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© 2002 American Society for Clinical Oncology Phase II Randomized Trial of Temozolomide and Concurrent Radiotherapy in Patients With Brain MetastasesByFrom the Metaxas Cancer Hospital, Piraeus, Greece. Address reprint requests to D. Antonadou, MD, Metaxas Cancer Hospital, 36 Kokinara St, 14562 Kifissia Greece, Piraeus, Greece; email: d_antona{at}hol.gr
PURPOSE: To determine the efficacy, tolerability, and safety of concurrent temozolomide and radiotherapy in patients with previously untreated brain metastases. PATIENTS AND METHODS: Fifty-two patients with brain metastases from solid tumors were randomized to oral temozolomide (75 mg/m2/d) concurrent with 40-Gy fractionated conventional external-beam radiotherapy (2 Gy, 5 d/wk) for 4 weeks versus 40-Gy radiotherapy alone. The group receiving temozolomide and radiotherapy continued temozolomide therapy (200 mg/m2/d) for 5 days every 28 days for an additional six cycles. The primary end points were radiologic response and neurologic symptom evaluation.
RESULTS: The objective response rate was significantly (P = .017) improved in patients receiving temozolomide and radiotherapy versus radiotherapy alone. Among 24 patients assessable for response in the temozolomide group, 23 (96%) of 24 responded, including nine (38%) patients with a complete response and 14 (58%) patients with a partial response. With radiotherapy alone, 14 (67%) of 21 assessable patients responded, including seven (33%) complete responses and seven (33%) partial responses. There was marked neurologic improvement in the group receiving temozolomide, and the proportion of patients requiring corticosteroids 2 months after treatment was lower in the temozolomide group compared with radiotherapy alone (67% v 91%, respectively). Daily temozolomide concurrent with radiotherapy was generally well tolerated; however, grade CONCLUSION: Temozolomide is safe, and a significant improvement in response rate was observed when administered in combination with radiotherapy in patients with previously untreated brain metastases. A larger randomized trial is warranted to verify these results.
BRAIN METASTASES occur in up to 40% of all cancer patients with metastatic disease1 and, in adults, are most frequently associated with primary tumors of the lung and breast and with melanoma. Brain metastases are associated with poor prognosis. The majority of patients suffer debilitating neurologic symptoms, including headaches, focal weakness, cognitive dysfunction, and seizures. For those patients with a single brain lesion, surgery or localized radiosurgery has become an accepted therapeutic option as a result of improvements in imaging and localization techniques,2 and adjuvant whole-brain radiotherapy (WBRT) after surgery has been shown to decrease the rate of recurrence, improve survival, and improve quality of life.3-5 However, solitary metastases are rare; therefore, localized radiation or craniotomy is not a practical consideration for most patients. Most metastases to the brain are supratentorial. The median overall survival for patients with supratentorial metastases is only 3 to 5 months and has not changed in 10 years.6-9 WBRT is the treatment of choice for patients with multiple brain metastases or lesions that are not amenable to surgical resection and results in improvements in specific neurologic symptoms in up to 90% of patients.10 However, WBRT is associated with a number of late complications, including brain atrophy and necrosis, endocrine dysfunction, and dementia.7,10 Although WBRT yields high response rates, response durations are generally short and the gain in survival is typically limited. No significant correlations have been observed between the primary tumor type (eg, breast, colorectal, melanoma, or lung) and survival. Patients with a solitary metastasis appear to have a longer median survival after WBRT, but this has mainly been observed in patient populations with a favorable prognosis,11,12 and is not universally accepted.13 The role of systemic chemotherapy in patients with brain metastases remains undefined. Although reported response rates range from 56% to 82% in patients with primary cancer of the lung and breast,14-16 the associated adverse events were severe. Clearly, a chemotherapeutic agent that is both efficacious and well tolerated would hold great potential for the treatment of patients with brain metastases from solid tumors. Temozolomide is a novel oral alkylating agent with demonstrated activity in primary and recurrent gliomas and metastatic melanoma.17-22 Temozolomide is highly bioavailable after oral administration,23 and it crosses the blood-brain barrier (BBB),24 achieving effective concentrations in the CNS.25,26 Adverse events are typically mild. The primary dose-limiting toxicity is myelosuppression; however, the incidence of grade 3/4 neutropenia and thrombocytopenia is generally less than 10%.17-22 However, unlike many other alkylating agents, this myelosuppression is reversible and noncumulative.27 In recently reported pivotal multicenter, phase II and phase III trials, temozolomide was administered at a dose of 200 mg/m2/d for 5 consecutive days every 28-day cycle.20-22 Furthermore, an extended continuous daily dosing regimen has been developed that is suitable for use in combination with conventional radiotherapy.28 This regimen is well tolerated and results in drug exposure that is more than two-fold greater than can be obtained with the standard 5-day schedule of 200 mg/m2/d every 28-day cycle.28 It has also been suggested that temozolomide may potentiate the cytotoxic effects of radiation.29 The goal of this study was to evaluate the efficacy and safety of continuous daily dosing with temozolomide concurrent with conventional external-beam radiotherapy in patients with previously untreated brain metastases from solid tumors. The primary end points were radiologic response and neurologic symptom evaluation. Secondary end points included overall survival, safety, and tolerability.
