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© 2000 American Society for Clinical Oncology Treatment of Brain Metastases of Small-Cell Lung Cancer: Comparing Teniposide and Teniposide With Whole-Brain Radiotherapy—A Phase III Study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative GroupFrom the Departments of Pulmonary Diseases and Medical Oncology, University Hospital Vrije Universiteit, Amsterdam, Departments of Neurology and Pulmonary Diseases, University Hospital, Groningen, and Department of Pulmonary Diseases, Academisch Ziekenhuis Dijkzigt, Rotterdam, the Netherlands; Department of Oncology, University Hospital, Gdansk, and Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Ospedale Regionale, Oncologia Medica, Aosta, Italy; Western General Hospital, Edinburgh, Scotland; and European Organization for the Research and Treatment of Cancer Data Center, Brussels, Belgium. Address reprint requests to Pieter E. Postmus, MD, PhD, Department of Pulmonary Diseases, University Hospital Vrije Universiteit, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands; email long{at}azvu.nl
PURPOSE: Approximately 60% of patients with small-cell lung cancer (SCLC) develop brain metastases. Whole-brain radiotherapy (WBRT) gives symptomatic improvement in more than 50% of these patients. Because brain metastases are a sign of systemic progression, and chemotherapy was found to be effective as well, it becomes questionable whether WBRT is the only appropriate therapy in this situation. PATIENTS AND METHODS: In a phase III study, SCLC patients with brain metastases were randomized to receive teniposide with or without WBRT. Teniposide 120 mg/m2 was given intravenously three times a week, every 3 weeks. WBRT (10 fractions of 3 Gy) had to start within 3 weeks from the start of chemotherapy. Response was measured clinically and by computed tomography of the brain. RESULTS: One hundred twenty eligible patients were randomized. A 57% response rate was seen in the combined-modality arm (95% confidence interval [CI], 43% to 69%), and a 22% response rate was seen in the teniposide-alone arm (95% CI, 12% to 34%) (P < .001). Time to progression in the brain was longer in the combined-modality group (P = .005). Clinical response and response outside the brain were not different. The median survival time was 3.5 months in the combined-modality arm and 3.2 months in the teniposide-alone arm. Overall survival in both groups was not different (P = .087). CONCLUSION: Adding WBRT to teniposide results in a much higher response rate of brain metastases and in a longer time to progression of brain metastases than teniposide alone. Survival was poor in both groups and not significantly different.
FOR PATIENTS WITH small-cell lung cancer (SCLC), treatment with combination chemotherapy results in considerable prolongation of life expectancy. However, most patients die of uncontrolled metastatic disease despite an initial impressive response to cytotoxic therapy. Approximately 10% of SCLC patients present with brain metastases at the time of diagnosis, and over 50% will develop symptomatic brain metastases during their remaining lifetime.1,2 The treatment for brain metastases has traditionally been whole-brain radiotherapy (WBRT). In several studies, WBRT was reported to result in a high response rate and/or good clinical improvement.2-9 These studies can be criticized because of their retrospective nature, diverse response criteria, and lack of currently used measurements of tumor size before and after therapy. The efficacy of chemotherapy against brain metastases of SCLC was evaluated in a number of pilot and phase II studies.10-17 There are no formal comparisons of these two treatment modalities for such patients available in the literature. However, in a review evaluating results of both treatment modalities, no major differences could be demonstrated.18 Tumor progression in the brain is not a separate phenomenon but usually an early sign of systemic failure,19 and systemic therapy is often indicated for tumor progression outside the brain, even when a good response is obtained at WBRT.20 Therefore, a direct comparison of WBRT and chemotherapy is impossible; to do this would require a group of patients without tumor outside the brain and only progressing in the brain. To recruit enough patients for such a study would be impossible even in a cooperative group. The phase II study performed by the European Organization for the Research and Treatment of Cancer (EORTC) Lung Cancer Cooperative Group (LCCG) recruited only 20 assessable patients in 6 years.20 Since the majority of SCLC patients become candidates for second-line chemotherapies, it is questionable whether WBRT should still be considered part of the treatment of brain metastases. On the other hand, radiotherapy is an effective local therapy against SCLC. To evaluate the role of WBRT in SCLC patients with tumor progression in the brain and concurrent systemic failure, a randomized phase III study was initiated by the EORTC LCCG comparing the efficacy of single-agent teniposide21 with or without WBRT.
