Annals of Oncology Advance Access published October 29, 2014
1
Phase II Randomized Study of Whole‐Brain Radiation Therapy with or without Concurrent Temozolomide for Brain Metastases from Breast Cancer K. I. Cao1, N. Lebas2, S. Gerber3, C. Levy4, R. Le Scodan1, C. Bourgier5, J.‐Y. Pierga6, A.
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Department of Radiation Oncology, Institut Curie, Paris, France
2
Department of Statistics, Institut Curie, Paris, France
3
Department of Radiology, Institut Curie, Paris, France
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Department of Radiation Oncology, Centre François Baclesse, Caen, France
5
Department of Radiation Oncology, Institut Gustave Roussy, Villejuif, France
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Department of Medical Oncology, Institut Curie, Paris, France
Correspondence: Dr Youlia M. Kirova, Radiation Oncology Department, Institut Curie, 26, rue d’Ulm, 75005, Paris, France, Phone: 33144324193, Fax: 33144324616, E‐mail address: [email protected]
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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Gobillion2, A. Savignoni2, and Y. M. Kirova1
2 ABSTRACT Background: To improve the therapeutic index of whole‐brain radiation therapy (WBRT) in the treatment of brain metastases from breast cancer, we investigated the efficacy and safety of WBRT combined with temozolomide (TMZ) in this population. Patients and Methods: This phase II multicenter prospective randomized study included patients with newly diagnosed intraparenchymal brain metastases from breast cancer,
30 Gy), with or without concomitant TMZ administered at a dosage of 75 mg/m2/day during the irradiation period. The primary endpoint was objective response rate six weeks after the end of treatment, defined as a partial or complete response on systematic brain MRI (modified WHO criteria). Secondary endpoints were progression‐free survival (PFS) and overall survival (OS), neurologic symptoms, and tolerability. Results: Between February 2008 and November 2010, 100 patients were enrolled in the study (50 in the WBRT + TMZ arm, 50 in the WBRT arm). Median age was 55 years [29 ‐79]. Median follow‐up was 9.4 months [1.0 – 68.1]. Objective responses rates at six weeks were 36% in the WBRT arm and 30% in the WBRT + TMZ arm (NS). In the WBRT arm, median PFS was 7.4 months and median OS was 11.1 months. In the WBRT + TMZ arm, median PFS was 6.9 months and median OS was 9.4 months. Treatment was well tolerated in this arm: the most common ≥ grade 2 acute toxicity was reversible lymphopenia. Conclusion: Whole‐brain radiation therapy combined with temozolomide did not significantly improve local control and survival in patients with brain metastases from breast cancer.
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unsuitable for surgery or radiosurgery. All patients received conformal WBRT (3 Gy x 10 to
3 Key‐words: brain metastases, metastatic breast cancer, whole‐brain radiation therapy, temozolomide Clinicaltrials.gov registration number: NCT00875355
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Key Message: "Brain metastases from breast cancer are a frequent situation. To improve the therapeutic index of whole‐brain radiation therapy, the association with concurrent temozolomide, with radiosensitizing properties, was applied in this phase II randomized study. This combination did not improve brain control among these patients. Multidisciplinary research projects in order to improve their prognosis are urgently needed."
4 BACKGROUND Breast cancer remains the second leading cause of CNS metastases after Non Small Cell Lung Cancer (NSCLC). HER2‐positive and triple‐negative subtypes are especially and independently at increased risk of developing secondary brain lesions (1,2). The improved extracranial disease control rate with progress in systemic therapies explains the higher prevalence of brain metastases (BM), related to the natural history of breast cancer. A diagnosis‐specific
diagnosis and the cancer subtype. This approach helps to take into account the heterogeneity of this population, which is an essential point (3). Surgical resection and radiosurgery are indicated in precise situations and only concern selected patients. In patients with large or multiple lesions (> 4), Whole Brain Radiation Therapy (WBRT) remains standard treatment but with limited efficacy, as the median overall survival is estimated to be less than 6 months (4). New therapeutic approaches are needed to optimize their management. However, some concomitant chemoradiotherapy regimens have been assessed in order to increase the therapeutic index of WBRT. Temozolomide (TMZ) is an oral alkylating agent that crosses the blood‐brain‐barrier with documented radiosensitizing properties. Synergistic effects of radiation therapy and TMZ have been described in vitro and in vivo (5). Main molecular mechanisms of this combination are based on enhanced capacity of double‐stranded breaks in DNA causing failure in DNA repair systems. Several phase II studies have shown interesting brain response rates using WBRT plus concurrent TMZ and a positive impact of this combination on quality of life was reported (6). It should be noted that all these clinical trials
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prognostic scoring system has been proposed for brain metastases according to the primary
5 enrolled patients with BM from various solid cancers. The frequency of BM from breast cancer ranged from 10% to 68.1% depending on the study (7,8). The aim of this study was to assess the efficacy and safety of WBRT with concomitant temozolomide in treatment of BM especially from breast cancer. PATIENTS AND METHODS
We developed a phase II, multicenter, randomized, open‐label study. Three French Cancer Centers participated: Institut Curie (Paris, Saint Cloud), Institut Gustave Roussy (Villejuif), Centre François Baclesse (Caen). Eligible patients were randomly assigned to two arms: the WBRT arm or the WBRT plus concomitant TMZ arm. In accordance with the Helsinki Declaration, the project was approved by the Institut Curie Breast Cancer Study Group and the ethics committee of involved centers in September 2007. The Clinicaltrials.gov registration number was NCT00875355. An independent data safety monitoring board met every six months to ensure quality monitoring. All patients and gave their written informed consent to participate in the study. Patients Eligible women were aged > 18 years with ECOG Performance Status 0 – 2, and had at least one brain lesion from histologically documented primary breast cancer. BM were either unresectable or unsuitable for radiosurgery, or the patient refused surgery. Patients with leptomeningeal metastases or prior cranial irradiation including stereotactic radiosurgery were excluded. Adequate hematologic, renal and hepatic functions were required. Complete eligibility criteria are given in Supplementary data (SD) file Table 1.
