Pathophysiology, clinical manifestations and supportive care of metastatic brain cancer.

Brain metastases (BrM) are tumours that originate in tissues outside the central nervous system and spread secondarily to involve mainly the brain. The management of patients with cerebral metastases is complex, costly, and in some instances controversial. Furthermore, even in patients with widespread systemic cancer, the symptoms of the disease are often controllable while the symptoms of the BrM may be disabling. The treatment of BrM is one of the few areas of neuro-oncology where real progress has been made in the last twenty years. Moreover, the costs of managing this disease are rising, as therapies become more intensive and the number of patients with BrM increases. Modern neuroradiological imaging techniques, which are able to discover BrM earlier in the course of systemic cancer, and the greater efficacy of specific treatments, which lengthens survival, have increased the prevalence. The aggressive treatment of BrM may add some benefits to the patient, but its excessive cost leads to the necessity for accurate cost-effectiveness analysis. The latter begins with a complete understanding of the disease: its diagnosis, natural history and results of various modalities of treatment. While the development of BrM usually indicates a poor prognosis for the patient, advances in supportive care have made it possible to reverse most of the neurological symptoms and to give patients a meaningful extension of useful life.

Controversies in the management of brain metastases: the role of chemotherapy.

The role of chemotherapy (CT) for brain metastases (BrM) is still controversial. Limited life expectancy and presence of the blood-brain barrier (BBB) have been considered as contraindications for relatively aggressive therapies, such as CT. Nevertheless, more recent studies emphasise the possibility that in addition to historical nitrosoureas, also platinum derivatives, etoposide, teniposide, gemcitabine, irinotecan, topotecan and temozolomide can pass the BBB as they are active against selected BrM. Interaction of cytotoxic agents with other drugs may represent a problem in the treatment of BrM. By far, the most important factor conditioning the response to cytotoxic agents is the chemosensitivity of different tumours. CT proved to be effective in patients with BrM from lung cancer, mainly small cell lung cancer, breast cancer, choriocarcinoma and germ cell tumours. In these malignancies the responses to CT are similar to those observed in other metastatic sites. This observation, confirmed by many studies, contrasts with the theory, emphasised in the past, of the brain as a sanctuary. In fact BBB may be important in protecting normal brain tissue and micrometastases from CT, but not when BrM are symptomatic and clinically evident. The clue to the treatment of chemosensitive tumours is to assess the most active drugs and combinations. Cisplatin and etoposide was confirmed to be the treatment of choice in many situations (BrM from lung and also from breast cancer). Newer drugs are now on study: topotecan and temozolomide seem to be particularly promising (alone or in association with other drugs) in the treatment of various BrM (also from melanoma) and could represent an alternative to more widely-used drugs or as second-line treatments.

The effect of anticonvulsant drugs on blood levels of methotrexate.

The reduced bioavailability of chemotherapeutic agents is one of the reasons that explains the limited efficacy of adjuvant chemotherapy in high grade glioma patients. We report how even the results of high dose sequential chemotherapy can be influenced by antiepileptic drugs.

Vinorelbine is an effective and safe drug for AIDS-related Kaposi's sarcoma: results of a phase II study.

PURPOSE: To assess the safety and efficacy of vinorelbine in patients with AIDS-related Kaposi's sarcoma (KS). PATIENTS AND METHODS: From December 1994 to May 1997, within the Italian Cooperative Group on AIDS and Tumors, we enrolled 36 patients with AIDS-related KS who experienced disease progression after one or more regimens of systemic chemotherapy. Patients were treated with vinorelbine 30 mg/m(2) every 2 weeks by intravenous bolus. RESULTS: Of 35 assessable patients, three (9%) had a clinical complete response and 12 (34%) had a partial remission, for an overall objective response rate of 43% (95% confidence interval, 26% to 61%). For the 15 patients with objective responses, the median duration of response from the beginning of therapy until the development of progression was 176 days, whereas the median progression-free survival and the median survival durations for 35 assessable patients were 151 days and 216 days, respectively. Vinorelbine also induced responses in patients who had become resistant to regimens that included other vinca alkaloids. Overall, vinorelbine was well tolerated. Toxicity, including neurologic toxicity, was mild and reversible. Neutropenia was the most frequent dose-limiting toxicity. CONCLUSION: Vinorelbine is safe and effective in the treatment of patients with advanced KS who have been previously treated with one or more chemotherapy regimens.

Role of brain biopsy in the management of focal brain lesions in HIV-infected patients. Gruppo Italiano Cooperativo AIDS & Tumori.