Patient Eligibility Eligibility criteria included the following: (1) histologic or cytologic evidence of SCLC; (2) brain metastases confirmed by contrast-enhanced computed tomography (CT); (3) evidence of extracranial tumor deposits; (4) no previous treatment with either chemotherapy or radiotherapy (prophylactic or therapeutic) for brain metastases; (5) no prior treatment with teniposide; (6) age less than 76 years; and (7) informed consent. Patients with uncontrolled infection, serious nonmalignant disease, and expected difficulty with follow-up were excluded from protocol therapy. The required initial laboratory data included WBC count greater than 3,000/µL, platelet count greater than 100,000/µL, creatinine concentration less than 150 µmol/L, and bilirubin concentration less than 25 µmol/L. Institutional review board approval of this protocol and a signed consent form were required. The pretreatment evaluation consisted of a complete history and physical, a neurologic examination by a neurologist (with neurologic function scored according to the method of Order et al22 ), and CT of the brain with a contrast agent. Extracranial tumor localization was documented with standard investigations, which thereby enabled response evaluation after therapy. Laboratory data included complete blood cell counts and serum chemistry analyses, including measurements of creatinine and bilirubin concentrations.
Treatment WBRT consisted of 30 Gy (midplane dose) in 10 fractions in 2 weeks with parallel opposing fields. Both fields were treated each day. WBRT had to be started within 3 weeks after the start of teniposide and continued during administration of teniposide. All cranial meningeal surfaces, including the anterior, middle, and posterior cranial fossae, were included with a minimum 1 cm margin. Treatment was given with megavoltage equipment with a minimum source-to-skin distance or target-to-skin distance of 80 cm. Corticosteroids (dexamethasone 2 mg, four times) were given during irradiation and tapered off as soon as possible after WBRT. A daily dose of dexamethasone (4 mg/dose, maximum of four doses) or an equipotent dose of another corticosteroid was administered if symptoms were considered to be caused mainly by CT-documented edema surrounding the metastases. The corticosteroid dose had to be reduced to the lowest clinically acceptable level as soon as neurologic signs and symptoms permitted and at least within 2 weeks after the start of chemotherapy.
Study Parameters During Therapy Toxicity was evaluated clinically and by WBC and platelet counts on the day the next chemotherapy course was planned. Toxicity was scored according to the WHO criteria. Nadir blood cell counts were not required by protocol and were left to the judgment of the individual physician. After treatment was stopped, patients were followed regularly until death. The duration of response and survival were measured from the first day of administration of teniposide.
Statistical Considerations
Randomization was done using the minimization technique,23 with patients stratified according to their institution, number of brain metastases (
Response rates were calculated based on all eligible patients and compared using Pearson’s Duration of survival, time to progression, and duration of response (complete and partial responders were considered together) curves were estimated using the Kaplan-Meier technique24 and compared using the log-rank test. Duration of response was defined as the time interval between the date of randomization and the date of disease progression. To adjust for possible prognostic factors, the Cox proportional hazards regression model25 was used. Although the sample size calculation was based on a one-sided type I error, all comparisons were performed using two-sided tests because more patients than expected were accrued and therefore the study would have been overpowered to detect the 3-month survival difference as specified earlier. The main analysis was performed on all eligible patients according to the intent-to-treat principle. The analysis of toxicity was based on the treatment patients actually received.
Patients and Therapy Patients were accrued to the study between 1989 and 1995. Of the 134 patients randomized, 14 (seven patients in each arm) were not eligible. The reasons for ineligibility were as follows: 11 patients had received prior chemotherapy for symptomatic brain metastases, one patient had adenocarcinoma, one patient had no brain metastases, and one patient was more than 75 years old. Characteristics of all eligible patients and their baseline neurologic statuses are listed in Table 1. Their previous therapies are listed in Table 2. The median interval between previous chemotherapy and the diagnosis of brain metastases was 3.5 months (range, 0 to 26 months). Patient characteristics were well balanced between treatment groups.
Details of the therapy administered to the patients entered onto this study are described in Table 3. In the combined-modality arm, six patients completed all 12 courses of protocol therapy, compared with none in the teniposide-only arm. Thirty-nine and 50 patients in the combined-modality and teniposide-only arms, respectively, stopped treatment because of tumor progression. Toxicity was the principal reason for interruption of treatment in five and three patients, respectively, and 17 patients stopped treatment for a variety of reasons, including refusal (n = 9), death due to non–tumor- or –treatment-related causes (n = 4), and unknown reasons (n = 3). These 17 patients were equally divided between the two treatment groups.
Toxicity In general, the toxicities associated with treatment were mild. The predominant form of toxicity was hematologic, leading to dose delays in 45 patients and dose reductions in eight patients. Nonhematologic toxicities were infrequent and included WHO grade 3 or 4 nausea and vomiting in 11% of combined-modality patients and 5% of teniposide-only patients and WHO grade 3 or 4 infection in 4% and 6%, respectively. Other nonhematologic toxicities not exceeding WHO grade 3 were observed in less than 3% of patients per treatment arm and included mucositis, headache, and cutaneous toxicities.
Clinical Response
Based on Eastern Cooperative Oncology Group performance status scoring after two courses, of the 60 patients in the teniposide-only arm, 30 (50%) improved and 10 (17%) remained stable. For the combined-modality arm, the corresponding figures were 28 (47%) and 10 (17%).
Tumor Response
Response outside the brain is also listed in Table 5. In the combined-modality arm, 20 of 60 patients responded, for a response rate of 33% (95% CI, 22% to 47%). The extracranial response rate in the teniposide-only arm was equal to the intracranial response rate, ie, 12 of 60 patients responded, for a response rate of 20% (95% CI, 11% to 32%). As opposed to the intracranial response rates, this difference was not statistically different (P = .099).
Time to Progression and Survival Time to progression in the brain, as assessed by contrast-enhanced brain CT scan, is shown in Fig 1. There was a significant difference in favor of the combined-modality treatment (P = .005). Time to progression outside the brain was not different between the two groups and is shown in Fig 2. The median duration of response was 4.5 months in the teniposide-only arm and 4.2 months in the combined-modality arm. The median survival of all patients was 3.2 months in the teniposide-only arm and 3.5 months in the combined-modality arm. Overall survival was not different between the two groups (P = .087); survival curves are shown in Fig 3.
Prognostic Factor Analysis Univariate analysis (stratifying for treatment) showed that poorer survival was associated with the use of corticosteroids (P = .0411), poor neurologic functioning (P = .0126), and poor performance status (P < .001). A multivariate model for survival was fitted and included the following and other potential prognostic factors: initial neurologic function status, prior chemotherapy, number of prior chemotherapy regimens, number of cycles of chemotherapy, and WHO performance status. The treatment effect was adjusted for these factors but was still not significant (P = .09). WHO performance status was the only variable retained in the final multivariate model at the 5% level of significance. After the WHO performance status was adjusted for, the treatment effect was still not significant (P = .073). Response to treatment inside the brain was analyzed using univariate logistic regression. The following variables were significant at the 5% level: use of corticosteroids (P = .001: use was associated with poorer survival), neurologic functioning (P = .002), performance status (P < .001), time from diagnosis of brain metastases to entry onto the trial (P = .024: shorter time period was associated with a higher probability of response), and treatment (P < .001). The multivariate logistic regression model retained the following variables at the 5% level of significance: use of corticosteroids (P = .017), time from diagnosis of brain metastases to entry onto the trial (P = .022), and treatment (P = .001).