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Study design
6 Initial tumor histology and molecular subtype were recorded for each patient. For ER and PR status, a cut‐off of 10% expression on immunochemistry analysis of tumor cells was applied. HER2 overexpression was defined as an immunohistochemistry score of 3 (+) or confirmed by FISH if 2+. All other IHC scores were defined as negative HER2 status. Treatment protocol All patients received hypofractionated conformal WBRT to a dose of 30 Gy in ten equal daily
opposed photon beams. In the WBRT + TMZ arm, oral temozolomide was administered continuously at a dose of 75 mg/m2/day (in a way similar to the prescribed dosage in the treatment of glioblastoma) (9), on an empty stomach each morning during the brain irradiation period also on weekends for a total of 14 days. Preventive oral administration of sulfamethoxazole‐trimethoprim was planned in this arm. No additional doses of TMZ were administered. Corticosteroids and antiepileptic drugs were prescribed at the lowest dosage, when necessary. Antiemetics were prescribed at the physician’s discretion. Patients had not received chemotherapy during the ten days preceding inclusion in the study protocol. The pretreatment assessment was performed within ten days of registration and included a complete clinical examination (medical history, physical examination) and laboratory tests (Complete Blood Count with platelets, creatinine, liver function tests with bilirubin, ALT, AST, ɣGT). A weekly medical consultation was required for each patient during the treatment period. Patients in the WBRT + TMZ arm were closely monitored for hematologic toxicity with twice weekly blood counts. Acute toxicities were reported using the NCI CTCAE v3 (Common Terminology Criteria for Adverse Events). Additional consultations were performed as necessary. If any ≥ grade II hematotoxicity was observed, temozolomide was immediately and definitely discontinued in the WBRT + TMZ arm.
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fractions, given five days a week. WBRT was delivered using a linear accelerator, with two
7 Assessment endpoints and follow‐up The primary endpoint of this study was the objective response rate (ORR) six weeks after the end of treatment, defined as complete or partial response on systematic gadolinium‐ enhanced brain MRI (magnetic resonance imaging) according to modified World Health Organization (WHO) criteria. MRI could be replaced by CT brain imaging when necessary. The required brain MRI sequences were T1, T2 and gadolinium‐enhanced T1 (axial slices).
dimensional) reconstruction. A measurable lesion was defined as a lesion with a diameter of at least 1 cm. Modified WHO criteria define four types of response: complete (100%), partial (50‐99%), stable disease and progression. A 2D method was used to measure brain lesions in this study. It included the two largest axial perpendicular diameters of each lesion, including its gadolinium enhancement but excluding peripheral edema. For each patient, measures could be recorded for up to five target lesions. All brain imaging examinations were reviewed by one blinded radiologist. Secondary survival endpoints were overall progression‐free survival (PFS) and overall survival (OS). PFS was measured from the date of diagnosis of BM to the date of progression. OS was measured from the date of diagnosis of BM to the date of death resulting from any cause. Toxic effects were also recorded. After the first assessment at six weeks, a longer follow‐up was planned for a maximum of two years (10). Patients were reviewed for neurological symptoms and response (brain MRI) every three months for six months, and then every six months. The last examination was planned at the two‐year follow‐up.
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Additional gadolinium‐enhanced T1 sequences in the coronal plane were used for 3D (three‐
8 Statistical analysis This was a phase II randomized trial and each arm was analyzed independently. A centralized permuted‐blocked randomization process was used. Within each treatment arm, a two‐ stage modified Fleming approach was proposed, allowing the study to be stopped only in the case of insufficient efficacy. The percentage defined in the null hypothesis was 30% and the expected percentage was 50%. Inclusion of 50 patients per arm were necessary to access the
Additional details on methodology are published as Supplementary Data. No comparison test was performed between the two arms concerning the primary endpoint. Statistical analysis was based on intent‐to‐treat analysis. Patients who died or lost to follow‐ up were considered to be non‐responders. The Kaplan‐Meier method was used for survival analysis, survival curves were compared with a log‐rank test. The Cox model was applied to evaluate the impact of adjusted prognostic factors in multivariate analysis. Survival rates and the Hazard Ratio (HR) associated with each prognostic factor were expressed with their Confidence Intervals (CI). Statistical analyses were performed using R software version 2.13.2 (11). RESULTS
Patients
In the first stage, nine partial responses (36%) were observed in each treatment arm, allowing to continue recruiting patients. Overall, 100 patients were enrolled between February 2008 and November 2010: 50 in the WBRT arm and 50 in the WBRT + TMZ arm (SD file Figure 1). Median age was 55 years [range: 29 – 79] and 12 patients were 70 years or older. Forty of the 100 patients had hormone receptor‐positive primary tumors, 33 had
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acceptable response rate of 50% with a power of 93% and with type I error α=0.09.
9 triple‐negative breast cancers (TNBC), and 19 had a HER2‐positive subtype. Median time to diagnosis of BM was 45 months [0 – 274]. The lung was the most common site of extracranial metastases. Patient characteristics are summarized in Table 1. At the initial clinical examination, 37 patients (74%) in the WBRT arm and 44 patients in the WBRT + TMZ arm (88%) reported neurologic symptoms, mostly headaches (46% in the WBRT arm, 54% in the WBRT + TMZ arm).
