Strahlenther Onkol 2012 188:910 916 DOI 10.1007/s00066-012-0158-4 Received: 16 May 2012 Accepted: 30 May 2012 Published online: 18. August 2012 Springer-Verlag 2012 D. Rades 1 S.G. Hakim 2 A. Bajrovic 3 J.H. Karstens 4 T. Veninga 5 V. Rudat 6 S.E. Schild 7 1 Department of Radiation Oncology, University of Lubeck 2 Department of Oral and Maxillofacial Surgery, University of Lubeck 3 Department of Radiation Oncology, University Medical Center Hamburg-Eppendorf 4 Department of Radiation Oncology, Medical University Hannover 5 Department of Radiation Oncology, Dr. Bernard Verbeeten Institute, Tilburg 6 Department of Radiation Oncology, Saad Specialist Hospital Al Khobar 7 Department of Radiation Oncology, Mayo Clinic Scottsdale Impact of zoledronic acid on control of metastatic spinal cord compression About 10 years ago, several randomized trials demonstrated that zoledronic acid was effective in reducing the rate of skeletal-related events in patients with bone metastases [4, 5, 6]. In these trials, skeletal-related events included pathologic fracture, metastatic spinal cord compression (MSCC), radiation therapy to bone, and surgery to bone. However, these outcomes filed under skeletal-related events are rather distinct. MSCC and pathological fractures are complications of bone metastasis, whereas radiotherapy and surgery are treatments that may be given for several indications. Radiotherapy may be administered for MSCC, pathological fractures, pain caused by uncomplicated bone metastases, stabilization of osteolytic lesions to avoid pathological fractures, or prophylactic to avoid MSCC if the vertebral column is involved. Therefore, it appears reasonable to perform studies that focus on a single component of skeletalrelated events. This matched-pair analysis is the first study that particularly examined the effect of zoledronic acid on MSCC, which occurs in up to 14% of all cancer patients during the course of their disease. The present study investigated whether the addition of zoledronic acid to radiotherapy could improve control of MSCC. Material and methods Study design The data of 98 patients treated for MSCC between 2006 and 2011 with radiotherapy and zoledronic acid (Zometa ; Novartis Pharma AG, Basel, Switzerland) were retrospectively analyzed. Each patient treated with radiotherapy plus zoledronic acid was matched with 2 patients from a cohort of 2,212 MSCC patients treated with radiotherapy alone between 1996 and 2011. The patients were matched for ten potential prognostic factors: age ( 64 years vs. 65 years; median age 64 years), gender, Eastern Cooperative Oncology Group (ECOG) performance score (ECOG 1 2 vs. ECOG 3 4), type of primary tumor (breast cancer vs. prostate cancer vs. myeloma/lymphoma vs. lung cancer versus other tumors), number of involved vertebrae (1 2 vs. 3), other bone metastases at the time of radiotherapy (no vs. yes), visceral metastases at the time of radiotherapy (no vs. yes), ambulatory status before radiotherapy (not ambulatory vs. ambulatory), time developing motor deficits before radiotherapy (1 7 vs. >7 days), and the radiotherapy regimen (5 fractions of 4 Gy vs. longer-course radiotherapy with 10 fractions of 3 Gy, 15 fractions of 2.5, or 20 fractions of 2 Gy). All of these ten factors should match between the 3 matched patients. Thus, 98 groups of 3 patients met these criteria. These 294 patients had motor deficits due to MSCC of one spinal segment of the thoracic and/or lumbar spine, which had been confirmed by spinal magnetic resonance imaging (MRI). All patients received 12 32 mg/day of dexamethasone until the end of the radiotherapy course. Patient characteristics related to the two treatment groups are summarized in. Tab. 1. Treatment Radiotherapy was performed with linear accelerators. The treatment volume