In this randomized study, it is once more demonstrated that the outcome of patients with brain metastases of SCLC is very poor. The main objective of our study, ie, prolongation of survival by the addition of WBRT to single-agent teniposide for such patients, was not met. Although the response rate inside the brain was significantly higher in the combined-modality arm, this was not translated into prolongation of overall survival, due to a high failure rate predominantly at extracranial sites that erased any survival advantage that might have been the result of a better local control of brain metastases. The response rate and survival after treatment with teniposide alone were disappointing, and the extracranial response rates in both arms were not statistically different. One might argue that, as a result of an overly optimistic projection of the treatment effect of WBRT (> 50% increase in survival), the study was improperly powered to assess the true benefit of the combined-modality arm. Indeed, this study looked for a large difference in survival. At the time of study design, it was considered that the additional burden of WBRT would be worthwhile only if it resulted in such an increase. The survival difference shown in this study was an improvement of the median of 0.3 months. One may ask whether this difference is clinically meaningful. Also, looking for smaller differences, eg, a 1-month difference in survival, would have meant the recruitment of an unrealistically large number of patients (at least 498 patients followed until death), given the time frame it took to complete our study and the decreasing number of SCLC patients enrolled onto phase III studies internationally.26
Teniposide alone was selected as the standard arm in this trial because of its reported activity as single-agent15,21 and the previous experience of the EORTC LCCG in a similar group of patients.16 The pretreatment of the majority of patients with etoposide might be important in explaining the low response rate. Results might have been improved by more effective chemotherapy for relapsed SCLC patients, such as carboplatin17 or carboplatin-paclitaxel.27 However, at the time this study was initiated, data on more effective second-line chemotherapy were not yet available. Whether WBRT combined with such chemotherapy leads to improvement in overall survival remains speculative, given the high percentage of patients with metastases in the brain after WBRT in the present study as well as in a recently presented prospective study of WBRT in patients with brain-only metastases of SCLC.20 In both studies, the standard WBRT dose of 10 fractions of 3 Gy was administered. Therefore, a higher dose of WBRT in patients with brain metastases of SCLC might be considered, especially if these patients have a response to second-line chemotherapy of tumor outside the brain. In a retrospective analysis,28 it was shown that an extended course of WBRT (> 45 Gy for > 4 weeks) resulted in a longer survival than a short course (< 30 Gy for Another important point for the convenience of the patient might be a shorter radiation schedule. Hypofractionation is, in general, equally effective, as was found in the study by Priestman et al.30 In a large study in a heterogeneous group of patients with brain metastases of several tumor types, they found a clinically irrelevant, although significant, survival difference (median survival was 84 days for the 10 x 3 Gy schedule, compared with 77 days after 2 x 6 Gy). Whether this result can be extrapolated to patients with SCLC is unknown. Furthermore, if one combines radiotherapy and chemotherapy, especially with radiosensitizing drugs, there is the potential risk of increased toxicity. Despite the fact that objective response rates in the brain were quite dissimilar in the treatment groups studied, the clinical response rates were virtually identical between these groups. No clear explanation for this finding can be put forth, although a dissociation of objective and clinical response is a well-known phenomenon in the neuro-oncologic literature.31 Corticosteroid treatment could not be held responsible. Of the patients assessable after two cycles (n = 88), the clinical improvement of patients receiving corticosteroids (n = 44) was not statistically different from that of patients not receiving dexamethasone (n = 44). These patients were equally distributed to treatment with teniposide alone (n = 45) or teniposide plus WBRT (n = 43, data not shown) The sooner treatment starts the better, as was found in the multivariate analysis for response. Given this finding, starting effective chemotherapy should be considered as well. If patients respond to second-line therapy outside the brain, their otherwise dismal prognosis improves.9 Therefore, optimal treatment of brain metastases is justified. Effective chemotherapy may make their situation to some extent comparable to the circumstances of patients with brain metastases as the single site of documented dissemination.32 In only 60% of the patients randomized for treatment with teniposide and WBRT, chemotherapy was continued after the first response evaluation at 6 weeks after the start of therapy. In the remaining 40% of patients randomized to the combined-modality arm, tumor progression was the most important reason for dropout. Because of the extremely poor prognosis of this subgroup of patients, it is questionable whether WBRT should be given to patients with progressive disease outside the brain that does not respond to second-line chemotherapy, since most patients will die within a few weeks. In this way, second-line chemotherapy, based on today’s standards, could be a method to select the patients who will benefit most from an additional treatment. Currently used, simple prognostic factors, such as performance status and neurologic function, should be taken into consideration as well, before any therapy is offered. Despite the results of combined-modality therapy and the possibility of improving the survival by using more effective chemotherapy in a second-line setting,33 the prognosis for patients with brain metastases of SCLC will probably never become very good. Other ways to prevent the morbidity of symptomatic brain metastases need to be investigated. An obvious approach is the use of prophylactic cranial irradiation. In complete responders after first-line treatment, prophylactic cranial irradiation significantly reduced the number of brain relapses34 and increased overall survival.29 For patients who do not achieve a favorable prognostic outcome after first-line therapy, ie, those without a complete response, a delay in brain metastases becoming symptomatic might be a way to improve their quality of life despite the predictable fatal outcome. In this setting, prophylactic cranial irradiation should be considered as a form of preventive palliation. In conclusion, WBRT added to single-agent teniposide results in a significantly higher objective response rate of brain metastases. Despite this finding, symptomatic improvement is not enhanced and survival remains poor with both teniposide and teniposide plus WBRT. Clearly, more effective chemotherapy regimens are needed to improve these disappointing results.
