Epirubicin is the 4' epimer of the anthracycline antibiotic doxorubicin, and has been used alone or in combination with other cytotoxic agents in the treatment of a variety of malignancies. Comparative and noncomparative clinical trials have demonstrated that regimens containing conventional doses of epirubicin achieved equivalent objective response rates and overall median survival as similar doxorubicin-containing regimens in the treatment of advanced and early breast cancer, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), non-Hodgkin's lymphoma, ovarian cancer, gastric cancer and nonresectable primary hepatocellular carcinoma. Recently, dose-intensive regimens of epirubicin have achieved high response rates in a number of malignancies including early and advanced breast cancer and lung cancer. The major acute dose-limiting toxicity of anthracyclines is myelosuppression. In vitro and clinical studies have shown that, at equimolar doses, epirubicin is less myelotoxic than doxorubicin. The lower haematological toxicity of epirubicin, as well as the recent introduction of supportive measures such as colony-stimulating factors, has allowed dose-intensification of epirubicin-containing regimens, which is particularly significant because of the definite dose-response relationship of anthracyclines. Cardiotoxicity, which is manifested clinically as irreversible congestive heart failure and/or cardiomyopathy, is the most important chronic cumulative dose-limiting toxicity of anthracyclines. Epirubicin has a lower propensity to produce cardiotoxic effects than doxorubicin, and its recommended maximum cumulative dose is almost double that of doxorubicin, thus allowing for more treatment cycles and/or higher doses of epirubicin. In summary, dose-intensive epirubicin-containing regimens, which are feasible due to its lower myelosuppression and cardiotoxicity, have produced high response rates in early breast cancer, a potentially curable malignancy, as well as advanced breast, and lung cancers. Furthermore, there is evidence to suggest that improved response rates can improve quality of life in some clinical settings, but whether this leads to prolonged survival has not yet been determined. Recently implemented supportive measures such as colony-stimulating factors, prophylactic antimicrobials and peripheral blood stem cell support may help achieve other potential advantages of dose-intensive epirubicin-containing regimens such as reductions in morbidity and length of hospital admissions.

Epirubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cancer chemotherapy.

Interferon-α (IFNα) is a pleiotropic cytokine with direct and indirect antitumour effects. These include prolongation of the cell cycle time of malignant cells, inhibition of biosynthetic enzymes and apoptosis, interaction with other cytokines, and immunomodulatory and antiangiogenic effects. The first clinical trials in solid tumours used crude preparations of natural IFNα and demonstrated that tumour regressions in solid tumours and haematological malignancies were possible. Since the advent of genetic engineering technology, recombinant (r) IFNα has been widely evaluated in solid tumours. This review discusses the use and potential of rIFNα in solid tumours; the first part focuses on malignant melanoma and metastatic renal cell carcinoma (RCC). In the adjuvant treatment of malignant melanoma, rIFNα has been tested in randomised trials in more than 6000 patients. High-dosage IFNα (≥10MU) prolongs disease-free survival (DFS) but not overall survival (OS). Low-dosage IFNα (≤3MU) has not been shown to prolong DFS or OS, and current data do not support its use outside clinical trials. The latest United Kingdom Co-ordinating Committee on Cancer Research meta-analysis of ten randomised trials that used adjuvant rIFNα has shown that there is a benefit in DFS but not OS. No conclusions can be reached for intermediate-dosage IFNα (5 to 10MU) until the mature results of the European Organization for Research and Treatment of Cancer (EORTC) study 18952 are available. In RCC, current evidence does not support the use of adjuvant IFNα. In metastatic malignant melanoma and RCC, reported response rates to rIFNα are approximately 15%. In a minority of responding patients, however, these responses can be long-standing. In metastatic malignant melanoma, IFNα combined with other cytotoxic agents with or without interleukin-2 has achieved high response rates but has not improved survival. In metastatic RCC, intermediate dosages of rIFNα should be used and therapy should probably be prolonged (≥12 months); response depends on prognostic factors such as good performance status, whereas survival is affected by factors such as low tumour burden. Nephrectomy should therefore be considered in patients with good performance status prior to IFNα immunotherapy in advanced RCC, even in patients with metastatic disease. The toxicity of high-dosage IFNα and the lack of definite benefit on OS with high- or low-dosage IFNα do not support its use outside clinical trials. Data from the ongoing US Intergroup studies, the ongoing EORTC 18991 study (long-term therapy with pegylated IFNα) and mature data from EORTC 18952 (intermediatedosage IFNα) will help establish the role of IFNα as adjuvant therapy in malignant melanoma.

Potential of interferon-alpha in solid tumours: part 1.

