27% with TAB250, and 37% with the HercepTest. Results for each antibody were compared with PCR results. The overall concordance for the HercepTest was 82%, which was significantly lower than that for CB11 (88%) or TAB250 (87%). The specificity for the HercepTest was 80% compared with 90% for TAB250 and 93% for CB11, while the positive predictive value for the HercepTest was 57% compared with 71% and 76% for TAB250 and CB11, respectively.

Development of tertiary hyperparathyroidism after phosphate supplementation in oncogenic osteomalacia.

Oncogenic osteomalacia is a rare paraneoplastic syndrome. It is characterized by bone pain, muscle weakness, gait disturbance, fractures and skeletal deformities. Hypophosphatemia, diminished renal phosphate reabsorption, decreased 1,25 dihydroxy Vitamin D and elevated alkaline phosphatase are the biochemical hallmarks of this disorder. Most tumors are of mesenchymal origin. We report the case of a 39-year-old woman with oncogenic osteomalacia caused by osteosarcoma of the right scapula which was unrecognized for several years. She subsequently developed tertiary hyperparathyroidism after treatment with oral phosphate and Vitamin D. This case illustrates that oncogenic osteomalacia may persist for many years before the tumor is discovered. This is because the tumors are frequently very small and are in obscure locations. The uniqueness of this case is the coexistence of hyperparathyroidism and oncogenic osteomalacia. Five other cases have been reported up to date. All patients had received phosphate supplement, ranging from 10 to 14 years prior to their diagnosis. Interestingly, our patient was on the treatment for only 2 years. The proposed mechanism is that exogenous phosphate stimulates parathyroid activity through sequestration of calcium.

Liarozole fumarate (R85246): in the treatment of ER negative, tamoxifen refractory or chemotherapy resistant postmenopausal metastatic breast cancer.

Three phase II studies were conducted to determine the efficacy and tolerability of liarozole fumarate (R85246; liarozole), a retinoic acid metabolism blocking agent (RAMBA) and aromatase inhibitor. Additionally, animal experiments in the MNU-induced rat mammary tumor model and in immature ovariectomized rats were conducted to further elucidate liarozole's mechanisms of action. Patients were postmenopausal with either: ER negative disease in first relapse (Group 1: 1n = 16); ER positive or unknown disease refractory to tamoxifen (Group 2; n = 16); ER positive, negative or unknown disease resistant or refractory to chemotherapy (Group 3; n = 27). Treatment was liarozole (150-300mg) twice daily orally until disease progression. Response rates were: 25% in group 1 (95% CI 11.0-52.3%: median duration (MD) 20 months; range 2-36.5); 25% in group 2 (95% CI 11.0-52.3%; MD 6.5 months: range 3.5-38): 11% in group 3 (95% CI 4.2-29.2%; MD 7 months; range 3-8.5). No significant improvement in quality of life scores (FLI-C) was noted. Toxicities observed were predominantly dermatological (skin disorders: 88%; dry mouth/eyes/lips: 69%). Plasma estradiol decreased from mean pre-treatment levels of 72.7 pM (9.1-1,839 pM) to below detection (9.2 pM) after 1 month. Liarozole, but not vorozole, partially inhibited estradiol induced uterine hypertrophy and demonstrated dose-dependent anti-tumor effects in the rats, only partially overcome by coadministration of estradiol. The clinical responses observed, together with our preclinical results, confirm liarozole's dual mechanism of action and provide a rationale for further evaluation of RAMBAs in the treatment of breast cancer.

Randomized phase II study of high-dose paclitaxel with or without amifostine in patients with metastatic breast cancer.

PURPOSE: To determine whether the neurotoxicity of paclitaxel 250 mg/m(2) given over 3 hours every 3 weeks could be reduced by pretreatment with amifostine 910 mg/m(2). Secondary objectives included comparing myelosuppression, myalgias, and response rates of the two groups. PATIENTS AND METHODS: Forty women with metastatic breast cancer were randomized to receive either paclitaxel alone (arm 1) or paclitaxel preceded by amifostine (arm 2). All were assessable for toxicity, and 37 were assessable for response. At baseline and after each cycle, all patients completed questionnaires for neurologic symptoms and had standardized neurologic examinations, including objective assessments of power and vibration sense. In addition, standard follow-up assessments for other toxicities and tumor response were undertaken. Changes from baseline after courses 1, 2, and 3 were assessed. The sample size was sufficient to detect a 50% improvement in the expected determination in sensory change. RESULTS: There were no differences observed in any of the measures of neurotoxicity. Other toxicity was similar in arms 1 and 2, including hair loss (95% v 90%), neurosensory changes (100% v 100%), fatigue/lethargy (85% v 90%), myalgia (95% v 90%), and grade 4 neutropenia (47% v 60%). Nausea, vomiting, dizziness, hypotension, and sneezing were more common in the amifostine arm. Response rates (22.2% v 36.8%) and paclitaxel pharmacokinetics were not significantly different. CONCLUSION: There was no protection from paclitaxel-related neurotoxicity or hematologic toxicity in this study. These results suggest that the mechanism of action of paclitaxel-related toxic effects is not amenable to the cytoprotective action of amifostine.

Doxorubicin-cisplatin chemotherapy for high-grade nonosteogenic sarcoma of bone. Comparison of treatment and control groups.