In this multicenter, retrospective study of 160 brain biopsies in the assessment of HIV-related focal brain lesions, diagnostic sensitivity was acceptable (87%), but the procedure carried considerable morbidity (7.5%) and mortality (3.1%). Moreover, it is not always possible to initiate the changes in therapy indicated by the results, and overall survival remains poor, with a median of 2 months. Criteria for brain biopsy for the diagnosis of focal brain lesions should be redefined to include selected patients for whom a less invasive approach does not yield a definitive diagnosis.

Domiciliary treatment of febrile episodes in cancer patients: a prospective randomized trial comparing oral versus parenteral empirical antibiotic treatment.

Hospitalization and empirical broad-spectrum, intravenous antibiotics are the standard treatment for febrile cancer patients. Recent evidence supports the suggestion that febrile episodes in a low-risk population can be managed successfully in an outpatient setting, but the optimal drug regimen is unknown. In a prospective randomized clinical trial we compared ciprofloxacin 750 mg p.o. twice a day with ceftriaxone 2 g i.v. as a single daily dose for the empiric domiciliary treatment of febrile episodes in low-risk neutropenic and nonneutropenic cancer patients. A total of 173 patients, accounting for 183 febrile episodes, were enrolled in the study. Overall, successful outcomes were recorded for 76 of 93 (82%) febrile episodes in patients who were randomized to the oral regimen and for 68 of 90 (75%) febrile episodes in patients randomized to the i.v. regimen: this difference was not statistically significant. The success rate was similar in all subgroups of patients: neutropenic and nonneutropenic, with documented infection and with fever of unknown origin. There were 3 deaths in the group of patients treated with the parenteral regimen, and two of these were related to treatment failure. Both treatments were well tolerated, and the cost of the oral regimen was lower. This prospective study suggests that domiciliary antibiotic empiric monotherapy is feasible in febrile nonneutropenic or low-risk neutropenic outpatients in whom a bacterial infection is suspected, and that either an oral or a parenteral regimen can be used. A number of factors may influence the choice between an orally and an i.v.-administered antibiotic, but owing to the easier administration and lower cost, the oral regimen seems to be preferable.

Interleukin-2, interferon-alpha and interleukin-2 plus interferon-alpha in renal cell carcinoma. A randomized phase II trial.

BACKGROUND: The purpose of the present study was to investigate the therapeutic effectiveness of interleukin-2 (IL-2) and interferon (IFN), either alone or in combination, in comparable groups of patients affected by advanced renal cell carcinoma (RCC). PATIENTS AND METHODS: In order to limit selection biases, treatment was allocated on a random basis. Patients randomized to IL-2 alone were scheduled to receive eight rlL-2 24-hour i.v. infusion cycles, days 1 to 4, at a daily dose of 18 x 10(6) lU/m2 for a total of 25 weeks. Patients randomized to IFN alone were scheduled to receive rIFN-alpha at a daily dose of 6 x 10(6) IU/m2, days 1, 3 and 5, every week for a total of 52 weeks. Patients randomized to the combination of IFN and IL-2 were given the same drugs at the same daily doses for a total of 24 weeks. Drug dose was modified according to toxicity. RESULTS: Twenty-three percent (95% CI:+/-17.5) of patients treated with IL-2 alone showed an objective response to treatment (9% CR). The corresponding figures in patients treated with IFN alone or IFN plus IL-2 were 9% (95% CI:+/-11.9) and 9% (95% CI:+/-11.9), respectively. Complete responses were observed only in patients treated with IL-2. The median duration of response in the IL-2 arm was 18 months (range, 9.5-24). The duration of the two responses achieved by IFN alone was seven and nine months, respectively. The corresponding figures in the two patients responding to the combination of IFN with IL-2 were 19 and 27 months, respectively. Total IL-2 dose appeared to be a major predictor of response. Only a minority of patients experienced grade 3-4 toxicity, the incidence being higher in those treated with IL-2 or IL-2 plus IFN. CONCLUSIONS: Neither IFN nor IL-2 or the combination of the two appear to be very active in patients with advanced RCC, even when trial entry was restricted to patients with relatively indolent disease. This stresses the need for the development of new approaches.

Anaplastic large cell (CD30/Ki-1+) lymphoma in HIV+ patients: clinical and pathological findings in a group of ten patients.

