Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma

The article by Franciosi et al.,1 who investigated front-line chemotherapy in 116 patients with brain metastases (107 were included in their analysis) treated at 9 different centers in Italy during a period of 6.5 years, merits comment. With appreciable effort the Italian Oncology Group for Clinical Research performed what to their knowledge is one of the largest trials in which chemotherapy was administered as front-line treatment for brain metastases. Cisplatin and etoposide were given for a maximum of six cycles (median, three cycles) to patients not amenable to surgery. Eligibility criteria included no prior treatment for brain metastases, normal bone marrow and renal function, and lack of severe cardiac disease. No restrictions were made with regard to established prognostic factors2, 3 such as performance status, age, or extracranial disease status. Follow-up included routine computed tomography (CT) scans of the brain after the second course and at every other course thereafter. Radiation therapy was allowed after the end of protocol chemotherapy. However, the authors did not provide any information regarding the number of patients receiving radiation therapy or any kind of salvage treatment for progressive brain metastases. As observed in previous clinical trials, the high response rate (complete plus partial remission [cr + pr] in 55% of the patients) of their initial Phase II study was not reproducible in a larger multiinstitutional setting (cr + pr in 38% of patients with brain metastases from breast carcinoma and 30% of patients with brain metastases from nonsmall cell lung carcinoma [nsclc]). Approximately 50% of patients who showed a cr or pr of brain metastases also responded at other sites. Certainly, this study raises important questions with regard to the future management of patients with brain metastases, in particular those with breast and lung carcinoma (including small cell carcinoma [sclc] and nsclc), which were found to be the most common primary tumors in large clinical series.2-5 The authors1 may be able to contribute further to the continuing search for the best treatment strategies by providing more detailed results of their study. Because their chemotherapy regimen was found to be ineffective in eight patients with brain metastases from malignant melanoma (no objective response), the remainder of my comments will focus on patients with breast and lung primary tumors, including sclc. The latter was not included in the study by Franciosi et al.,1 although other groups reported comparable response rates for sclc using, for example, teniposide (cr + pr in 33% of patients).6 Therefore, it appears justified to include sclc in the discussion, which hopefully will contribute to the design of future studies comparing the effects of chemotherapy and radiation therapy. Recently, radiologic response rates of 30–35% have been reported after chemotherapy for brain metastases from both sclc and nsclc.1, 6-8 Summarizing our own data, it could be speculated that slightly higher radiologic response rates may be observed after radiation therapy (cr + pr in >60% of breast carcinoma metastases and 40–50% of squamous cell carcinoma and adenocarcinoma metastases, respectively [the latter included some nonlung primary tumors as well]).4, 9 This holds true when examining the results of 150 lesions, each of which was scored separately,9 as well as results of 144 patients,4 which were evaluated using the same criteria as in the study by Franciosi et al.1 Certainly, this hypothesis can be verified only in a prospective trial because various selection factors may have influenced these differences. It may even be more important to compare clinical response rates and quality-adjusted survival, which are the most important criteria from the patients' point of view. Unfortunately (and comparable to many radiation therapy studies), Franciosi et al.1 did not report any data regarding palliation or quality of life. The same holds true for location of failure (development of new lesions versus progression of treated lesions) and late neurotoxicity. The median survival was approximately 8 months for both breast carcinoma and nsclc patients (1-year survival rates were approximately 33% and 25%, respectively).1 The median time to progression was approximately 4 months and the median duration of response was approximately 8 months in both groups, respectively. Three patients died from toxic events, some of which may have been influenced by additional corticosteroid treatment. Conversely, remission rates and time to progression appear at best to be equivalent to those reported from radiation therapy trials. However, survival data appear to be better, which possibly may be explained by the activity of chemotherapy in extracerebral disease sites (a desirable effect because, e.g., patients with uncontrolled extracranial disease treated with stereotactic radiosurgery had a median survival of only 4.4 months, despite a local control rate of 92% in the brain),5 the administration of salvage therapy, or just different distribution of prognostic factors (e.g., the chemotherapy-related inclusion criteria mentioned earlier usually are not considered in radiation therapy trials). The latter explanation may be supported by the shorter survival times (e.g., 5 months7) reported in other chemotherapy studies. Over the course of >10 years, it increasingly has been discussed that chemotherapy may be effective in the treatment of brain metastases from breast and lung carcinoma.1, 6-8, 10, 11 Active agents also include 5-fluorouracil, cyclophosphamide, and methotrexate, as well as teniposide and carboplatin.6-8, 10, 11 Several recent trials reported chemotherapy-associated death rates of 3–10%.1, 6, 7 This is an important issue regarding the palliative nature of the treatment. Franciosi et al.1 suggested that additional, especially randomized, studies are warranted to compare the results of chemotherapy and radiation therapy. However, this suggestion has been made for several years without actually resulting in a properly designed trial. From my point of view, the authors of the majority of chemotherapy trials missed the opportunity to provide detailed information regarding predictive factors for response, prognostic factors for survival, and the influence of additional radiation therapy as well as various salvage modalities on outcome. This information would be desirable for a rationally designed randomized study to decide for example whether to include patients without extracranial disease or those pretreated with chemotherapy and to choose both a suitable combination of drugs (or different combinations for different primary tumors) and a suitable radiation therapy arm for comparison. The number of patients presented by Franciosi et al.1 as well as the close CT follow-up in their study may provide a basis for more detailed analyses of predictive and prognostic factors than presented in their article, possibly helping us to move this issue further. Carsten Nieder M.D.*, * Department of Experimental, Radiation Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas