RESUMO
Purpose To establish whether maintenance lapatinib after first-line chemotherapy is beneficial in human epidermal growth factor receptor (HER) 1/HER2-positive metastatic urothelial bladder cancer (UBC). Methods Patients with metastatic UBC were screened centrally for HER1/HER2 overexpression. Patients who screened positive for HER1/2 and who did not have progressive disease during chemotherapy (four to eight cycles) were randomly assigned one to one to lapatinib or placebo after completion of first-line/initial chemotherapy for metastatic disease. The primary end point was progression-free survival (PFS). Results Between 2007 and 2013, 446 patients with UBC were screened, and 232 with HER1- or HER2-positive disease were randomly assigned. The median PFS for lapatinib and placebo was 4.5 (95% CI, 2.8 to 5.4) and 5.1 (95% CI, 3.0 to 5.8) months, respectively (hazard ratio, 1.07; 95% CI, 0.81 to 1.43; P = .63). The overall survival for lapatinib and placebo was 12.6 (95% CI, 9.0 to 16.2) and 12.0 (95% CI, 10.5 to 14.9) months, respectively (hazard ratio, 0.96; 95% CI, 0.70 to 1.31; P = .80). Discontinuation due to adverse events were similar in both arms (6% lapatinib and 5% placebo). The rate of grade 3 to 4 adverse events for lapatinib and placebo was 8.6% versus 8.1% ( P = .82). Preplanned subset analysis of patients strongly positive for HER1/HER2 (3+ on immunohistochemistry; n = 111), patients positive for only HER1 (n = 102), and patients positive for only HER2 (n = 42) showed no significant benefit with lapatinib in terms of PFS and overall survival ( P > .05 for each). Conclusion This trial did not find significant improvements in outcome by the addition of maintenance lapatinib to standard of care.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/química , Carcinoma de Células de Transição/tratamento farmacológico , Receptores ErbB/análise , Quinazolinas/administração & dosagem , Receptor ErbB-2/análise , Neoplasias da Bexiga Urinária/química , Neoplasias da Bexiga Urinária/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células de Transição/secundário , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Lapatinib , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Quinazolinas/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Neoplasias da Bexiga Urinária/patologiaRESUMO
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-Guérin (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.
Assuntos
Antineoplásicos/uso terapêutico , Interferon-alfa/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto/estatística & dados numéricos , Humanos , Interferon-alfa/genética , Neoplasias/genética , Neoplasias/patologiaRESUMO
Interferon-alpha (IFNalpha) 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 IFNalpha and demonstrated that tumour regressions in solid tumours and haematological malignancies were possible. Since the advent of genetic engineering technology, recombinant (r) IFNalpha has been widely evaluated in solid tumours. This review discusses the use and potential of rIFNalpha in solid tumours; the first part focuses on malignant melanoma and metastatic renal cell carcinoma (RCC). In the adjuvant treatment of malignant melanoma, rIFNalpha has been tested in randomised trials in more than 6000 patients. High-dosage IFNalpha (> or =10MU) prolongs disease-free survival (DFS) but not overall survival (OS). Low-dosage IFNalpha (< or =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 rIFNalpha has shown that there is a benefit in DFS but not OS. No conclusions can be reached for intermediate-dosage IFNalpha (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 IFNalpha. In metastatic malignant melanoma and RCC, reported response rates to rIFNalpha are approximately 15%. In a minority of responding patients, however, these responses can be long-standing. In metastatic malignant melanoma, IFNalpha 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 rIFNalpha 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 IFNalpha immunotherapy in advanced RCC, even in patients with metastatic disease. The toxicity of high-dosage IFNalpha and the lack of definite benefit on OS with high- or low-dosage IFNalpha 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 IFNalpha) and mature data from EORTC 18952 (intermediate-dosage IFNalpha) will help establish the role of IFNalpha as adjuvant therapy in malignant melanoma.
Assuntos
Antineoplásicos/uso terapêutico , Interferon Tipo I/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Interferon-alfa/fisiologia , Neoplasias Renais/tratamento farmacológico , Melanoma/tratamento farmacológico , Neoplasias/patologia , Proteínas RecombinantesRESUMO
PURPOSE: The development of liver metastases from breast cancer is associated with a very poor prognosis, estimated at 4 months median survival. Since treatment with many chemotherapeutic agents is relatively contraindicated, we assessed the safety, tolerability and potential efficacy of combination chemotherapy with vinorelbine and cisplatin (ViP). METHOD: Pilot study in 11 patients with histologically confirmed breast carcinoma, radiological evidence of liver metastases and serum bilirubin greater than 1.5 times the upper limit of normal. Patients received up to six cycles of cisplatin (75 mg/m2) every 21 days and vinorelbine (20 mg/m2) on days 1 and 8 of every 21-day cycle. Measurement of liver lesions was performed on CT scan every 8 weeks into treatment. RESULTS: The most frequently reported adverse event was myelosuppression. Other adverse effects included nausea, vomiting and mild neurotoxicity. Two patients died after one treatment with ViP, one of whom suffered an intracerebral haemorrhage that was possibly treatment-related. Improvement in liver function tests was observed in 10 patients, and mean time to normalization of bilirubin levels was 36 days. Partial responses were documented radiologically in 7 out of 11 patients treated. Median overall survival from trial entry was 6.5 months (range 11-364 days), with one patient alive 13 months from trial entry. CONCLUSION: Normalization of liver function is possible with ViP treatment of metastatic breast cancer, offering the potential to prolong survival. Phase II clinical trials of this regimen in this patient group should include measurement of quality of life in order to assess risk versus benefit.