A phase II study of SB939, a novel pan-histone deacetylase inhibitor, in patients with translocation-associated recurrent/metastatic sarcomas-NCIC-CTG IND 200†.

BACKGROUND: A subgroup of sarcomas is characterized by defining chromosomal translocations, creating fusion transcription factor oncogenes. Resultant fusion oncoproteins associate with chromatin-modifying complexes containing histone deacetylases (HDAC), and lead to epigenetic transcriptional dysregulation. HDAC inhibitors were shown to be effective in vitro, reversing gene repression by these complexes, restoring PTEN expression and apoptosis via the PI3K/Akt/mTOR pathway. PATIENTS AND METHODS: SB939 is an oral inhibitor of classes 1 and 2 HDAC. Eligible patients with recurrent or metastatic translocation-associated sarcoma (TAS) by local pathology were treated with 60 mg/day every other day for 3 of 4 weeks. Central pathology review was conducted with fusion oncogenes characterized, and HDAC2 expression correlated with efficacy in pre-specified methods. RESULTS: Twenty-two patients were treated with a median of 2 cycles. Fourteen patients were assessable for response with confirmed specific chromosomal translocations; 8 had a best response of stable disease (SD) (median duration 5.4 months) with no confirmed objective responses. The 3-month progression-free survival (PFS) rate was 49%. Among those with HDAC2 score ≥5, 7/10 had SD, versus 0/3 with HDAC2 score <5. SB939 was considered as well tolerated with <10% patients experienced ≥grade 3 toxicity. CONCLUSION: This study was stopped prematurely due to prolonged unavailability of SB939. No objective responses were seen. Although the observed SD in HDAC2 high patients was interesting, due to the small sample size, no definitive conclusion can be drawn about the efficacy of SB939 in this patient population. CLINICAL TRIAL: NCT01112384.

Phyllodes tumors of the breast: The British Columbia Cancer Agency experience.

PURPOSE: Phyllodes tumors of the breast are uncommon fibroepithelial lesions for which optimal management remains unclear. This retrospective population-based study reports treatment and outcomes for patients with phyllodes tumors and evaluates characteristics that influence outcome. MATERIALS AND METHODS: Data were analysed on 183 patients with newly diagnosed phyllodes tumors from 1999 to 2014. Five-year Kaplan-Meier local recurrence and survival were compared between cohorts with benign (n=83), borderline (n=50) and malignant phyllodes tumor (n=49) histology. RESULTS: Median (range) follow-up was 65 (0.5-197) months. Local excision was performed in 163 and mastectomy in 19 patients. Eleven patients with malignant phyllodes tumors received radiation therapy. Overall, local recurrence occurred in 8.7%, distant metastases in 4.4%, and cause specific deaths in 3.8%. Five-year Kaplan-Meier outcomes among women with benign, borderline, and malignant phyllodes tumors were: local recurrence 6% vs 9% vs 21%, P=0.131; overall survival 96% vs 100% vs 82%, P=0.002; and disease-free survival 94% vs 91% vs 67%, P<0.001. Five-year Kaplan-Meier local recurrence among women with negative vs close vs positive margins were 8% vs 6% vs 37%, P<0.001. Corresponding rates for intermediate vs pushing vs infiltrative borders were 6% vs 6% vs 33%, P=0.006. Positive margins and infiltrative tumor borders were associated with increased local recurrence (all P≤0.006), and the latter remained significant in exploratory analyses after adjusting for margin status and phyllodes tumor classification. CONCLUSIONS: Five-year outcomes among women with phyllodes tumors were comparable to those reported in the literature. Exploratory analysis has suggested that infiltrative tumor borders may be used in conjunction with margin status to assess local recurrence risk.

Combination chemotherapy with doxorubicin, dacarbazine, and ifosfamide in advanced adult soft tissue sarcoma. Canadian Sarcoma Group--National Cancer Institute of Canada Clinical Trials Group.

