Survival outcomes in patients with early stage, resected pancreatic cancer - a comparison of gemcitabine- and 5-fluorouracil-based chemotherapy and chemoradiation regimens.

PURPOSE: We conducted a comparative survival analysis between patients with resected pancreatic cancer who received adjuvant treatment with either gemcitabine- or 5-fluorouracil-based chemotherapy and chemoradiation regimens. PATIENTS AND METHODS: The Surveillance, Epidemiology and End Results (SEER)-Medicare database was used to identify patients with pancreatic cancer diagnosed from 1998 to 2005 who received curative surgery and adjuvant chemotherapy with either 5-fluorouracil or gemcitabine. These groups were subdivided by treatment with radiotherapy. Patients were followed until death, study end-point or a maximum of 5 years after diagnosis. RESULTS: Three hundred and fifty-nine patients received 5-fluorouracil and 346 received gemcitabine. Compared with chemoradiation with 5-fluorouracil, outcomes for patients who received chemoradiation with gemcitabine did not differ. Patients who received gemcitabine without radiation had increased hazards (poorly differentiated tumours: HR = 1.50, p = 0.01; moderately differentiated tumours, HR = 1.28, p = 0.11). However, outcomes of patients who received 5-fluorouracil without radiation varied with tumour grade. In moderately differentiated tumours, patients had better outcomes with 5-fluorouracil when compared with chemoradiation with 5-fluorouracil (HR = 0.42, p = 0.02). In poorly differentiated tumours, the opposite was true (HR 2.10, p = 0.09). CONCLUSION: Patients with low-grade resected pancreatic cancer may have better outcomes with 5-fluorouracil-based chemotherapy without radiation when compared with 5-fluorouracil with radiation.

Novel erythropoiesis stimulating protein (NESP) for the treatment of anaemia of chronic disease associated with cancer.

Anaemia is a common haematologic disorder in patients with cancer and has a multifactorial aetiology, including the effects of the malignancy itself and residual effects from previous therapy. Novel erythropoiesis stimulating protein (NESP, darbepoetin alfa), a protein with additional sialic acid compared with erythropoietin (EPO), stimulates erythropoiesis by the same mechanism as recombinant human erythropoietin (rHuEPO) but it is biochemically distinct. NESP, with its approximately 3-fold greater serum half-life, can maintain haemoglobin levels as effectively as rHuEPO in anaemic patients with chronic renal failure and do so with less frequent dosing. We investigated the ability of NESP to safely increase haemoglobin levels of anaemic patients with non-myeloid malignancies not receiving chemotherapy. NESP was administered under the supervision of a physician at doses of 0.5, 1.0, 2.25 or 4.5 mcg kg(-1)wk(-1)for a maximum of 12 weeks. This report includes 89 patients completing the study by November 2000. NESP was well tolerated, with no reported dose-limiting toxicities or treatment-related severe adverse events. Increasing doses of NESP corresponded with increased efficacy. The percentage (95% confidence interval) of patients responding ranged from 61% (42%, 77%) in the 1.0 mcg kg(-1)wk(-1)group to 83% (65%, 94%) in the 4.5 mcg kg(-1)wk(-1)group.

Myelodysplastic syndrome at a large tertiary care community hospital: analysis according to the international prognostic scoring system.

The outcome of patients diagnosed myelodysplastic syndromes (MDS) between 1990 and 1997 from William Beaumont Hospital (WBH) was analyzed according to the International Prognostic Scoring System (IPSS) risk categorization. A retrospective study of 195 MDS patients wa s performed. Seventy-nine patients with MDS, in whom a karyotype was obtained and with an adequate follow-up were included in the final analysis. Cases of proliferative CMML (WBC > 12x10(9)/l) were excluded from the study. The overall median survival was 3.1 years, and median survival stratified by IPSS was 3.4, 4.1 and 0.5 years for the INT-1, INT-2 and high risk group and not yet reached for the low risk group. The overall survival by IPSS subcategorization were 6.88, 5.29, 5.30 and 2.12 years for the low, INT-1, INT-2, and high risk groups respectively. Cytogenetics were significant in predicting the overall survival. The IPSS score stratified patients into risk categories for development of AML. The risk of development into AML was 8, 8, 33 and 54% for the low, INT-1, INT-2 and high risk groups, respectively. We conclude that IPSS score can be useful in predicting survival and AML evolution in some MDS patients.