encompassed one normal vertebra above and below the metastatic lesions. A dose of 4 mg of zoledronic acid adjusted for creatinine clearance was administered intravenously over 15 min in 100 ml of hydration solution (either 0.9% sodium chloride or 5% glucose solution) every 3 4 weeks. Serum creatinine was monitored before each administration. Patients were strongly encouraged to take daily oral supplements of 500 mg calcium and 400 IU vitamin D. Of the 98 receiving zoledronic acid, 15 patients (15%) had received zoledronic acid treatment for median 10 months (range 3 34 months) prior to radiotherapy. In 83 patients (85%) zoledronic acid treat- 910 Strahlentherapie und Onkologie 10 2012
Tab. 1 Distribution of the ten potential prognostic factors in the two treatment groups ment was started during or immediately before radiotherapy. Following radiotherapy, zoledronic acid was given for median 9.5 months (range 1 37 months). Investigated endpoints Patients receiving RT alone n (%) 64 years (n=150) 100 (51) 50 (51) 65 years (n=144) 96 (49) 48 (49) Female (n=204) 136 (69) 68 (69) Male (n=90) 60 (31) 30 (31) 1 2 (n=168) 112 (57) 56 (57) 3 4 (n=126) 84 (43) 42 (43) Breast cancer (n=171) 114 (58) 57 (58) Prostate cancer (n=36) 24 (12) 12 (12) Myeloma/lymphoma (n=24) 16 (8) 8 (8) Lung cancer (n=24) 16 (8) 8 (8) Other tumors (n=39) 26 (13) 13 (13) 1 2 (n=63) 42 (21) 21 (21) 3 (n=231) 154 (79) 77 (79) No (n=48) 32 (16) 16 (16) Yes (n=246) 164 (84) 82 (84) No (n=162) 108 (55) 54 (55) Yes (n=132) 88 (45) 44 (45) Not ambulatory (n=60) 40 (20) 20 (20) Ambulatory (n=234) 156 (80) 78 (80) 1 7 days (n=72) 48 (24) 24 (24) >7 days (n=222) 148 (76) 74 (76) Short-course RT (n=66) 44 (22) 22 (22) Longer-course RT (n=228) 152 (78) 76 (78) RT radiotherapy. Patients receiving RT plus zoledronic acid n (%) Both treatment groups were compared for local control of MSCC (absence of an infield recurrence of MSCC in the irradiated region of the spinal cord), overall control of MSCC (freedom from in-field and out-field recurrences of MSCC), and survival. Recurrence was defined either as recurrence of motor deficits if therapy led to improvement in motor function or as progression of motor deficits if therapy resulted in no change. Because local control of MSCC was a major endpoint of the present study, only patients who experienced improvement or no further progression of motor function were included. The diagnosis of a recurrence of MSCC was confirmed with MRI. Freedom from recurrence and survival were calculated from the last day of radiotherapy. Statistical considerations Local control, overall control and survival rates were calculated with the Kaplan Meier method [1]. The univariate evaluation of the differences between the Kaplan Meier curves was performed with the log-rank test. The prognostic factors found to be significant (p<0.05) or showed a strong trend (p 0.08) in the univariate analysis were included in a multivariate analysis, which was performed with the Cox proportional hazards model. Results All patients were followed until death or for median of 12 months (range 6 39 months) in those alive at the last follow-up visit. The median follow-up in survivors was 12 months (range 6 37 months) in patients receiving zoledronic acid, and 12 months (range 6 39 months) in patients treated with radiotherapy alone. The 1-year local control rate of MSCC was 84% for the entire cohort. The results of the univariate analysis are summarized in. Tab. 2. Radiotherapy plus zoledronic acid resulted in better 1-year local control than radiotherapy alone (90% vs. 81%, p=0.042,. Fig. 1). In addition, improved local control was significantly associated with female gender (p=0.017), favorable type of primary tumor (p=0.002), and longer-course radiotherapy (p=0.006). In the multivariate analysis