Primary endpoint: objective response rate
Three patients in the WBRT arm and ten patients in the WBRT + TMZ arm died as a result of tumor progression before the first assessment at six weeks. No treatment‐related toxic effect was documented. Three other patients in the WBRT + TMZ arm did not complete the first assessment. Two patients were lost to follow‐up and one patient discontinued because of tumor progression. Thirty seven patients in the WBRT + TMZ arm and 47 patients in the WBRT arm were therefore assessable for the primary endpoint. The response rate was 36% (n = 18/50) [95% CI=22.9‐50.8] in the WBRT arm versus 30% (n = 15/50) [95% CI=17.9‐44.6] in the WBRT + TMZ arm on intent‐to‐treat analysis. No complete response was documented in either of the two arms. Results are summarized in Table 2. Responses rates by treatment arm and by molecular subtype are provided in SD file Table 2. Survival Median OS was 11.1 months [95% CI 8.3 – 15.3] and 9.4 months [95% CI 7.3 – 13.4] and median PFS was 7.4 months [95% CI 5.3 – 13.1] and 6.8 months [95% CI 4.6 – 8.6] in the WBRT arm and the WBRT + TMZ arm, respectively. These differences in PFS and OS were not statistically significant (Figure 1).
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Follow‐up ended in November 2012. Median follow‐up was 9.4 months [range: 1.0 – 68.1].
10 For information purposes, HER2‐positive cancers had the longest median OS: 16.1 months and 20.2 months in the WBRT arm and the WBRT + TMZ arm, respectively. Median PFS was 15.0 months and 13.1 months, respectively. For HR‐positive cancer, median OS was 9.3 months and 9.4 months, median PFS was 6.7 months and 5.1 months. Interestingly, for TNBC, median OS was 4.9 and 9.2 months in the WBRT arm and the WBRT + TMZ arm. Median PFS was 2.8 months and 8.0 months respectively (SD file Tables 3 and 4).
after 24 months of follow‐up (9 patients in each arm) (SD file Figures 2 and 3). Multivariate analysis showed that HER2‐positive breast cancer subtype treated with trastuzumab was positively associated with OS (HR=0.47; 95% CI=0.23‐0.95]. A PS of 2 at study entry was strongly associated with poor OS and PFS (HR=5.40; 95% CI=2.91‐10.00, and HR=3.73, 95% CI=2.12‐6.58, respectively]. Neurologic symptoms At the six‐week assessment, 22 patients in the WBRT arm (44%) and 12 patients in the WBRT + TMZ arm (24%) experienced neurologic symptoms. Balance disorders were the most common symptoms (12 patients and 5 patients, respectively). No significant difference was observed between the two arms. An improvement in neurologic symptoms was reported by 31 patients in the WBRT arm (62%) and 27 patients in the WBRT + TMZ arm (54%). Safety All patients were assessable for tolerability. No significant difference was observed between the two arms. Tolerability in the WBRT + TMZ arm was good, with mostly grade 1 or 2 toxicity. As expected, hematotoxicity was the most common category of adverse effects in this arm. Grade 3‐4 lymphopenia was observed in 39% of patients and no patient
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More than 50% of patients died during the first ten months. Eighteen patients were still alive
11 experienced ≥ grade 2 thrombocytopenia. Toxicity assessment results are displayed in Table 3. DISCUSSION To our knowledge, this is the first randomized trial to assess the efficacy of the WBRT‐ temozolomide combination for brain metastases from breast cancer. No improvement in the
Temozolomide is an alkylating agent with documented activity in the CNS (9). Six phase II studies have assessed the TMZ and WBRT combination in patients with newly diagnosed BM from various primary cancers (6–8,12–14). Our study population was more homogeneous, as all patients had BM from breast cancer. It is difficult to compare the results of this study with those of previous studies due to the heterogeneity of study populations and treatment protocols. A protracted low‐dose TMZ regimen was mostly used. None of the previously published studies demonstrated any efficacy on OS. Results of the first study by Antonadou et al (7), showing an ORR of 96% in the WBRT + TMZ arm versus 67% in the WBRT arm (p=0.017), were not confirmed in lung cancer in phase III study by the same authors (15). A two‐week treatment schedule with no additional TMZ was used in our study. Gamboa‐ Vignolle et al showed promising results with this practical schedule in a population mostly presenting BM from breast cancer (8). A dose‐dense regimen of TMZ was combined with WBRT at a dose of 30 Gy. The response rate was significantly better in the WBRT + TMZ arm: 78.6% versus 48.1% in the WBRT arm (p=0.019), with a similar difference to that observed in the study by Antonadou et al (7). This response rate was reflected by improved PFS: 11.8 months versus 5.6 months (p=0.005), but with a small sample size.
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control of BM was observed after six weeks of WBRT + TMZ in this population.
12 This study presents a number of limitations. No systematic quality of life and neurocognitive assessment was performed in this phase II exploratory study. The statistical power of the analysis was also decreased by the high proportion of deaths and patients lost to follow‐up before the first radiologic assessment. Several explanations can be proposed for our results. Chemotherapy is active but has limited efficacy on BM due to poor diffusion across the blood‐brain barrier (16). There is no evidence of the efficacy of TMZ as single‐agent therapy
in our study, the radiosensitizing effect of TMZ may be effective but not sufficient to achieve a long‐term satisfactory clinical outcome. When the study was designed in 2007, limited information was available on the role of O6‐methylguanine methyltransferase (MGMT)‐ mediated chemoresistance (19) and MGMT expression analysis was not performed in this study. Several approaches designed to improve the efficacy and safety of WBRT are currently under investigation. Molecular subtype is a prerequisite for personalized treatment for advanced breast cancer. Two phase II studies are assessing the efficacy of WBRT combined with two anti‐HER2 agents, trastuzumab (NCT01363986) and lapatinib (NCT01622868), respectively. Data are still lacking for TNBC. Advances with molecular analysis of breast cancer BM, in comparison with primary breast cancer, could provide new therapeutic targets (20). Conclusion Brain metastases, a cause of significant morbidity and poor prognosis, remain a turning point in the cancer process. The combination of WBRT plus temozolomide did not improve local control of brain metastases from breast cancer in this study. Based on these findings, this combination cannot be recommended. Further investigations are needed to improve the management of these patients.