Paravertebral muscle metastases as imaged by magnetic resonance venography: a brief report.

Paraspinal muscle metastasis as initially suggested by an electromyographic pattern of isolated posterior primary ramus denervation and subsequently confirmed by magnetic resonance imaging has been reported. However, despite widespread systemic tumor dissemination, metastases to other skeletal muscle occurs infrequently. Uniquely, the paraspinal muscles are drained by the paravertebral plexus of veins. Valveless and at very low pressures, they communicate directly by collaterals with the portal system. Valsalva maneuvers with sudden increases of pressure within the intra-abdominal and intrathoracic cavities can force venous blood from the systemic circulation into the paravertebral plexus of veins. These same venous surges potentially carry tumor emboli to the vertebrae and/or from the vertebral medulla to the adjacent paravertebral muscle by the venous communicators. The inherent increased vascularity of metastatic tumor relative to the surrounding paraspinal muscle as demonstrated by magnetic venous angiography for the first time now permits earlier confirmation and biopsy of the electromyographic-suspected metastatic lesion. In this reported instance of a magnetic resonance imaging-recognized primary lung metastasis confirmed by magnetic resonance venography, there is the future promise of identifying earlier and smaller lesions by this technique.

Use of tamoxifen for breast cancer: twenty-eight years later.

PURPOSE: The mechanisms of antitumor activity, clinical pharmacology, toxicity, and efficacy of tamoxifen in women with early and advanced breast cancer and the drug's potential role in prevention of breast cancer were reviewed. DESIGN: A comprehensive review of the literature from 1966 to 1994 was conducted; reports were identified using the Cancerline and Medline data bases. RESULTS: The cellular actions of tamoxifen are not completely understood, but it appears that the drug's antiproliferative effects are mediated primarily by inhibition of the activities of estrogen through binding to estrogen receptors (ERs). Disease-free and overall survival rates have been increased in postmenopausal women with ER-positive tumors when tamoxifen has been used as adjuvant therapy (irrespective of nodal status). In premenopausal women, adjuvant therapy with tamoxifen has been associated with prolongation of disease-free survival, but its impact on survival remains to be defined. Tamoxifen is the initial hormonal treatment of choice in both premenopausal and postmenopausal women with ER-positive metastatic disease. Retrospective review of adjuvant therapy studies showed an approximately 39% reduction in the incidence of contralateral primary breast carcinoma in tamoxifen-treated women, which indicates that tamoxifen could have a role in breast cancer prevention. CONCLUSION: The use of tamoxifen has resulted in a substantial modification of breast cancer's natural history, particularly in postmenopausal women. Ongoing clinical trials will examine the effects of tamoxifen therapy on lipids, coagulation proteins, bone, and endometrium, and its effectiveness as an agent in the prevention of breast cancer.

Advances in therapy for hairy cell leukemia. A review.