Forty-three adult patients with locally advanced or metastatic soft tissue sarcoma entered a pilot study of combination chemotherapy comprising 50 mg of doxorubicin/m2 by intravenous bolus, 850 mg of dacarbazine/m2 by 1-hour infusion, and 5 g of ifosfamide/m2 by 24-hour infusion with mesna uroprotection. The overall response rate in 40 assessable patients was 25% with two complete remissions. Twenty-four episodes of infection occurred in 148 courses (16%). These infections were usually associated with neutropenia (granulocyte count less than 0.5 X 10(9)/L), which occurred in 70% of the courses. These results do not differ from those elicited by each agent alone, and may reflect inadequacies of dose intensity or scheduling, or evaluation in a study population with adverse prognostic factors.

Comparison of extramedullary plasmacytomas with solitary and multiple plasma cell tumors of bone.

Patients with solitary osseous plasmacytomas (SOP) differ from those with extramedullary plasmacytomas (EMP) in that they are younger and the proportion of males is smaller. The median survival of the two groups is similar: 86.4 mo for SOP, and 100.8 mo for EMP. Progression-free survival, however, is much better for EMP. Only five EMP patients have progressed following initial radiation therapy: one developed a single bony lesion, two progressed to multiple myeloma, and two developed multiple EMP. Thus, 71% of EMP patients are progression free at 10 yr, and most deaths do not result from plasma cell neoplasia. In contrast, 13 SOP patients have progressed to develop additional osteolytic lesions, so that only 16% of SOP patients are progression free at 10 yr; death resulted from progression to multiple myeloma in most of these patients. In EMP patients the occurrence of involved lymph nodes at the time of diagnosis in seven, and initial relapse in regional nodes in three, suggest that consideration should be given to including regional lymph nodes in the radiation fields used to treat these patients.

Randomized trial of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptor-positive breast cancer: a report of the National Cancer Institute of Canada Clinical Trials Group. Breast Cancer Site Group.

PURPOSE AND METHODS: By the mid 1980s, tamoxifen alone was considered standard adjuvant therapy for postmenopausal women with node-positive, estrogen receptor (ER)- or progesterone receptor (PgR)-positive breast cancer. From 1984 through 1990, 705 eligible postmenopausal women with node-positive, ER- or PgR-positive breast cancer were randomized to a National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) study that compared tamoxifen 30 mg by mouth daily for 2 years (TAM) versus TAM plus chemotherapy with all-intravenous cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 given every 21 days for eight cycles (CMF). RESULTS: There were no significant differences in overall survival, recurrence-free survival, locoregional recurrence-free survival, or distant recurrence-free survival between the two treatment arms. However, there was significantly greater severe toxicity, which included leukopenia (P < .0001), nausea and vomiting (P < .0001), and thromboembolic events (P < .0001), as well as significantly more mild or greater toxicity, which included thrombocytopenia (P = .04), anemia (P = .02), infection (P = .0004), mucositis (P = .0001), diarrhea (P = .0001), and neurologic toxicity (P = .006), in women who received TAM plus CMF. CONCLUSION: The addition of CMF to TAM adds no benefit and considerable toxicity in this group of women.

Treatment of recurrent and metastatic head and neck cancer with cisplatin/etoposide/bleomycin.

Cisplatin/etoposide/bleomycin (DEB) was given as an outpatient regimen in a novel weekly schedule to 27 patients with recurrent and/or widely metastatic cancer of the head and neck region. Six of these patients also received mitomycin (DEB/M) when their disease failed to respond after at least three weekly DEB doses. All but three patients had been treated previously with radiotherapy directed to the primary site and regional nodal disease; four had also received chemotherapy with cisplatin or carboplatin. Before treatment with DEB, 19 patients had distant metastases. Of an intended 12 doses per patient, a mean of 8.2 was achieved. Myelosuppression was the major toxicity, with neutropenia in 45% of patients and significant anemia in 26%. The overall response rate to DEB in 27 patients was 59%, increasing to 70% after the addition of mitomycin. There were two complete and 17 partial responses. The median duration of response was 12 weeks and median survival was 6 months, with 20% of patients surviving 1 year. We conclude that the relatively short survival time together with the significant toxicity of the DEB/M regimen does not warrant its routine use in clinical practice. However, this regimen, or one patterned on it, should be evaluated in combination with radiotherapy as the initial treatment for selected patients with previously untreated head and neck cancer.