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in advanced breast cancer with BM (17,18). Although there were some long‐term survivors
13 ACKNOWLEDGMENTS We would like to acknowledge the following investigators who also participated in this trial (provision of study materials and patients): A. Fourquet (MD), A. Labib (MD), F. Campana (MD), R. Dendale (MD), B. Asselain (MD), B. De La Lande (MD), M. Bollet (MD), L. Ollivier (MD), H. Marsiglia (MD), P. Cottu (MD), V. Dieras
T. Delozier (MD), D. Allouache (MD), C. Segura (MD), F. Toudic (MD), C. Delcambre (MD), O. Switsers (MD), J.M. Ollivier (MD), S. Heymann (MD), V. Mosseri (MD), S. Armanet, A. Blondel, G. Tchtchat, C. Gautier. Special thanks to Schering Plough, France. FUNDING This work was supported by Schering Plough, France. No grant support received. DISCLOSURE The authors have declared no conflicts of interest.
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(MD), T. Dorval (MD), L. Mignot (MD), S. Scholl (MD), V. Laurence (MD), V. Marchand (MD),
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lung cancer and breast cancer patients with brain metastases. Cancer. November 1, 2008;113(9):2524–31. 15. Antonadou D, Coliarakis N, Paraskevaidis M, Athanasiou H, Sarris G, Synodinou M, et al. O‐67 A multi‐institutional trial comparing survival of patients with brain metastases from lung cancer treated with temozolomide plus radiotherapy versus to radiotherapy alone. Lung Cancer. 2003;41:S22–3. 16. Deeken JF, Löscher W. The Blood‐Brain Barrier and Cancer: Transporters, Treatment, and Trojan Horses. Clin Cancer Res. March 15, 2007;13(6):1663–74. 17. Trudeau ME, Crump M, Charpentier D, Yelle L, Bordeleau L, Matthews S, et al. Temozolomide in metastatic breast cancer (MBC): a phase II trial of the National Cancer Institute of Canada – Clinical Trials Group (NCIC‐CTG). Ann Oncol. January 6, 2006;17(6):952– 6. 18. Siena S, Crinò L, Danova M, Del Prete S, Cascinu S, Salvagni S, et al. Dose‐dense temozolomide regimen for the treatment of brain metastases from melanoma, breast cancer, or lung cancer not amenable to surgery or radiosurgery: a multicenter phase II study. Ann Oncol Off J Eur Soc Med Oncol ESMO. March 2010;21(3):655–61. 19. Hegi ME, Liu L, Herman JG, Stupp R, Wick W, Weller M, et al. Correlation of O6‐ Methylguanine Methyltransferase (MGMT) Promoter Methylation With Clinical Outcomes in Glioblastoma and Clinical Strategies to Modulate MGMT Activity. J Clin Oncol. September 1, 2008;26(25):4189–99. 20. Salhia B, Kiefer J, Ross JTD, Metapally R, Martinez RA, Johnson KN, et al. Integrated genomic and epigenomic analysis of breast cancer brain metastasis. PloS One. 2014;9(1):e85448.
16 Figure 1. Kaplan–Meier curves of (A) Overall Survival and (B) Progression‐Free Survival Table 1. Patient characteristics at baseline Table 2. Objective Response Rate (ORR) at six weeks
Table 3. Toxicity assessment
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Table 1. Patient characteristics at baseline Arm WBRT No. of Patients (%) n = 50 (100%)
Arm WBRT + TMZ No. of Patients (%) n = 50 (100%)
57.8 38 - 79
53.6 29 - 78
6 (12) 28 (56) 12 (24) 4 (8)
8 (16) 30 (60) 8 (16) 4 (8)
38 (76) 12 (24) 24.7
33 (66) 17 (34) 24.6
46 (92) 3 (6) 1* (2)
41 (82) 8 (16) 1* (2)
17 (34) 12 (24) 15 (30) 6 (12)
23 (46) 7 (14) 18 (36) 2 (4)
15 (30) 11 (22) 16 (32) 4 (8) 4 (8)
5 (10) 11 (22) 19 (38) 12 (24) 3 (6)
32 (64)
29 (58)
13 (26)
12 (24)
3 (6)
1 (2)
4.6
3.6
2.7
2.6
8 (16) 42 (84) 33 (66) 22 (44) 25 (50)
7 (14) 43 (86) 26 (52) 25 (50) 22 (44)
Age (years) Mean Range ECOG performance status 0 1 2 Unknown Menopausal status Yes No Mean BMI (kg/m²) Primary breast cancer Histological type NSTBC ILC Other Subtype ER+ HER2HER2+ ER- PR- HER2Unknown Initial stage I II III IV Unknown Adjuvant chemotherapy (yes) Adjuvant hormonotherapy (yes) Adjuvant trastuzumab if HER2+ Metastatic breast cancer Mean number of BM Mean number of metastatic sites Metastatic sites Isolated BM Extracranial sites -Lung -Liver -Bone
Mean number of prior CT regimen
2.5
2.9
ECOG, Eastern Oncology Cooperative Group ; NSTBC, Non Specific Type Breast Carcinoma ; ILC, Invasive Lobular Carcinoma ; ER, Estrogen Receptor ; PR, Progesterone Receptor; BM, Brain Metastases; CT, chemotherapy *Mixed type (Non Specific Type and Invasive Lobular Carcinoma) and Mucinous Carcinoma
Table 2. Objective Response Rate (ORR) at six weeks ORR CR PR SD PD Not evaluated
Arm WBRT No of Patients (%) n = 50 0 18 (36) 26 (52) 3 (6) 3 (6)
Arm WBRT + TMZ No of Patients (%) n = 50 0 15 (30) 18 (36) 4 (8) 13 (26)
CR, complete response ; PR, partial response ; SD, stable disease ; PD, progressive disease
Table 3. Toxicity assessment
Type of event
Hematologic Lymphopenia Neutropenia Anemia Thrombopenia Non Hematologic Asthenia Nausea Vomiting Headaches
Arm WBRT
Arm WBRT + TMZ
No of Patients n = 50 (100%)
No of Patients n = 50 (100%)
Grade 2
Grade 3
Grade 4
Any grade ≥2 (%)
Grade 2
Grade 3
Grade 4
Any grade ≥2 (%)
13 0 0 1
9 0 2 0
2 0 0 0
24 (48) 0 2 (4) 1 (2)
14 3 2 2
16 1 2 0
1 0 0 0
31 (62) 4 (8) 4 (8) 2 (4)
6 6 3 9
2 0 1 0
1 0 0 0
9 (18) 6 (12) 4 (8) 9 (18)
7 10 8 5
3 0 0 0
0 0 0 0
10 (20) 10 (20) 8 (16) 5 (10)
1
Phase II Randomized Study of Whole‐Brain Radiation Therapy with or without Concurrent Temozolomide for Brain Metastases from Breast Cancer K. I. Cao1, N. Lebas2, S. Gerber3, C. Levy4, R. Le Scodan1, C. Bourgier5, J.‐Y. Pierga6, A.