Patient Eligibility Patients (  18 years of age) with histologically proven cancer at the primary site (either lung or breast) and from an unknown primary tumor with brain metastases assessable by contrast-enhanced computed tomographic (CT) scan or gadolinium-enhanced magnetic resonance imaging (MRI) were eligible for the study. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status  2; a life expectancy of 3 months; and adequate hematologic, renal, and hepatic function (including absolute neutrophil count 1,500/mm3, platelet count 100,000/mm3, serum creatinine and total serum bilirubin 1.5 times the upper limit of normal, and AST and ALT 3 times the upper limit of normal). Eligible patients must have fully recovered from all ongoing toxicities (except alopecia) resulting from previous therapy, and were also required to have given written informed consent. Any patient who had received prior chemotherapy or radiotherapy for brain metastases, or had any uncontrollable, life-threatening systemic disease was ineligible. Pregnant or lactating women were also ineligible.
Study Design
Treatment
Statistical Methods The primary study end points were radiologic response (assessed by World Health Organization criteria), and neurologic functional status (ie, level I, fully functional; level II, fully functional not able to work; level III, stays in bed and needs help half the time; level IV, requires help all the time). Secondary end points were overall survival, safety, and tolerability. The baseline comparability of the treatment groups was explored with respect to demographic data and other patient characteristics. Patient age and sex were compared with one-way analysis of variance and Pearson’s exact two-sided test, respectively. The duration of RT, total dose, ECOG performance status, and laboratory results were compared with the Wilcoxon rank sum test. Pearson’s exact test was also used to compare histologic diversity, the number of patients with at least one adverse event, and the number of subjects with complete or partial response. Finally, odds ratios and the corresponding 95% confidence intervals were constructed in each group for all categorical variables.
All P values were derived from two-sided, log-rank tests and were not adjusted for prognostic variables. A value of P
Patient Characteristics Between October 1999 and June 2000, 52 patients were randomized, and 48 patients (25 in the TMZ + RT group and 23 in the RT group) completed RT and were assessable for efficacy and safety. Four patients refused treatment, two in each treatment group. The demographics and baseline disease characteristics of the assessable patients are listed in Table 1. The two treatment groups were evenly balanced. Among 25 assessable patients in the TMZ + RT group, 16 (64%) had non–small-cell lung cancer, five (20%) had small-cell lung cancer, and two (8%) had breast cancer; 19 (76%) patients had multiple brain metastases. Among 23 assessable patients in the RT group, 15 (65%) had non–small-cell lung cancer, four (17%) had small-cell lung cancer, and three (13%) had breast cancer; the majority (70%) had multiple brain metastases. Five (20%) of 25 patients in the TMZ + RT and seven (30%) of 23 in the control group had metastases in other organs. The majority of patients in both treatment groups had level I or II neurologic function at baseline. Median follow-up was 4 months.
Response of Brain Lesions to Treatment Forty-five patients were assessable for response. One patient in the TMZ + RT group discontinued further treatment because of disease progression in the lung. In the RT group, one patient died 15 days after the completion of RT, and one patient was lost to follow-up immediately after RT. As shown in Table 2, the objective response rate in the TMZ + RT group (96%) was significantly (P = .017) superior to that achieved with RT alone (67%). Among 24 patients assessable for response in the TMZ + RT group, 23 responded, including nine (38%) patients with a complete response and 14 (58%) patients with a partial response, and the one remaining patient had stable disease. In the RT group, 14 (67%) of 21 assessable patients responded, including seven (33%) complete responses and seven (33%) partial responses. Five (24%) additional patients had stable disease. All responses were evaluated 2 months after the end of radiation treatment and were confirmed 1 month later.
Neurologic Symptom Evaluation The effects of treatment on neurologic functional status (ie, level I to IV as defined in Patients and Methods, under Statistical Methods) are listed in Table 3. The functional status of the patient was assessed by two examiners and was also self-assessed by the patient. A baseline functional assessment before the start of treatment demonstrated that neurologic functional status was well balanced between treatment groups and that the majority of patients had level I and II functional status (Table 1). In the TMZ + RT group, the proportion of patients with level I and II status increased from 80% before treatment to 92% after RT, whereas the proportion of patients with level III status decreased from 20% to 8% (Table 3). In comparison, in the RT group, the proportion of patients with level I and II status increased from 74% to 81%, whereas the proportion of patients with level III status decreased from 26% to 19%.