Sarcoma and Cystosarcoma phyllodes tumors of the breast--a retrospective review of 58 cases.

A retrospective review of 58 rare breast neoplasms encountered at the British Columbia Cancer Agency between 1972 and 1992 was undertaken. There were 38 cystosarcoma phyllodes tumors, 6 carcinosarcomas, and 14 other sarcomas. Initial management involved total mastectomy in 37 cases, wide excision in 14, and excision biopsy in 7. Recurrence developed in 19 patients. Local recurrence developed in 7 patients following mastectomy, 2 incidences following wide excision, and 2 following excision biopsy. There was no significant difference in recurrence in relation to the surgical approach. Tumor grade was a significant predictor for metastatic recurrence but not for local recurrence. Adequate surgical excision remains the only curative therapy for these rare tumors. In selected cases, partial mastectomy is an acceptable treatment.

Quality of life, appetite, and weight change in patients receiving dose-intensive chemotherapy.

Quality of life was assessed by self-report questionnaires in 30 patients receiving dose-intensive chemotherapy for either non-small-cell lung cancer (20 patients) or recurrent head and neck cancer (10 patients). Megestrol acetate was given daily to try to improve appetite and prevent the weight loss usually associated with this chemotherapy. Appetite did not change significantly overall during the first 4 weeks of chemotherapy, but it did improve in those patients still receiving chemotherapy at 8 weeks. Changes in global quality of life were significantly correlated with changes in appetite, fatigue, energy level, and physical function. Thus, these parameters may have more relevance to patients' perceptions of quality of life than does weight change, and should be used more frequently as endpoints in studies of supportive care and palliative treatment of patients with cancer.

Phase II trial of megestrol in the supportive care of patients receiving dose-intensive chemotherapy.

Megestrol acetate was given daily to lung cancer patients undergoing therapy with CODE and to recurrent head and neck cancer patients receiving DEB/M in an attempt to prevent weight loss. The outcomes in this study were compared with the same outcomes in similar groups of patients treated with the same chemotherapy regimens, but in which prednisone was used as the main supportive drug along with co-trimoxazole, ketoconazole, and either cimetidine or sucralfate. Weight loss was less pronounced in the current patients than in the previous ones. Nevertheless, there were several factors that led us to conclude that megestrol is not an adequate substitute for prednisone in patients receiving this kind of chemotherapy.

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.

Breast cancer after treatment for osteosarcoma.

Two cases of patients with primary osteosarcoma who developed subsequent new primary infiltrating ductal carcinoma of breast are presented. The relationship of irradiation from diagnostic radiology, chemotherapy given, and possible genetic factors are discussed. A recommendation for the lifetime follow-up program of a patient with osteosarcoma should include careful attention to breast self-examination and regular breast examination by the attending physician.

Radiotherapy of extramedullary plasmacytoma of the head and neck.

The purpose of this study is to report the results of megavoltage irradiation in 23 previously unreported cases of extramedullary plasmacytoma of the head and neck. It has been found that 3500 cGy (rad) in three weeks provides good local control of disease with minimal morbidity and a significant proportion do not go on to multiple myeloma. Prognostic factors of significance with respect to subsequent development of multiple myeloma include site and presence or absence of bone destruction. The presence or absence of an M protein peak appears to be of no significance.

Perioperative chemotherapy for primary sarcoma of bone.