1
Department of Radiation Oncology, Institut Curie, Paris, France
2
Department of Statistics, Institut Curie, Paris, France
3
Department of Radiology, Institut Curie, Paris, France
4
Department of Radiation Oncology, Centre François Baclesse, Caen, France
5
Department of Radiation Oncology, Institut Gustave Roussy, Villejuif, France
6
Department of Medical Oncology, Institut Curie, Paris, France
Correspondence: Dr Youlia M. Kirova, Radiation Oncology Department, Institut Curie, 26, rue d’Ulm, 75005, Paris, France, Phone: 33144324193, Fax: 33144324616, E‐mail address: [email protected]
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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Gobillion2, A. Savignoni2, and Y. M. Kirova1
2 ABSTRACT Background: To improve the therapeutic index of whole‐brain radiation therapy (WBRT) in the treatment of brain metastases from breast cancer, we investigated the efficacy and safety of WBRT combined with temozolomide (TMZ) in this population. Patients and Methods: This phase II multicenter prospective randomized study included patients with newly diagnosed intraparenchymal brain metastases from breast cancer,
30 Gy), with or without concomitant TMZ administered at a dosage of 75 mg/m2/day during the irradiation period. The primary endpoint was objective response rate six weeks after the end of treatment, defined as a partial or complete response on systematic brain MRI (modified WHO criteria). Secondary endpoints were progression‐free survival (PFS) and overall survival (OS), neurologic symptoms, and tolerability. Results: Between February 2008 and November 2010, 100 patients were enrolled in the study (50 in the WBRT + TMZ arm, 50 in the WBRT arm). Median age was 55 years [29 ‐79]. Median follow‐up was 9.4 months [1.0 – 68.1]. Objective responses rates at six weeks were 36% in the WBRT arm and 30% in the WBRT + TMZ arm (NS). In the WBRT arm, median PFS was 7.4 months and median OS was 11.1 months. In the WBRT + TMZ arm, median PFS was 6.9 months and median OS was 9.4 months. Treatment was well tolerated in this arm: the most common ≥ grade 2 acute toxicity was reversible lymphopenia. Conclusion: Whole‐brain radiation therapy combined with temozolomide did not significantly improve local control and survival in patients with brain metastases from breast cancer.
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unsuitable for surgery or radiosurgery. All patients received conformal WBRT (3 Gy x 10 to
3 Key‐words: brain metastases, metastatic breast cancer, whole‐brain radiation therapy, temozolomide Clinicaltrials.gov registration number: NCT00875355
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Key Message: "Brain metastases from breast cancer are a frequent situation. To improve the therapeutic index of whole‐brain radiation therapy, the association with concurrent temozolomide, with radiosensitizing properties, was applied in this phase II randomized study. This combination did not improve brain control among these patients. Multidisciplinary research projects in order to improve their prognosis are urgently needed."
4 BACKGROUND Breast cancer remains the second leading cause of CNS metastases after Non Small Cell Lung Cancer (NSCLC). HER2‐positive and triple‐negative subtypes are especially and independently at increased risk of developing secondary brain lesions (1,2). The improved extracranial disease control rate with progress in systemic therapies explains the higher prevalence of brain metastases (BM), related to the natural history of breast cancer. A diagnosis‐specific
diagnosis and the cancer subtype. This approach helps to take into account the heterogeneity of this population, which is an essential point (3). Surgical resection and radiosurgery are indicated in precise situations and only concern selected patients. In patients with large or multiple lesions (> 4), Whole Brain Radiation Therapy (WBRT) remains standard treatment but with limited efficacy, as the median overall survival is estimated to be less than 6 months (4). New therapeutic approaches are needed to optimize their management. However, some concomitant chemoradiotherapy regimens have been assessed in order to increase the therapeutic index of WBRT. Temozolomide (TMZ) is an oral alkylating agent that crosses the blood‐brain‐barrier with documented radiosensitizing properties. Synergistic effects of radiation therapy and TMZ have been described in vitro and in vivo (5). Main molecular mechanisms of this combination are based on enhanced capacity of double‐stranded breaks in DNA causing failure in DNA repair systems. Several phase II studies have shown interesting brain response rates using WBRT plus concurrent TMZ and a positive impact of this combination on quality of life was reported (6). It should be noted that all these clinical trials
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prognostic scoring system has been proposed for brain metastases according to the primary
5 enrolled patients with BM from various solid cancers. The frequency of BM from breast cancer ranged from 10% to 68.1% depending on the study (7,8). The aim of this study was to assess the efficacy and safety of WBRT with concomitant temozolomide in treatment of BM especially from breast cancer. PATIENTS AND METHODS
We developed a phase II, multicenter, randomized, open‐label study. Three French Cancer Centers participated: Institut Curie (Paris, Saint Cloud), Institut Gustave Roussy (Villejuif), Centre François Baclesse (Caen). Eligible patients were randomly assigned to two arms: the WBRT arm or the WBRT plus concomitant TMZ arm. In accordance with the Helsinki Declaration, the project was approved by the Institut Curie Breast Cancer Study Group and the ethics committee of involved centers in September 2007. The Clinicaltrials.gov registration number was NCT00875355. An independent data safety monitoring board met every six months to ensure quality monitoring. All patients and gave their written informed consent to participate in the study. Patients Eligible women were aged > 18 years with ECOG Performance Status 0 – 2, and had at least one brain lesion from histologically documented primary breast cancer. BM were either unresectable or unsuitable for radiosurgery, or the patient refused surgery. Patients with leptomeningeal metastases or prior cranial irradiation including stereotactic radiosurgery were excluded. Adequate hematologic, renal and hepatic functions were required. Complete eligibility criteria are given in Supplementary data (SD) file Table 1.