We compared the clinical and pathological features of 10 HIV+ CD30+ anaplastic large cell lymphoma (ALCL) patients with 28 HIV+ CD30- non-Hodgkin's lymphoma (NHL) patients. The incidence of ALCL among 38 HIV+ systemic NHL patients was 26%. Clinical features were similar in all the HIV-related NHL cases, but ALCL patients seemed to differ from HIV+ CD30- systemic NHL only in the greater frequency of lung tumours (40% v 21%) without concomitant mediastinal mass, bone marrow (75% v 18%) and gastroenteric involvement (40% v 25%). Among the HIV+ ALCL patients, histologic subtypes did not differ in frequency from ALCL in the general population. The B phenotype was predominant (50%) as in other HIV-related NHL. EBV genoma, studied in all HIV+ ALCL patients, was present in 3/10 by in situ hybridization (ISH) and in 5/10 cases using PCR. The clinical course of lymphomas was similar in CD30 positive and negative NHL patients. Overall survival also was short in our series, particularly in HIV+ ALCL (84 v 188 d), probably because of profound immunodepression of the ALCL patients. Our findings suggest that severe immunodepression due to HIV infection determines-more than any other factor-the clinical features of HIV+ ALCL, making them very similar to those of other high-grade systemic HIV+ NHL.

Continuous non chronomodulated infusion of floxuridine in metastatic renal cell carcinoma (MRCC): report of 17 cases.

AIMS AND BACKGROUND: MRCC responds poorly to usual treatments. Recently floxuridine (FUDR) has been administered by chronomodulated infusion, obtaining interesting results. In order to simplify the infusion, we used continuous non chronomodulated infusion. METHODS: We treated 17 patients affected by MRCC with continuous non chronomodulated infusion of FUDR. Toxicity was evaluated according to WHO criteria. Responses were recorded as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). RESULTS: Sixty-four courses of therapy were administered; 15/17 patients, treated with a median of 4 cycles, were evaluable for the response. Only 1 patient showed a grade 3 toxicity (mucositis and diarrhoea); 6 patients showed grade 1-2 diarrhoea; 2 grade 1-2 nausea and vomiting; 1 grade 2 anaemia and thrombocytopenia. No patient obtained CR; 2 PR (lasting 7 and 9 months respectively) and 4 SD (lasting 4,5,6 and 9 months) were observed. CONCLUSIONS: In our experience continuous non chronomodulated infusion of FUDR did not show important general toxicity. The observed responses were not good enough. We think that a better selection of patients (good performance status) and the use of FUDR in an earlier stage of disease, can obtain better results.

Retrospective analysis of 156 cases of metastatic renal cell carcinoma: evaluation of prognostic factors and response to different treatments.

BACKGROUND: Metastatic renal cell carcinoma is a "capricious" tumor. Many prognostic factors have been evaluated, treatment is still controversial, and results are not coincident. METHODS: We reviewed 156 patients with metastatic renal cell carcinoma. Survival from the time of diagnosis was the end point of the study. The influence on survival of age, sex, nephrectomy, disease-free interval, performance status, site and number of metastases was analyzed. Univariate and multivariate analysis were done. Survival according to different therapies was also evaluated. RESULTS: In our study, no nephrectomy, a disease-free interval < 24 months, > 2 metastatic sites and a performance status > 2 proved to be risk factors. According to the number of risk factors, 3 groups of patients were identified (low, intermediate and high risk). We observed 3 kinds of responses to treatments: 1) in untreated patients (n = 48), median overall survival was 6 months, and the 24-month survival rate was 8%; 2) in patients treated with hormone therapy and/or chemotherapy (n = 73), median overall survival was 13 months, and the 24-month survival rate was 24%; 3) in patients treated with interferon and/or interleukin-2 (n = 35), median overall survival was 16 months and the 24-month survival rate was 34%. CONCLUSIONS: Our results are only partially in accordance with those observed by other authors. Risk factors and treatment must be determined in more defined and selected studies.

Possible correlation between some biologic effects and the clinical course in patients treated with continuous infusion of interleukin-2 plus alpha-2 interferon for metastatic renal cell carcinoma.

BACKGROUND: Interleukin-2 therapy is known to cause many biologic effects, which are enhanced by the administration of interferon prior to or immediately after interleukin-2 infusion. Some of these effects could be related to the clinical response. METHODS: Sixteen patients with metastatic renal cell carcinoma were treated with continuous infusion of interleukin-2 plus alpha-2 interferon. Differential leukocyte count and lymphocyte subset evaluation were performed every 3 days during interleukin-2 treatment. At each cycle, the presence of the following antibodies was tested: antithyroid, antinuclear, antiplatelet and antierythrocyte. RESULTS: Fifteen patients were evaluable for response. No complete response was observed. Five patients obtained partial response (33%) and 3 stable disease (20%): 2 of them underwent surgical resection of metastases and obtained complete response. Some of our patients showed a significant increase in eosinophils, CD25+ lymphocytes and antithyroid antibodies. The association of these parameters, calculated with a "score" system, was also related to a better clinical response. CONCLUSIONS: Eosinophils, CD25+ lymphocytes and antithyroid antibodies could have a predictive value for the efficacy of interleukin-2 and alpha-2 interferon therapy in metastatic renal cell carcinoma.

