European Journal of Cancer and Clinical Oncology最新文献

We studied the safety, tolerance, and clinical effects of the combined administration of subcutaneous recombinant human interleukin-2 and interferon alfa-2b in 54 patients with advanced cancer, for whom no effective standard therapy was available. Treatment courses consisted of a 2-day interleukin-2 pulse (14.4–18 million units (MU) m²/day), followed by 3.6 up to 4.8 MU/m²/day, 5 days per week, over 6 consecutive weeks and interferon alfa-2b at 3 up to 6 MU/m², administered two-three times weekly for 6 weeks. Overall, patients received more than 90% of the projected dose of interleukin-2 and interferon alfa-2b, respectively. Of 54 evaluable patients (32 renal cell cancer, 12 melanoma, eight colorectal cancer, one B-cell lymphoma, one Hodgkin's disease), four complete responses occurred in patients with renal cell carcinoma, and a greater than 50% reduction in tumour size (partial response) in six renal cell carcinoma patients and one melanoma patient. Moreover, 21 patients (13 renal carcinoma) had stable disease. The median duration of response was 19 months (range 16–22 months) in complete responders. Clinical responses were associated with a mean peripheral blood eosinophil count of more than 1,000/μL (P < 0.05 versus non-responders). Systemic toxicities included fever, chills, nausea, anorexia, and hypotension limited to WHO grades I and II in more than 80% of patients treated. No treatment-related deaths occurred. This combination of subcutaneously administered recombinant interleukin-2 and interferon alfa-2b has significantly diminished the side effects normally observed with high-dose intravenous recombinant interleukin-2, which requires admission to hospital. It has been shown to induce objective tumour regression in out-patients with progressive metastatic renal cell carcinoma and malignant melanoma.

The scheduling of chemotherapeutic agents may be important in optimising their antitumour actions. This has been explored in non-Hodgkin lymphoma, osteogenic sarcoma and bladder cancer with improved results using intensive, weekly dosing schemas. We began a phase II study of cisplatin, 5-fluorouracil and vinblastine in non-small cell lung cancer (NSCLC) on a weekly schedule. 38 patients with advanced or metastatic NSCLC were entered; 32 are evaluable for response. 11 patients were treated with 5-fluorouracil 1.5 g/m² and vinblastine 4 mg/m² by 24-h continuous infusion, and cisplatin 30 mg/m² over 30 min, 6–8 h after the start of the infusion. Because of prohibitive myelotoxicity, the next 27 patients received 5-fluorouracil 1.2 g/m² and vinblastine 3 mg/m². None had had prior chemotherapy while 6 had had previous radiation therapy. Myelosuppression was the predominant toxic effect. Other side-effects included neuropathy, diarrhoea, mucositis, nausea and vomiting. 32 patients are evaluable for response: there have been 14 partial remissions (44%). Responses have occurred chiefly in lung and lymph nodes. The median survival on this study is 7 months, and responders did not live longer than non-responders. While this regimen is well tolerated by the majority of patients and has a response rate comparable to other active regimens identified in single institution studies, survival does not appear to be enhanced. We conclude that the schedule manipulation described here does not enhance the therapeutic index of these drugs in NSCLC.

This multinational, multicentre study represents the introduction of recombinant interleukin-2 (rIL-2) in Europe. From December 1987 to June 1989, 57 eligible patients with metastatic renal cell cancer were treated with rIL-2 administered as continuous intravenous infusion. 8 out of 51 evaluable patients responded (16%), 2 complete remission (CR) and 6 partial remission (PR). 10 patients had no change (20%). The response duration for CR was 209 and 394+ days. The median response duration for PR was 371 (range 140–506+) days. Dose-limiting grade 3–4 toxicities were hypotension in 52% of the patients, arrhythmia (4%), dyspnoea (8%), creatinine rise (4%), peripheral neurotoxicity (10%) and central neurotoxicity (10%). Toxicities most often recovered solely on interrupted therapy. 2 patients died due to catheter-related septicaemia and one patient died of rIL-2 induced renal failure. The study confirmed the antitumour efficacy of rIL-2 in renal cell cancer. Toxicities were numerous, but manageable by close observation in a normal oncology ward without routine use of an intensive care unit.

Hairy cell leukaemia (HCL) is a chronic progressive disease of predominantly middle-aged men. Alpha interferon has been shown to induce significant responses in HCL patients. With interferon treatment the platelet count normalizes first, followed by the haemoglobin and neutrophil counts. The number of hairy cells in the bone marrow decreases and granulocytic, erythroid and megakaryocytic cells increase. Interferon is well tolerated with the most common side effect being a flu-like syndrome. A number of HCL patients will develop neutralizing antibodies and in these cases the chemotherapeutic agents pentostatin and 2-chlorodeoxyadenosine should be considered. Preliminary results with these agents are promising and further trials are ongoing to confirm their clinical promise.