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Study design
6 Initial tumor histology and molecular subtype were recorded for each patient. For ER and PR status, a cut‐off of 10% expression on immunochemistry analysis of tumor cells was applied. HER2 overexpression was defined as an immunohistochemistry score of 3 (+) or confirmed by FISH if 2+. All other IHC scores were defined as negative HER2 status. Treatment protocol All patients received hypofractionated conformal WBRT to a dose of 30 Gy in ten equal daily
opposed photon beams. In the WBRT + TMZ arm, oral temozolomide was administered continuously at a dose of 75 mg/m2/day (in a way similar to the prescribed dosage in the treatment of glioblastoma) (9), on an empty stomach each morning during the brain irradiation period also on weekends for a total of 14 days. Preventive oral administration of sulfamethoxazole‐trimethoprim was planned in this arm. No additional doses of TMZ were administered. Corticosteroids and antiepileptic drugs were prescribed at the lowest dosage, when necessary. Antiemetics were prescribed at the physician’s discretion. Patients had not received chemotherapy during the ten days preceding inclusion in the study protocol. The pretreatment assessment was performed within ten days of registration and included a complete clinical examination (medical history, physical examination) and laboratory tests (Complete Blood Count with platelets, creatinine, liver function tests with bilirubin, ALT, AST, ɣGT). A weekly medical consultation was required for each patient during the treatment period. Patients in the WBRT + TMZ arm were closely monitored for hematologic toxicity with twice weekly blood counts. Acute toxicities were reported using the NCI CTCAE v3 (Common Terminology Criteria for Adverse Events). Additional consultations were performed as necessary. If any ≥ grade II hematotoxicity was observed, temozolomide was immediately and definitely discontinued in the WBRT + TMZ arm.
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fractions, given five days a week. WBRT was delivered using a linear accelerator, with two
7 Assessment endpoints and follow‐up The primary endpoint of this study was the objective response rate (ORR) six weeks after the end of treatment, defined as complete or partial response on systematic gadolinium‐ enhanced brain MRI (magnetic resonance imaging) according to modified World Health Organization (WHO) criteria. MRI could be replaced by CT brain imaging when necessary. The required brain MRI sequences were T1, T2 and gadolinium‐enhanced T1 (axial slices).
dimensional) reconstruction. A measurable lesion was defined as a lesion with a diameter of at least 1 cm. Modified WHO criteria define four types of response: complete (100%), partial (50‐99%), stable disease and progression. A 2D method was used to measure brain lesions in this study. It included the two largest axial perpendicular diameters of each lesion, including its gadolinium enhancement but excluding peripheral edema. For each patient, measures could be recorded for up to five target lesions. All brain imaging examinations were reviewed by one blinded radiologist. Secondary survival endpoints were overall progression‐free survival (PFS) and overall survival (OS). PFS was measured from the date of diagnosis of BM to the date of progression. OS was measured from the date of diagnosis of BM to the date of death resulting from any cause. Toxic effects were also recorded. After the first assessment at six weeks, a longer follow‐up was planned for a maximum of two years (10). Patients were reviewed for neurological symptoms and response (brain MRI) every three months for six months, and then every six months. The last examination was planned at the two‐year follow‐up.
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Additional gadolinium‐enhanced T1 sequences in the coronal plane were used for 3D (three‐
8 Statistical analysis This was a phase II randomized trial and each arm was analyzed independently. A centralized permuted‐blocked randomization process was used. Within each treatment arm, a two‐ stage modified Fleming approach was proposed, allowing the study to be stopped only in the case of insufficient efficacy. The percentage defined in the null hypothesis was 30% and the expected percentage was 50%. Inclusion of 50 patients per arm were necessary to access the
Additional details on methodology are published as Supplementary Data. No comparison test was performed between the two arms concerning the primary endpoint. Statistical analysis was based on intent‐to‐treat analysis. Patients who died or lost to follow‐ up were considered to be non‐responders. The Kaplan‐Meier method was used for survival analysis, survival curves were compared with a log‐rank test. The Cox model was applied to evaluate the impact of adjusted prognostic factors in multivariate analysis. Survival rates and the Hazard Ratio (HR) associated with each prognostic factor were expressed with their Confidence Intervals (CI). Statistical analyses were performed using R software version 2.13.2 (11). RESULTS
Patients
In the first stage, nine partial responses (36%) were observed in each treatment arm, allowing to continue recruiting patients. Overall, 100 patients were enrolled between February 2008 and November 2010: 50 in the WBRT arm and 50 in the WBRT + TMZ arm (SD file Figure 1). Median age was 55 years [range: 29 – 79] and 12 patients were 70 years or older. Forty of the 100 patients had hormone receptor‐positive primary tumors, 33 had
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acceptable response rate of 50% with a power of 93% and with type I error α=0.09.