Another measure of treatment efficacy is the requirement for medication to palliate neurologic symptoms. During treatment, the proportion of patients in each treatment group who required anticonvulsants was similar (48% of patients in the TMZ + RT group compared with 44% in the RT group). However, 2 months after the completion of RT, anticonvulsants were required by 29% of patients in the TMZ + RT group compared with 38% in the RT group. Similarly, 2 months after RT was completed, the proportion of patients in the TMZ + RT group who required corticosteroids decreased from 100% to 67% compared with a decrease from 100% to 91% in the RT group.
Overall Survival
Among 20 patients who died in the TMZ + RT group, 18 (90%) died from systemic disease; among 22 patients who died in the RT group, 19 (86%) died from systemic disease. RT delayed death attributable to neurologic causes.
Safety and Tolerability
The treatment of patients with brain metastases from solid tumors continues to evolve. RT is the current treatment of choice for patients with multiple lesions or inoperable solitary lesions, demonstrating improvements in neurologic function in up to 90% of patients.6 However, WBRT is associated with brain atrophy and necrosis, endocrine dysfunction, and dementia.7,10 Although WBRT is effective with regard to improvement of neurologic symptoms, patients with brain metastases in addition to systemic disease may require additional therapies to achieve meaningful improvements in overall survival. In the present study, the addition of TMZ to RT in patients with brain metastases significantly improved the objective response rate compared with RT alone. Importantly, the addition of TMZ to RT did not diminish the well-documented improvements in neurologic function that can be achieved with RT alone. Indeed, the proportion of patients with improved neurologic function was greater in the TMZ + RT group. The use of corticosteroids, another indicator of treatment efficacy, decreased significantly in the TMZ + RT group, but was nearly static in the RT group. The decision to continue treatment with TMZ was taken after the already effective treatment with this schedule in glioma tumors,30 although tumor histology varies in our study. The rationale was that we had to provide the best quality of radiation therapy, the prolonged schedule, in order to minimize radiation treatment–induced side effects and the six cycles of temozolomide with the aim to consolidate the objective response rate acquired with the combined treatment. Addition of TMZ via the continuous daily dosing regimen concurrent with RT was well tolerated in this study, with no reported grade 3/4 hematologic toxicity. Although cumulative myelosuppression is a well-documented, dose-limiting side effect associated with alkylating agents, only mild to moderate myelosuppression (mainly thrombocytopenia) occurred in a small number of TMZ-treated patients during the postirradiation cycles and was completely reversible and noncumulative. When neutropenia or thrombocytopenia developed, it resolved quickly and resulted in only minor treatment delays up to 1 week. TMZ has an acceptable safety profile in patients with brain metastasis. The objective response rate of 96% achieved in this study with concurrent TNZ and RT compares favorably with other studies of chemoradiotherapy in patients with brain metastases. In a study of small-cell lung cancer patients, combination teniposide and WBRT achieved a response rate of 57%. Although time to progression in the brain was longer (P = .005) in the combination therapy group (compared with teniposide alone), there was no improvement in overall survival.31 Among 18 patients with non–small-cell lung cancer and brain metastases, aggressive treatment with WBRT and vinorelbine, ifosfamide, and cisplatin chemotherapy achieved an objective response rate of 56% in brain lesions.15 Unfortunately, all patients reported grade 4 neutropenia, and the majority of patients (78%) developed neutropenic fever. A similar 50% response rate in brain lesions was also achieved in 30 non–small-cell lung cancer patients treated with cisplatin, ifosfamide, and irinotecan with growth factor support.32 The role of chemotherapy in patients with brain metastases remains controversial, primarily because of the paucity of agents that effectively cross the BBB without causing severe systemic adverse effects.14,15,33 Although there are data suggesting that the BBB is disrupted when brain metastases are present and that chemotherapy can be effective against brain metastases from chemosensitive solid tumors,14,16,34 an agent such as TMZ that can readily cross the BBB may have greater potential in the treatment of brain metastases. Moreover, TMZ could be effective as early front-line therapy when the BBB may be relatively intact. Indeed, in patients with metastatic melanoma without brain metastases at the time of treatment, TMZ may reduce the incidence of metastasis to the CNS.35 Another important consideration when selecting a chemotherapy agent to combine with RT is tolerability. This study demonstrated that administration of TMZ using the continuous daily dosing regimen developed by Brock et al28 is safe and well-tolerated when combined with RT. The total