1. Newman SJ, Hansen HH: Frequency, diagnosis, and treatment of brain metastases in 249 consecutive patients with bronchogenic carcinoma. Cancer 33: 492-496, 1974[Medline] 2. Hirsch FR, Paulson OB, Hansen HH, et al: Intracranial metastases in small cell carcinoma of the lung: Prognostic aspects. Cancer 51: 529-533, 1983[Medline] 3. Nugent JL, Bunn PA, Matthews MJ, et al: CNS metastases in small cell bronchogenic carcinoma: Increasing frequency and changing pattern with lengthening survival. Cancer 44: 1885-1893, 1976 4. Cox JD, Komaki R, Byhardt RW, et al: Results of whole brain irradiation for metastases from small cell carcinoma of the lung. Cancer Treat Rep 64: 957-961, 1980[Medline] 5. Baglan RJ, Marks JE: Comparison of symptomatic and prophylactic irradiation of brain metastases from oat cell carcinoma of the lung. Cancer 47: 41-45, 1981[Medline] 6. Lucas CF, Robinson P, Hoskin PJ, et al: Morbidity of cranial relapse in small cell lung cancer and the impact of radiation therapy. Cancer Treat Rep 70: 565-570, 1986[Medline] 7. Giannone L, Johnson DH, Hande KR, et al: Favorable prognosis of brain metastases in small cell lung cancer. Ann Int Med 106: 386-389, 1987 8. Carmichael J, Crane JM, Bunn PA, et al: Results of therapeutic cranial irradiation in small cell lung cancer. Int J Radiat Oncol Biol Phys 14: 455-459, 1988[Medline] 9. Hagedorn HE, Haaxma-Reiche H, Canrinus AA, et al: Results of whole brain radiotherapy for brain metastases of small cell lung cancer. Lung Cancer 8: 293-300, 1993 10. Kristjansen PG, Hansen HH: Brain metastases from small cell lung cancer treated with combination chemotherapy. Eur J Cancer Clin Oncol 24: 545-549, 1988[Medline] 11. Twelves CJ, Souhami RL, Harper PG, et al: Cerebral metastases in small cell lung cancer respond to systemic chemotherapy. Br J Cancer 61: 147-150, 1990[Medline] 12. Lee JS, Murphy WK, Glisson BS, et al: Primary chemotherapy of brain metastases in small-cell lung cancer. J Clin Oncol 7: 916-922, 1989[Abstract] 13. Postmus PE, Haaxma-Reiche H, Sleijfer DTh, et al: High dose etoposide for brain metastases of small cell lung cancer: A phase II study. Br J Cancer 59: 254-256, 1989[Medline] 14. Viens P, Lagrange JL, Thyss A, et al: Brain metastases of lung cancer: Excessive toxicity of high dose VP 16-213. Eur J Cancer Clin Oncol 24: 1905-1906, 1988[Medline] 15. Giaccone G, Donadio M, Bonardi GM, et al: Teniposide (VM26): An effective treatment for brain metastases of small cell carcinoma of the lung. Eur J Cancer Clin Oncol 24: 629-631, 1988[Medline]
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Arriagada R, Le-Chevalier T, Borie F, et al: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl Cancer Inst 87: 183-190, 1995 Submitted March 23, 1999; accepted May 12, 2000. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
3.0 x 109/L or the platelet count was 
3.0 x 109/L and 
2 test. The logistic regression model was used for both the univariate and multivariate prognostic factor analyses of response rate. The factors studied were previous chemotherapy (yes v no), age (