Preoperative chemotherapy for primary osteosarcoma has usually been accompanied by a prolonged delay between withdrawal before operation and resumption after. This is because animal studies showed impaired wound healing associated with perioperative chemotherapy. Clinical studies, however, have not shown this to be the case. The authors describe their experience in eight patients who had osteosarcoma and Ewing's sarcoma of the extremities and received one to three cycles of chemotherapy preoperatively. Chemotherapy consisted of Adriamycin, cis-platinum and vincristine. Definitive surgery on the primary tumour was done 1 to 4 days after the last dose. Amputation was performed on seven patients and tumour resection for limb salvage on one. No wound healing or infectious complications were encountered. The ensuing course of chemotherapy was not delayed by the surgical procedure. The authors conclude that it is feasible to combine neoadjuvant chemotherapy and early surgery in the management of high-grade primary bone sarcoma.

Multiple gingival metastases from angiosarcoma of the breast.

Metastases to the jaws and oral soft tissue occur rarely. Such metastases may result in the presenting symptoms and signs of malignant disease or may develop during the course of a previously diagnosed malignant condition. A case of multiple gingival metastases in a patient with angiosarcoma of the breast is reported.

Preoperative administration of high-dose methotrexate for osteosarcoma.

Nine patients, aged 9 to 27 years (median 16 years), with osteosarcoma were given high-dose methotrexate followed by folinic acid rescue before amputation. The dose of methotrexate was 12 g/m2 for children under 12 years of age and 8 g/m2 for those over 12 years. Amputation was done after two to five (median four) courses of the drug. Between 5% and 60% of tumour cells were nonviable on histologic examination. No renal or hematologic toxicity was encountered. Mild mucositis and abnormal liver chemistry were present, usually after the third dose of methotrexate. Patients who achieved higher serum methotrexate levels at 24 hours after administration also had greater tumour necrosis. Postoperatively, chemotherapy was changed to cis-platinum, doxorubicin, cyclophosphamide, actinomycin and bleomycin. Seven patients finished their medication 17 to 35 months after diagnosis. One patient died after refusing chemotherapy postoperatively and another is alive with pulmonary metastases. Preoperative chemotherapy is a novel approach to the treatment of osteosarcoma and further modification of the treatment protocol may improve results.

Phase II trial of 10-EDAM in advanced soft tissue sarcoma. A study of the Canadian Sarcoma Group and the National Cancer Institute of Canada Clinical Trials Group.

BACKGROUND: Inoperable locally recurrent soft tissue sarcomas (STS) are incurable with chemotherapy. Therefore the National Cancer Institute of Canada Clinical Trials Group are performing phase II studies in an attempt to find better drugs. PATIENTS AND METHODS: Thirty-one evaluable patients with incurable soft tissue sarcoma were treated with the antifol 10-EDAM at a dose of 80 mg per m2/week. RESULTS: Mucositis was the most common toxicity. Only 41% of patients received > or = 90% of the planned dose time because of dose modification mainly for grade 1 mucositis. Two patients died after neutropenic episodes. Toxicity otherwise was generally mild (< grade 2). One patient had a pathologically confirmed complete response but relapsed after four months. Another had a partial response lasting 16 weeks. Eleven other patients had stabilization of disease. CONCLUSIONS: In this study, 10-EDAM was not found to be an effective agent to treat advanced soft tissue sarcoma.

Computed tomography of retroperitoneal and mesenteric sarcomas: a pictorial essay.

Retroperitoneal and mesenteric sarcomas are rare tumours that often do not present until they are very large. Computed tomography (CT) is helpful for diagnosis and for planning therapy. This pictorial essay illustrates the spectrum of CT manifestations of these tumours that the authors have encountered and includes a review of the various aspects of clinical presentation and treatment.

Phase II study of topotecan (NSC 609 699) in patients with recurrent or metastatic soft tissue sarcoma.