Interferon-alpha is effective in the treatment of HIV-1-related, severe, zidovudine-resistant thrombocytopenia. A prospective, placebo-controlled, double-blind trial.

OBJECTIVE: To determine the effect of interferon-alpha for severe, zidovudine-resistant, HIV-1-related thrombocytopenia. DESIGN: Prospective, randomized, double-blind, placebo-controlled, multicenter, crossover trial. SETTING: Outpatient clinics in Central Northern Italy. PATIENTS: 15 sequential patients positive for HIV-1 with platelet counts less than 25 x 10(9)/L who were refractory to 1 month of full-dose (1000 mg/d) zidovudine. INTERVENTION: Interferon-alpha (3 million units) or placebo (1 mL saline) three times a week subcutaneously for 4 weeks, followed by a 4-week washout period. Patients were then switched to the alternative treatment for the next 4 weeks, followed by another 4 weeks of washout, and they were randomly assigned to either sequence of treatment. Patients received zidovudine (200 mg three times daily) throughout the study. MEASUREMENTS: The primary end point was the platelet count (measured weekly). Secondary end points were qualitative assessment of the platelet response; bleeding time; p24 antigen in serum; CD4/CD8 counts; beta 2-microglobulin in serum; and platelet-associated IgG. RESULTS: Interferon-alpha significantly increased platelet counts in the 12 patients who completed the study (baseline level, 15.6 +/- 7.1 x 10(9)/L; after 4 weeks of interferon-alpha therapy, 82.2 +/- 52.2 x 10(9)/L). The estimated increase in the platelet count after interferon-alpha compared with placebo was 60.0 x 10(9)/L (95% CI, 23.2 to 96.8 x 10(9)/L). The increase was already statistically significant after 3 weeks (66.6 +/- 49.7 x 10(9)/L) and remained significantly increased 1 week after discontinuing interferon-alpha therapy (58.2 +/- 45.0 x 10(9)/L). Placebo did not modify the platelet count. The bleeding time was significantly shortened by interferon-alpha. Four of 12 patients who had more serious alterations of some measures reflecting disease severity did not respond to interferon-alpha. No relevant side effects were observed. CONCLUSIONS: Interferon-alpha is a safe and effective treatment for zidovudine-resistant, HIV-related thrombocytopenia.

Reversible anergy in circulating lymphocytes of cancer patients during interleukin-2 therapy.

Interleukin-2 plays a crucial role in enhancing the antitumor immune response. Clinical trials, mainly in renal cell carcinoma and melanoma patients, have been carried out with encouraging results. Recent reports demonstrated that interleukin-2 therapy may depress the immune response either in vitro or in vivo. We decided to monitor, in nine renal cancer patients, the proliferative responses and the parallel variations in Ca2+ homeostasis of peripheral blood lymphocytes collected before, during and after the first cycle of a 3-day interleukin-2 systemic administration. The proliferative response to phytohemagglutinin or concanavalin A significantly dropped early during interleukin-2 infusion. Consistently, an impairment in mobilizing Ca2+, either from internal stores or via influx from outside, was observed. Results obtained with a mAb-alpha CD3 molecular complex strongly suggested that the TCR/CD3 signal transduction pathway was defective. In contrast, no major variations were observed in the general machinery controlling Ca2+ homeostasis nor in the total Ca(2+)-releasable pool. Patients' lymphocytes, cultured in vitro for 3 days in medium alone, showed an almost complete recovery in their ability to respond to mitogens. In conclusion, we show that interleukin-2 administration in cancer patients induces a reversible state of anergy in circulating lymphocytes, assessed both by the reduction in the proliferative response and the block of the mitogen-activated intracellular Ca2+ signalling.

Thrombotic thrombocytopenic purpura associated with HIV infection: report of two cases.

We report two cases of thrombotic thrombocytopenic purpura (TTP) in advanced stage HIV-positive patients (CD4+ < 0.05 x 10(9)/L). Clinical symptoms were relevant, but their course was not fulminant; the two patients responded to different therapies (plasma or plasma plus plasmapheresis, and steroids), showing rapid improvement in symptoms. One patient remained asymptomatic with zidovudine only, while the other relapsed (probably due to an intercurrent infection). This second person is now asymptomatic on zidovudine plus low doses of steroids.