9 triple‐negative breast cancers (TNBC), and 19 had a HER2‐positive subtype. Median time to diagnosis of BM was 45 months [0 – 274]. The lung was the most common site of extracranial metastases. Patient characteristics are summarized in Table 1. At the initial clinical examination, 37 patients (74%) in the WBRT arm and 44 patients in the WBRT + TMZ arm (88%) reported neurologic symptoms, mostly headaches (46% in the WBRT arm, 54% in the WBRT + TMZ arm).
Primary endpoint: objective response rate
Three patients in the WBRT arm and ten patients in the WBRT + TMZ arm died as a result of tumor progression before the first assessment at six weeks. No treatment‐related toxic effect was documented. Three other patients in the WBRT + TMZ arm did not complete the first assessment. Two patients were lost to follow‐up and one patient discontinued because of tumor progression. Thirty seven patients in the WBRT + TMZ arm and 47 patients in the WBRT arm were therefore assessable for the primary endpoint. The response rate was 36% (n = 18/50) [95% CI=22.9‐50.8] in the WBRT arm versus 30% (n = 15/50) [95% CI=17.9‐44.6] in the WBRT + TMZ arm on intent‐to‐treat analysis. No complete response was documented in either of the two arms. Results are summarized in Table 2. Responses rates by treatment arm and by molecular subtype are provided in SD file Table 2. Survival Median OS was 11.1 months [95% CI 8.3 – 15.3] and 9.4 months [95% CI 7.3 – 13.4] and median PFS was 7.4 months [95% CI 5.3 – 13.1] and 6.8 months [95% CI 4.6 – 8.6] in the WBRT arm and the WBRT + TMZ arm, respectively. These differences in PFS and OS were not statistically significant (Figure 1).
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Follow‐up ended in November 2012. Median follow‐up was 9.4 months [range: 1.0 – 68.1].
10 For information purposes, HER2‐positive cancers had the longest median OS: 16.1 months and 20.2 months in the WBRT arm and the WBRT + TMZ arm, respectively. Median PFS was 15.0 months and 13.1 months, respectively. For HR‐positive cancer, median OS was 9.3 months and 9.4 months, median PFS was 6.7 months and 5.1 months. Interestingly, for TNBC, median OS was 4.9 and 9.2 months in the WBRT arm and the WBRT + TMZ arm. Median PFS was 2.8 months and 8.0 months respectively (SD file Tables 3 and 4).
after 24 months of follow‐up (9 patients in each arm) (SD file Figures 2 and 3). Multivariate analysis showed that HER2‐positive breast cancer subtype treated with trastuzumab was positively associated with OS (HR=0.47; 95% CI=0.23‐0.95]. A PS of 2 at study entry was strongly associated with poor OS and PFS (HR=5.40; 95% CI=2.91‐10.00, and HR=3.73, 95% CI=2.12‐6.58, respectively]. Neurologic symptoms At the six‐week assessment, 22 patients in the WBRT arm (44%) and 12 patients in the WBRT + TMZ arm (24%) experienced neurologic symptoms. Balance disorders were the most common symptoms (12 patients and 5 patients, respectively). No significant difference was observed between the two arms. An improvement in neurologic symptoms was reported by 31 patients in the WBRT arm (62%) and 27 patients in the WBRT + TMZ arm (54%). Safety All patients were assessable for tolerability. No significant difference was observed between the two arms. Tolerability in the WBRT + TMZ arm was good, with mostly grade 1 or 2 toxicity. As expected, hematotoxicity was the most common category of adverse effects in this arm. Grade 3‐4 lymphopenia was observed in 39% of patients and no patient
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More than 50% of patients died during the first ten months. Eighteen patients were still alive
11 experienced ≥ grade 2 thrombocytopenia. Toxicity assessment results are displayed in Table 3. DISCUSSION To our knowledge, this is the first randomized trial to assess the efficacy of the WBRT‐ temozolomide combination for brain metastases from breast cancer. No improvement in the
Temozolomide is an alkylating agent with documented activity in the CNS (9). Six phase II studies have assessed the TMZ and WBRT combination in patients with newly diagnosed BM from various primary cancers (6–8,12–14). Our study population was more homogeneous, as all patients had BM from breast cancer. It is difficult to compare the results of this study with those of previous studies due to the heterogeneity of study populations and treatment protocols. A protracted low‐dose TMZ regimen was mostly used. None of the previously published studies demonstrated any efficacy on OS. Results of the first study by Antonadou et al (7), showing an ORR of 96% in the WBRT + TMZ arm versus 67% in the WBRT arm (p=0.017), were not confirmed in lung cancer in phase III study by the same authors (15). A two‐week treatment schedule with no additional TMZ was used in our study. Gamboa‐ Vignolle et al showed promising results with this practical schedule in a population mostly presenting BM from breast cancer (8). A dose‐dense regimen of TMZ was combined with WBRT at a dose of 30 Gy. The response rate was significantly better in the WBRT + TMZ arm: 78.6% versus 48.1% in the WBRT arm (p=0.019), with a similar difference to that observed in the study by Antonadou et al (7). This response rate was reflected by improved PFS: 11.8 months versus 5.6 months (p=0.005), but with a small sample size.
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control of BM was observed after six weeks of WBRT + TMZ in this population.