radiation dose of 40 Gy with a daily dose of 2 Gy was chosen in this study with the goal of decreasing the radiation treatment–induced side effects and improving the therapeutic outcome. Unfortunately, it is difficult to demonstrate improvements in survival in these poor-prognosis patients. Despite the fact that response rates were higher in the TMZ + RT group in this study, this did not translate into a substantial survival benefit compared with RT alone, and the majority of patients’ disease progressed at the primary site of disease or developed other metastases (liver). The optimal treatment for patients with brain metastases continues to evolve. The status of extracranial disease is of primary importance when selecting patients for surgery or stereotactic RT that will be followed by WBRT. Even with these treatment options, which are mainly indicated in patients with good performance status, the benefit in survival is limited. The majority of the patients with multiple brain metastases will be treated by WBRT, or by supportive care for those with uncontrolled extracranial disease and level III or IV neurologic status.36 The failure of current treatment modalities to improve survival highlights the need for new treatment options, such as the combination of WBRT with agents such as TMZ, which we have shown significantly improved the response rate, improved functional status, decreased corticosteroid use, and may ultimately improve survival. However, larger randomized trials will be needed to determine the impact of this regimen on survival. In a large review of 1,292 patients to define the prognostic factors in patients with brain metastases, Lagerwaard et al37 concluded that the three strongest prognostic factors are performance status, response to steroids, and evidence of systemic disease. There was no effect of histology or distribution of brain metastases on clinical outcome in patients with primary lung cancer. Thus, for clinical trials of combined-modality treatment with WBRT plus new chemotherapy agents such as TMZ, these prognostic factors should be used to select the patient population that is most likely to benefit from this treatment approach. In summary, the objective response rate of 96% achieved with the combination of TMZ and RT is substantially higher than that previously reported for any other chemoradiotherapy regimen. Despite the increased response rate, given the observation that the majority (76%) had multiple brain metastases, a factor known to correlate with poor prognosis,38 the symptomatic improvement was not significantly enhanced and survival remains poor in both groups. The results of this randomized phase II study support the efficacy and safety of TMZ and RT in the treatment of patients with previously untreated brain metastases from a variety of solid tumors and need to be confirmed in a phase III randomized trial.
We thank Stacey Paloudis for her support and Alexandros Sagriotis for the statistical analysis.
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24. Baker SD, Wirth M, Statkevich P, et al: Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer. Clin Cancer Res 5: 309-317, 1999 25. Patel M, McCully C, Godwin K, et al: Plasma and cerebrospinal fluid pharmacokinetics of temozolomide. Proc Am Soc Clin Oncol 14: 461a, 1995 (abstr 1485) 26. Agarwala S, Reyderman L, Statkevich P, et al: Pharmacokinetic study of temozolomide penetration into CSF in a patient with dural melanoma. Ann Oncol 9: 138a, 1998 (suppl 4, abstr 659) 27. Brada M, Judson I, Beale P, et al: Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies. Br J Cancer 81: 1022-1030, 1999[CrossRef][Medline]
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31. Postmus PE, Haaxma-Reiche H, Smit EF, et al: 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 Group. J Clin Oncol 18: 3400-3408, 2000 32. Fujita A, Fukuoka S, Takabatake H, et al: Combination chemotherapy of cisplatin, ifosfamide, and irinotecan with rhG-CSF support in patients with brain metastases from non-small cell lung cancer. Oncology 59: 291-295, 2000[CrossRef][Medline] 33. Levin VA, Leibel SA, Gutin PH: Neoplasms of the central nervous system, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA, Lippincott-Raven, 1997, pp 2022-2082 34. Minotti V, Crino L, Meacci ML, et al: Chemotherapy with cisplatin and teniposide for cerebral metastases in non-small cell lung cancer. Lung Cancer 20: 93-98, 1998[CrossRef][Medline] 35. Summers Y, Middleton MR, Calvert H, et al: Effects of temozolomide (TMZ) on central nervous system (CNS) relapse in patients with advanced melanoma. Proc Am Soc Clin Oncol 18: 531a, 1999 (abstr 2048) 36. Cappuzzo F, Mazzoni F, Maestri A, et al: Medical treatment of brain metastases from solid tumours. Forum (Genova) 10: 137-148, 2000[Medline] 37. Lagerwaard FJ, Levendag PC, Nowak PJ, et al: Identification of prognostic factors in patients with brain metastases: A review of 1292 patients. Int J Radiat Oncol Biol Phys 43: 795-803, 1999[CrossRef][Medline] 38. Lentzsch S, Reichardt P, Weber F, et al: Brain metastases in breast cancer: Prognostic factors and management. Eur J Cancer 35: 580-585, 1999[CrossRef][Medline] Submitted April 30, 2001; accepted May 28, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