OBJECTIVE: To evaluate the role of chemotherapy with a combination of doxorubicin (adriamycin) and cisplatin in high-grade, nonosteogenic, non-Ewing's sarcoma (non-OSA) of bone. DESIGN: A case series comparison with a literature-derived control group. SETTING: A university-affiliated tertiary care centre. PATIENTS: Thirty patients with a diagnosis of non-OSA. Of these, 8 had low-grade disease (grade 1 or 2) and 22 had high-grade disease (grade 3). Eleven of the 22 with high-grade disease had malignant fibrous histiocytoma. Seventeen patients with nonmetastatic high-grade non-OSA were compared with a literature cohort of 37 patients who met the eligibility criteria of nonmetastatic, high-grade non-OSA treated with surgery, with or without radiotherapy. The mean follow-up was 25.2 months. INTERVENTIONS: Eight patients with low-grade tumour underwent surgery alone; 22 patients with high-grade tumour underwent surgery and 6 courses of adriamycin (75 mg/m2 every 3 weeks) and cisplatin (100 mg/m2 every 3 weeks). MAIN OUTCOME MEASURES: Disease-free survival and overall survival in those with high-grade tumours treated with or without chemotherapy. RESULTS: Of 8 patients who had low-grade tumours and underwent surgery alone, 3 had systemic relapse. Of the 22 having high-grade tumours, 4 did not receive chemotherapy because of age and comorbid conditions. Of the other 18, 13 received 3 courses of chemotherapy preoperatively and 3 courses postoperatively, 4 received all 6 courses postoperatively and 1 received all chemotherapy preoperatively to treat metastatic disease. In the 17-patient cohort used for comparison with the literature control group, disease-free survival was 57% at a mean follow-up of 25.6 months and overall survival was 57% at a mean follow-up of 30.1 months. In the control group, disease-free survival was 16% at a mean follow-up of 20.9 months and overall survival was 26% at a mean follow-up of 29.9 months. These differences are significant: p = 0.0000, chi 2 = 41.61 for disease-free survival and p = 0.0000, chi 2 = 46.49 for overall survival. CONCLUSIONS: The findings of this study support the use of adjuvant chemotherapy in patients with high-grade non-OSA, in whom malignant fibrous histiocytoma was the predominant histologic subtype.

Phase II study of dexverapamil plus anthracycline in patients with metastatic breast cancer who have progressed on the same anthracycline regimen.

The purpose of this study is to evaluate whether metastatic breast cancer that has progressed on an anthracycline-containing drug regimen will subsequently respond to that identical regimen if dexverapamil, a modulator of P-glycoprotein-mediated drug resistance, is given concomitantly. Eligible patients received 180 mg/m2 dexverapamil every 6 h for 15 doses with the anthracycline administered 30 min after the seventh dose. Blood for dexverapamil levels was drawn before and 30 min after this dose. When possible, biopsies were obtained to measure mdr-1 expression by reverse transcription-PCR and by image cytometry. Of the 21 patients entered onto the trial, 20 were evaluable for response. There were two partial responses (10%) that both lasted for 6 months, and two additional patients had stable disease. Seven patients had asymptomatic cardiotoxicity consisting of hypotension (24%), bradycardia (5%), or prolongation of the P-R interval (14%). Two patients developed acute congestive heart failure, one on dexverapamil and one 10 days after stopping it. Dexverapamil did not seem to increase anthracycline toxicity. The median trough dexverapamil plus norverapamil level on day 3 was 1110 ng/ml (range, 186-3385 ng/ml), and the median peak level was 2164 ng/ml (range, 964-8382 ng/ml). There was poor correlation between reverse transcription-PCR and image cytometry for the level of mdr-1 expression. Because dexverapamil has been shown to affect doxorubicin pharmacokinetics subsequent to the initiation of this trial, it cannot be concluded that the responses seen were necessarily due to P-glycoprotein inhibition. Additional studies are necessary to determine whether mdr-1 modulators can reverse clinical drug resistance in breast cancer patients. The intrinsic cardiotoxicity of dexverapamil makes it less suitable for such studies than several other available agents.

neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. Toronto Breast Cancer Study Group.

PURPOSE: It remains a challenge to predict which women with axillary node-negative (ANN) breast cancer at greatest risk of relapse may benefit most from adjuvant therapy. Increases in neu/erbB-2 have been implicated in breast cancer prognosis. Although overexpression has been investigated extensively, this study represents the first prospective assessment of the prognostic value of neu/erbB-2 DNA amplification in a cohort of women with newly diagnosed ANN. METHODS: A consecutive series of women was monitored for recurrence (median follow-up duration, 36 months) and tumors from 580 individuals were analyzed for amplification. The association of amplification with risk of recurrence was examined in survival analyses with traditional and histologic markers as prognostic factors. RESULTS: Neu/erbB-2 was amplified in 20% of cases. We found an increased risk of disease recurrence when neu/erbB-2 was amplified > or = twofold that persisted with adjustment for other prognostic factors (relative risk, 2.36; P = .002). We found some evidence that amplification was more important in patients who received chemotherapy compared with untreated patients. CONCLUSION: neu/erbB-2 amplification is an independent prognostic factor for risk of recurrence in ANN breast cancer. Women with tumors without neu/erbB-2 amplification have a good prognosis; aggressive therapy in this group is therefore difficult to justify. On the other hand, even with adjuvant chemotherapeutic treatment, women whose tumors exhibit neu/erbB-2 amplification have an increased risk of recurrence. We encourage a randomized trial to compare more aggressive adjuvant chemotherapy versus standard chemotherapy for ANN women whose tumors exhibit neu/erbB-2 amplification.

A Phase II Study of Docetaxel in Chemotherapy-Naïve Patients With Recurrent or Metastatic Adult Soft Tissue Sarcoma.

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) weekm(-1) (planned 33.3 mg m(-2) weekm(-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-naïve patients with advanced STS was modest.