This paper aims to summarize current experience with alpha interferon and provide direction for future study. There are four areas in which alpha interferon has proven or potential activity: antiviral, premalignant, adjuvant and advanced disease settings. The three main viral diseases in which interferon alfa-2b has been shown to have activity are chronic viral hepatitis, acquired immunodeficiency syndrome, and human papilloma virus infections. In vitro studies suggest that alpha interferon may inhibit transformation of some premalignant conditions into malignant disease; e.g., vaginal intraepithelial neoplasia. In the adjuvant setting, it is possible that a biological response modifier, such as alpha interferon, may have a role in helping the immune system to destroy residual tumour cells following tumour bulk reduction with radiation or chemotherapy. A higher response rate has been seen in patients with small tumour bulk compared to those with large tumour bulk (e.g., malignant melanoma, ovarian carcinoma), and in patients with early, rather than late, disease (e.g., chronic myelogenous leukaemia, hairy cell leukaemia, multiple myeloma, non-Hodgkin's lymphoma). This may be due to efficacy in a small tumour bulk setting or due to an immunoadjuvant role. In advanced disease, the question is how best to exploit the possible synergistic effects between alpha interferon and other therapeutic modalities. The optimum dose, schedule and patient populations for combined treatment have yet to be determined. The major objective of this paper is to determine how best to capitalize upon the current state of knowledge to build for future trials of alpha interferon, and to determine whether the existing data suggest an adjuvant role for interferon after initial tumour regression.

The role of alpha interferon in patients with chronic lymphocytic leukaemia (CLL) has yet to be well established. In studies carried out to date, a significantly higher response rate has been observed in previously untreated patients compared to those who have received prior chemotherapy. Patients with early-stage CLL also respond better than patients with advanced disease. Responses to alpha interferon are transient and complete responses are rare. It is not yet known whether alpha interferon can induce clonal remission, and response is usually measured in terms of the reduction in peripheral blood lymphocyte levels. In one study, a normalization of immunoglobulin levels was observed, and in another there was an increase in the absolute number of granulocytes. Further studies are needed to investigate the role of combined therapy with alpha interferon and cytotoxic agents or other cytokines, and to assess the ability of alpha interferon to prolong response duration after remission induction with chemotherapy. Toxicity is tolerable when alpha interferon is given in a low dose (e.g., 2 million units (MU)/m² three times a week) and low doses have been shown to be as effective as high doses in CLL patients.

Synthetic oligonucleotides can be used to control the expression of specific genes. When targeted to messenger RNAs, oligonucleotides inhibit translation (the antisense strategy). Oligonucleotides can also be targeted to specific sequences of the DNA double helix where they inhibit transcription (the antigene strategy). Both strategies can be applied to control the expression of oncogenes in tumour cells. The mRNAs of several oncogenes have been chosen as targets for antisense oligonucleotides (myc, myb, bc12, abl, ras…). Discrimination between the proto-oncogene and the oncogene can be achieved in the case of ras oncogenes where activation results from point mutations in the coding sequence. Regulatory sequences involved in controlling the transcription of oncogenes can also be used as targets for antigene oligonucleotides (myc, ras).

A phase II trial of chemotherapy in carcinoid and islet cell pancreatic tumours has been conducted with the FAP protocol: 5-fluorouracil 400 mg/m² per day (5-FU) for 3 days, 50 mg/m² doxorubicin on day 2, and 90 mg/m² cisplatin on day 2, repeated every 4 weeks. 24 patients, 20 non-pretreated and 4 pretreated, were included. For non-pretreated patients we observed 1 complete response and 2 partial responses. The response rate was 15% (95% confidence interval 0–31%). No response was observed in the pretreated patients. The toxicity was mainly digestive and haematological with 7 patients experiencing vomiting grade 3 and 3 patients with leucopenia grade 3. We conclude that the FAP protocol is of poor efficiency in endocrine tumours.

To clarify the mechanism by which the luteinising hormone-releasing hormone agonist, buserelin, may have direct effects on breast cancer cells, factors potentially influencing its action have been studied in the MCF-7 breast cancer cell line. Oestradiol and epidermal growth factor (EGF), which stimulate the growth of MCF-7 cells in culture, reversed, at least in part, the inhibitory effects of buserelin. Insulin also abolished growth inhibition. Quantitative effects of buserelin differed according to the batch of fetal calf serum used as media supplement. These data suggest that the direct inhibitory effects of buserelin on breast cancer cells are mediated at least in part by an antagonism of growth-promoting factors.