BACKGROUND: Hairy cell leukemia (HCL) is a chronic B-cell malignancy, typically seen in middle-aged men, characterized by pancytopenia, splenomegaly, immunologic abnormalities, and morphologically typical neoplastic mononuclear cells in the blood, bone marrow, liver, spleen, and other tissues. Diagnosis is confirmed by demonstration of hairy cells in biopsy specimens from the bone marrow or spleen or in peripheral blood. The natural history of this lymphoproliferative disorder varies. Patients may die early during the initial phase of therapy; others may require no therapy; and for some, splenectomy alone, without further treatment, may suffice for many years. Recently, the nucleosides pentostatin (2'-deoxycoformycin) (DCF) and 2'-chlorodeoxyadenosine (2-CdA) have been shown to produce greater numbers of durable complete remissions with curative potential in patients with HCL. The treatment options, with emphasis on major therapeutic advances with alpha-interferon, DCF, and 2-CdA, are reviewed in this article. METHODS: Studies on HCL published from 1958 to 1992 were reviewed using the Cancerline and Medline retrieval systems and other bibliographies. RESULTS: Management of HCL has changed in the last decade as a result of three new effective agents: alpha-interferon DCF, and 2-CdA. DCF has produced an overall response rate of 86% and a complete remission rate of 62%. 2-CdA has yielded an overall response rate of 95% and a complete remission rate of 82%. Alpha-interferon has given an overall response rate of 82% and a complete remission rate of 8%. Other agents with limited activities include chlorambucil, cyclophosphamide, cytarabine, vincristine, doxorubicin, and zorubicin hydrochloride. The effects of lithium carbonate, immunotherapy, splenic irradiation, androgens, and leukaphoresis are minimal and transient. CONCLUSIONS: Modern management of HCL with 2-CdA and DCF is now potentially curative rather than palliative in some patients; however, the optimal therapeutic approach remains uncertain. Alpha-interferon has been approved by the Food and Drug Administration as the first-line drug therapy, followed by DCF in non-responding patients. 2-CdA remains an experimental therapy, but its higher response rate and ease of administration may make it the first-line treatment of choice. Additional research into the biology of HCL and further clinical trials are needed to determine the optimal treatment strategy for this disorder. Therefore, the best therapeutic approach at the current time is to include patients with HCL in ongoing clinical trials.

Phase I trial of Taxotere: five-day schedule.

BACKGROUND: Taxotere, a semisynthetic compound structurally related to taxol, has a broad spectrum of activity in murine transplantable tumors; in the B16 melanoma model, it caused a total log cell kill 2.5 times greater than that caused by taxol at equitoxic doses. PURPOSE: We conducted a phase I study of Taxotere (a) to determine its qualitative and quantitative toxic effects and a starting dose for phase II trials, (b) to investigate its clinical pharmacology, and (c) to document its antitumor activity. METHODS: Taxotere was given as a 1-hour infusion at a starting dose of 1 mg/m2 per day for 5 consecutive days. The 5-day course of therapy was repeated every 21 days. Thirty-nine cancer patients with advanced disease were entered in the study; at least three patients were entered at each dose level. Initial dose escalations were planned at 100% increments until biologic activity was observed; subsequent escalations were planned at 50% increments until grade 2 toxicity (the National Cancer Institute's Common Toxicity Criteria) occurred and then at 25% increments until the maximum tolerated dose was established. RESULTS: Thirty-nine patients were entered in the study. Successive dose levels used were 1, 4, 8, 16, 12, and 14 mg/m2 per day. The dose-limiting toxic effects were granulocytopenia and concurrent mucositis. Grade 4 granulocytopenia associated with grade 3 mucositis developed in six of 12 patients treated at a dose of 16 mg/m2 per day, two of 10 treated at 12 mg/m2 per day, and two of eight treated at 14 mg/m2 per day. Because these toxic effects occurred concurrently, all patients so affected developed neutropenic fevers and required hospitalization. Neither cardiac nor neurologic toxic effects were noted. Anti-tumor activity was observed in six patients with ovarian cancer and in one with breast carcinoma. Although pharmacokinetic parameters were consistent between day 1 and day 5 for individual patients, considerable variation existed among those treated at the same dose level. A relationship was observed between the area under the curve for plasma concentration of drug x time (AUC) on day 1 and the percentage decrease in absolute granulocyte counts. CONCLUSION: Granulocytopenia associated with oral mucositis is the dose-limiting toxicity of this schedule. We recommended a starting dose of 14 mg/m2 per day for phase II studies of this 5-day schedule. Dose modifications on days 2-5 based on the day-1 AUC may allow individualized dosing.

Carcinoma of the male breast.