12 This study presents a number of limitations. No systematic quality of life and neurocognitive assessment was performed in this phase II exploratory study. The statistical power of the analysis was also decreased by the high proportion of deaths and patients lost to follow‐up before the first radiologic assessment. Several explanations can be proposed for our results. Chemotherapy is active but has limited efficacy on BM due to poor diffusion across the blood‐brain barrier (16). There is no evidence of the efficacy of TMZ as single‐agent therapy
in our study, the radiosensitizing effect of TMZ may be effective but not sufficient to achieve a long‐term satisfactory clinical outcome. When the study was designed in 2007, limited information was available on the role of O6‐methylguanine methyltransferase (MGMT)‐ mediated chemoresistance (19) and MGMT expression analysis was not performed in this study. Several approaches designed to improve the efficacy and safety of WBRT are currently under investigation. Molecular subtype is a prerequisite for personalized treatment for advanced breast cancer. Two phase II studies are assessing the efficacy of WBRT combined with two anti‐HER2 agents, trastuzumab (NCT01363986) and lapatinib (NCT01622868), respectively. Data are still lacking for TNBC. Advances with molecular analysis of breast cancer BM, in comparison with primary breast cancer, could provide new therapeutic targets (20). Conclusion Brain metastases, a cause of significant morbidity and poor prognosis, remain a turning point in the cancer process. The combination of WBRT plus temozolomide did not improve local control of brain metastases from breast cancer in this study. Based on these findings, this combination cannot be recommended. Further investigations are needed to improve the management of these patients.
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in advanced breast cancer with BM (17,18). Although there were some long‐term survivors
13 ACKNOWLEDGMENTS We would like to acknowledge the following investigators who also participated in this trial (provision of study materials and patients): A. Fourquet (MD), A. Labib (MD), F. Campana (MD), R. Dendale (MD), B. Asselain (MD), B. De La Lande (MD), M. Bollet (MD), L. Ollivier (MD), H. Marsiglia (MD), P. Cottu (MD), V. Dieras
T. Delozier (MD), D. Allouache (MD), C. Segura (MD), F. Toudic (MD), C. Delcambre (MD), O. Switsers (MD), J.M. Ollivier (MD), S. Heymann (MD), V. Mosseri (MD), S. Armanet, A. Blondel, G. Tchtchat, C. Gautier. Special thanks to Schering Plough, France. FUNDING This work was supported by Schering Plough, France. No grant support received. DISCLOSURE The authors have declared no conflicts of interest.
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(MD), T. Dorval (MD), L. Mignot (MD), S. Scholl (MD), V. Laurence (MD), V. Marchand (MD),
14 REFERENCES
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16 Figure 1. Kaplan–Meier curves of (A) Overall Survival and (B) Progression‐Free Survival Table 1. Patient characteristics at baseline Table 2. Objective Response Rate (ORR) at six weeks
Table 3. Toxicity assessment
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17
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Table 1. Patient characteristics at baseline Arm WBRT No. of Patients (%) n = 50 (100%)
Arm WBRT + TMZ No. of Patients (%) n = 50 (100%)
57.8 38 - 79
53.6 29 - 78
6 (12) 28 (56) 12 (24) 4 (8)
8 (16) 30 (60) 8 (16) 4 (8)
38 (76) 12 (24) 24.7
33 (66) 17 (34) 24.6
46 (92) 3 (6) 1* (2)
41 (82) 8 (16) 1* (2)
17 (34) 12 (24) 15 (30) 6 (12)
23 (46) 7 (14) 18 (36) 2 (4)
15 (30) 11 (22) 16 (32) 4 (8) 4 (8)
5 (10) 11 (22) 19 (38) 12 (24) 3 (6)
32 (64)
29 (58)
13 (26)
12 (24)
3 (6)
1 (2)
4.6
3.6
2.7
2.6
8 (16) 42 (84) 33 (66) 22 (44) 25 (50)
7 (14) 43 (86) 26 (52) 25 (50) 22 (44)
Age (years) Mean Range ECOG performance status 0 1 2 Unknown Menopausal status Yes No Mean BMI (kg/m²) Primary breast cancer Histological type NSTBC ILC Other Subtype ER+ HER2HER2+ ER- PR- HER2Unknown Initial stage I II III IV Unknown Adjuvant chemotherapy (yes) Adjuvant hormonotherapy (yes) Adjuvant trastuzumab if HER2+ Metastatic breast cancer Mean number of BM Mean number of metastatic sites Metastatic sites Isolated BM Extracranial sites -Lung -Liver -Bone
Mean number of prior CT regimen
2.5
2.9
ECOG, Eastern Oncology Cooperative Group ; NSTBC, Non Specific Type Breast Carcinoma ; ILC, Invasive Lobular Carcinoma ; ER, Estrogen Receptor ; PR, Progesterone Receptor; BM, Brain Metastases; CT, chemotherapy *Mixed type (Non Specific Type and Invasive Lobular Carcinoma) and Mucinous Carcinoma
Table 2. Objective Response Rate (ORR) at six weeks ORR CR PR SD PD Not evaluated
Arm WBRT No of Patients (%) n = 50 0 18 (36) 26 (52) 3 (6) 3 (6)
Arm WBRT + TMZ No of Patients (%) n = 50 0 15 (30) 18 (36) 4 (8) 13 (26)
CR, complete response ; PR, partial response ; SD, stable disease ; PD, progressive disease
Table 3. Toxicity assessment
Type of event
Hematologic Lymphopenia Neutropenia Anemia Thrombopenia Non Hematologic Asthenia Nausea Vomiting Headaches
Arm WBRT
Arm WBRT + TMZ
No of Patients n = 50 (100%)
No of Patients n = 50 (100%)
Grade 2
Grade 3
Grade 4
Any grade ≥2 (%)
Grade 2
Grade 3
Grade 4
Any grade ≥2 (%)
13 0 0 1
9 0 2 0
2 0 0 0
24 (48) 0 2 (4) 1 (2)
14 3 2 2
16 1 2 0
1 0 0 0
31 (62) 4 (8) 4 (8) 2 (4)
6 6 3 9
2 0 1 0
1 0 0 0
9 (18) 6 (12) 4 (8) 9 (18)
7 10 8 5
3 0 0 0
0 0 0 0
10 (20) 10 (20) 8 (16) 5 (10)