BACKGROUND: New drugs are needed for treatment of unresectable or metastatic soft tissue sarcoma. Topotecan, a semisynthetic derivative of the alkaloid, camptothecin, exerts its cytotoxic effect through inhibition of topoisomerase I. PATIENTS AND METHODS: Thirty-two adult patients with locally advanced or metastatic soft tissue sarcoma entered this phase II study of topotecan, administered at 1.5 mg/m2/day IV x 5 days every 3 weeks. All had measurable disease and none had received previous chemotherapy. RESULTS: There were 3 partial responses (10.3%; 95% CI 2.2-27.4%) in 29 evaluable patients. Grade 3 or 4 neutropenia occurred in 25 patients, and there was a 17% incidence of infection/neutropenic fever leading to one toxic death. CONCLUSIONS: Topotecan, in this dose and schedule, has low activity in adult soft tissue sarcoma.

Efficacy of weekly cisplatin-based chemotherapy in recurrent and metastatic head and neck cancer.

After disease recurrence or dissemination, patients who had been treated previously with radiation with or without surgery for cancer of the head and neck were given either cisplatin (16 patients), cisplatin/etoposide (15 patients), or cisplatin/etoposide/5-fluorouracil (5-FU) (19 patients) in an ambulatory care clinic. Intravenous (i.v.) cisplatin 25 mg/m2 was given weekly, while etoposide was given i.v. (80 mg/m2) on day 1 and orally (160 mg/m2) on day 2 of every odd-numbered week. In the three-drug regimen, 5-FU 500 mg/m2 i.v. was given every even-numbered week. Patients in all three groups received daily oral prednisone to decrease myelosuppression and oral co-trimoxazole and ketoconazole to prevent infection. The supportive drugs were given to all groups to keep these variables constant. As expected, myelosuppression did not occur in the cisplatin group, while the rates of severe neutropenia (less than 1.0 x 10(9)/L) in the two- and three-drug groups were 26% and 74%, respectively. The incidence of infection requiring hospitalization was low (2.5%). The response rate (complete plus partial) was lowest in the cisplatin group (6%) and higher in the cisplatin/etoposide (47%) and cisplatin/etoposide/5-FU (53%) groups. Because of the low response rate and the short time to progression (5 weeks) in the cisplatin group, 9 of these 16 patients were treated subsequently with cisplatin/etoposide. Time to progression and response duration were similar in the cisplatin/etoposide and cisplatin/etoposide/5-FU groups--12 and 14 weeks, and 12 and 9 weeks, respectively. Median survival times of the cisplatin and cisplatin/etoposide/5-FU groups were 36 and 34 weeks, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

A National Cancer Institute of Canada clinical trials group phase II study of eniluracil (776C85) and oral 5-fluorouracil in patients with advanced squamous cell head and neck cancer.

UNLABELLED: BACKGROUND/PATIENTS AND METHODS: Thirty-two patients with recurrent head and neck cancer (HNC) following radiotherapy and/or surgery were treated with eniluracil (10 mg/m2) and 5-fluorouracil (5-FU) (1 mg/m2) (E5F) orally twice daily for 28 days followed by a seven-day treatment free period. Thirty-five-day cycles were repeated until disease progression, unacceptable toxicity or patient refusal. Doses were modified for toxicity. Standard toxicity and response criteria were used. RESULTS: Thirty-two patients were accrued; thirty-two and twenty-eight patients were evaluable for toxicity and response, respectively. Twelve patients received three or more cycles of E5F. Drug related toxicities were usually grade 1-2 intensity and included lethargy, nausea or diarrhea (> or = 25% of patients), and anorexia, rash or itch, stomatitis or vomiting (12%-24% of patients). Hematologic toxicity was generally mild; two patients experienced grade 3-5 leukopenia or thrombocytopenia. No significant biochemical toxicity was seen. One patient was withdrawn (severe nausea and vomiting) and one patient died because of drug related toxicity (thrombocytopenia). In the final analysis there were one complete and four partial responses for a 15.6% overall response. CONCLUSIONS: E5F demonstrates activity in chemotherapy naïve patients with advanced HNC cancer with acceptable toxicity profile. Further investigation of E5F with other active agents is warranted in HNC.