The natural history and current management of carcinoma of the breast in men is reviewed. Articles published from 1942 to 1992 on the natural history, clinical manifestations, diagnosis, and treatment of carcinoma of the breast in men were identified using CANCERLINE and MEDLINE. Carcinoma of the breast affects approximately 1000 men per year in the United States; 300 men per year will die of metastatic disease. The mean age at diagnosis is 59 years. The causes of breast cancer in men are unknown. The most common clinical manifestation of breast cancer in men is a painless, firm subareolar mass or a mass in the upper outer quadrant of the breast. Diagnosis can be confirmed by fine-needle aspiration or surgical biopsy. Infiltrating ductal carcinoma is the predominant histologic type. Treatment is similar to that of women with breast cancer. Men with axillary nodal metastasis should receive adjuvant systemic combination chemotherapy or tamoxifen, or both, after primary surgical treatment. Because most men with carcinoma of the breast have estrogen- and progesterone-receptor-positive tumors, distant metastatic disease should be treated initially with hormonal therapies. The epidemiology, prognostic factors, survival by stage, pattern of metastasis, and response to treatment in men are similar to those in women with breast carcinoma. The data suggest, however, that breast cancers in men are more likely to respond to hormonal manipulation.

Inflammatory breast cancer: a review.

PURPOSE: The natural history of inflammatory breast cancer and the recent advances in its management were reviewed. DESIGN: The English medical literature from 1924 to 1990 was reviewed using the Cancerline and Medline retrieval systems, and through a manual review of bibliographies of identified articles. RESULTS: The majority of patients with inflammatory breast cancer treated only with local therapies died 18 to 24 months after diagnosis. A combined modality approach with chemotherapy, surgery, and radiation therapy has improved disease-free and overall survival rates for inflammatory breast cancer. Approximately 35% to 55% of patients treated with combined modality regimens remain disease-free and alive at 5 years. CONCLUSION: Induction combination chemotherapy administered with radiation therapy, mastectomy, both, or with additional chemotherapy favorably alters the natural history of inflammatory breast cancer. New drug combinations and high-dose chemotherapy with autologous bone marrow support are being evaluated to improve further patient survival.

Outcome of patients with acute myocardial infarction who are ineligible for thrombolytic therapy.

OBJECTIVE: To determine what proportion of patients with acute myocardial infarction are not eligible for thrombolytic therapy and to assess their natural history. DESIGN: Retrospective chart review. SETTING: A large community-based hospital. PATIENTS: All patients with acute myocardial infarction hospitalized during a 27-month period. MEASUREMENTS: Of 1471 patients with acute myocardial infarction, 230 (16%) received thrombolytic therapy according to the protocol and an additional 97 (7%) received nonprotocol thrombolytic therapy, primary coronary balloon angioplasty, or both because of contraindications. The other 1144 patients (78%) did not receive reperfusion therapy. MAIN RESULTS: The patients who did not receive thrombolytic therapy were older, more likely to be women, and more likely to have a history of hypertension, previous myocardial infarction, or chronic angina (all comparisons, P less than 0.002). An average of 1.9 reasons for exclusion were identified per patient among the ineligible patients. Mortality was fivefold higher among ineligible patients (19%; Cl, 16% to 21%) than among protocol-treated patients (4%; Cl, 1% to 6%) (P less than 0.001). In-hospital mortality rates for excluded patients were 28% (Cl, 23% to 32%) in elderly patients (age, greater than 76 years; n = 396); 29% (Cl, 23% to 35%) in patients with stroke or bleeding risk (n = 209); 17% (Cl, 14% to 20%) in patients with delayed presentation (greater than 4 hours after the onset of chest pain; [n = 599]); 14% (Cl, 11% to 16%) in patients with an ineligible electrocardiogram (ECG) (n = 673); and 26% (Cl, 21% to 32%) in patients with a miscellaneous reason for exclusion (n = 243). Independent predictors of increased mortality were: age greater than 76 years, stroke or other bleeding risk, ineligible ECG, or the presence of two or more exclusion criteria. CONCLUSIONS: Thrombolytic therapy is currently used in the United States for only a minority of patients with acute myocardial infarction: those who have low-risk prognostic characteristics.