The second part of this review examines the use of recombinant interferon-alpha (rIFNalpha) in the following solid tumours: superficial bladder cancer, Kaposi's sarcoma, head and neck cancer, gastrointestinal cancers, lung cancer, mesothelioma and ovarian, breast and cervical malignancies. In superficial bladder cancer, intravesical rIFNalpha has a promising role as second-line therapy in patients resistant or intolerant to intravesical bacille Calmette-Guerin (BCG). In HIV-associated Kaposi's sarcoma, rIFNalpha is active as monotherapy and in combination with antiretroviral agents, especially in patients with CD4 counts >200/mm(3), no prior opportunistic infections and nonvisceral disease. rIFNalpha has shown encouraging results when used in combination with retinoids in the chemoprevention of head and neck squamous cell cancers. It is effective in the chemoprevention of hepatocellular cancer in hepatitis C-seropositive patients. In neuroendocrine tumours, including carcinoid tumour, low-dosage (</=3 MU) or intermediate-dosage (5 to 10 MU) rIFNalpha is indicated as second-line treatment, either with octreotide or alone in patients resistant to somatostatin analogues. Intracavitary IFNalpha may be useful in malignant pleural effusions from mesothelioma. Similarly, intraperitoneal IFNalpha may have a role in the treatment of minimal residual disease in ovarian cancer. In breast cancer, the only possible role for IFNalpha appears to be intralesional administration for resistant disease. IFNalpha may have a role as a radiosensitising agent for the treatment of cervical cancer; however, this requires confirmation in randomised trials. On the basis of current evidence, the routine use of rIFNalpha is not recommended in the therapy of head and neck squamous cell cancers, upper gastrointestinal tract, colorectal and lung cancers, or mesothelioma. Pegylated IFNalpha (peginterferon-alpha) is an exciting development that offers theoretical advantages of increased efficacy, reduced toxicity and improved compliance. Further data from randomised studies in solid tumours are needed where rIFNalpha has activity, such as neuroendocrine tumours, minimal residual disease in ovarian cancer, and cervical cancer. A better understanding of the biological mechanisms that determine response to rIFNalpha is needed. Studies of IFNalpha-stimulated gene expression, which are now feasible, should help to identify molecular predictors of response and allow us to target therapy more selectively to patients with solid tumours responsive to IFNalpha.

Potential of interferon-alpha in solid tumours: part 2.

Despite advances in standard therapies and chemotherapeutic regimens, survival remains poor for patients with lung cancer, the leading cause of cancer death in the world. Consequently, there is substantial interest in identifying potentially exploitable new targets in lung cancer. Over the past 5 years, targeted therapies have become firmly established as therapeutic options in non-small-cell lung cancer. The epidermal growth factor receptor inhibitors and vascular endothelial growth factor receptor inhibitors have proven activity and have rapidly gained widespread use. It is anticipated that the usefulness of additional classes of agents will be established in the near future. Of particular interest and importance are agents that are effective against tumor cells resistant to chemotherapy. Several new classes of agents are currently under investigation, including histone deacetylase inhibitors, DNA-methyltransferase inhibitors, proapoptotic agents, agents that antagonize antiapoptosis molecules, heat shock protein inhibitors, and hypoxia-inducible factor-1α antagonists, among others. Further development of these approaches is awaited with interest.

Targeted Therapy in Non-Small Cell Lung Cancer

Interferons in the Treatment of Solid Tumors

Thirty-four patients with previously untreated advanced non-small-cell lung cancer were treated with a combination of polychemotherapy and recombinant interferon. Chemotherapy consisted of cyclophosphamide, 400 mg/m2, epidoxorubicin, 50 mg/m2, and cisplatin, 40 mg/m2 (CAP) i.v. on day 4; recombinant alpha 2b interferon (r alpha 2b IFN) was given i.m. daily at the dose of 3-5 MU from days 1 to 7. The treatment was repeated every 4 weeks. In the 32 eligible patients the overall response rate was 19.3% (95% C.L. 7.4-37.4%). Non-hematologic toxicity consisted formerly in flulike symptoms and fatigue complained of by 37.5% and 31.2% of patients, respectively, and vomiting reported in 68.7% of patients; grade III-IV myelotoxicity was observed in 12.5% of cases. In no case was the toxicity life threatening. The median overall actuarial survival and progression-free survival were 37 and 20 weeks, respectively. This study indicates that the combination of CAP chemotherapy and r alpha IFN is feasible and active in the treatment of advanced non-small-cell lung cancer.

Combination Chemotherapy and Interferon α2b in the Treatment of Advanced Non-Small-Cell Lung Cancer

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Combination Chemotherapy and Interferon α2b in the Treatment of Advanced Non-Small-Cell Lung Cancer