of local control, the addition of zoledronic acid [relative risk (RR) 2.75; 95% confidence interval (CI) 1.13 8.20; p=0.024], and longer-course radiotherapy (RR 2.51; 95% CI 1.15 5.29; p=0.022) maintained significance, whereas gender (RR 1.42; 95% CI 0.54 3.59; p=0.47) and primary tumor type (RR 1.32; 95% CI 0.95 1.78; p=0.10) did not. The 1-year overall control rate of MSCC was 79% for the entire cohort. The results of the univariate analysis of overall control are summarized in. Tab. 3. Radiotherapy plus zoledronic acid resulted in better 1-year overall control than radiotherapy alone (87% vs. 75%, p=0.016,. Fig. 1). In addition to the treatment regimen, improved overall control was significantly associated with female gender (p=0.003) and longer-course radiotherapy (p=0.009). A trend was observed for favorable primary tumor type (p=0.053). In the multivariate analysis, the addition of zoledronic acid (RR 2.74; 95% CI 1.29 6.76; p=0.008), and longer- Strahlentherapie und Onkologie 10 2012 911
course radiotherapy (RR 2.40; 95% CI 1.10 4.05; p=0.025) maintained significance. showed a strong trend (RR 2.25; 95% CI 0.99 5.02; p=0.054), and primary tumor type was not significant (RR 1.07; 95% CI 0.79 1.41; p=0.63). The 1-year survival rate for the entire cohort was 55%. The addition of zoledronic acid did not significantly improve survival at 1 year (60% vs. 52%, p=0.17). On univariate analysis (. Tab. 4), improved survival was associated with age 64 years (p=0.005), female gender (p<0.001), better (p<0.001), favorable tumor type (p<0.001), involvement of only 1 2 vertebrae (p=0.012), absence of visceral metastases (p<0.001), being ambulatory prior to radiotherapy (p<0.001), and a slower development of motor deficits (p<0.001). A trend was observed for absence of other bone metastases (p=0.051). On multivariate analysis, survival was significantly associated with gender (RR 1.64; 95% CI 1.01 2.65; p=0.047), visceral metastases (RR 4.41; 95% CI 2.97 6.62; p<0.001), ambulatory status (RR 2.06; 95% CI 1.32 3.23; p=0.001), and time developing motor deficits (RR 2.47; 95% CI 1.01 1.46; p=0.047). Primary tumor type (RR 1.14; 95% CI 0.98 1.32; p=0.09), age (RR 1.10; 95% CI: 0.77 1.57; p=0.59), ECOG performance status (RR 1.11; 95% CI 0.71 1.73; p=0.63), number of involved vertebrae (RR 1.19; 95% CI 0.93 1.55; p=0.16), and other bone metastases (RR 1.05; 95% CI 0.57 1.83; p=0.88) were not significant in the multivariate analysis of survival. Acute radiotherapy-related toxicity did not exceed grade 1 according to CT- CAE 3.0, and late toxicity such as myelopathy did not occur. Acute grade 3 toxicity rates likely related to zoledronic acid were 1% for hypocalcemia, 1% for anemia, and 1% for serum creatinine increase. Osteonecrosis of the jaw was observed in 4 patients after median 10 months (range 7 13 months) of zoledronic acid treatment. Discussion Zoledronic acid is effective in reducing the rate of skeletal-related events in patients with bone metastases. In 2002, Saad et al. [6] presented a trial of patients Abstract Zusammenfassung Strahlenther Onkol 2012 188:910 916 Springer-Verlag 2012 DOI 10.1007/s00066-012-0158-4 D. Rades S.G. Hakim A. Bajrovic J.H. Karstens T. Veninga V. Rudat S.E. Schild Impact of zoledronic acid on control of metastatic spinal cord compression Abstract Background. Zoledronic acid was demonstrated to reduce the rate of skeletal-related events, a hypernym including various outcomes, in patients with bone metastases. In contrast to other studies, this matched-pair analysis focused solely on the impact of zoledronic acid on metastatic spinal cord compression (MSCC). Patients and methods. Data from 98 patients with MSCC receiving radiotherapy plus zoledronic acid were matched 1:2 to 196 patients receiving radiotherapy alone for ten potential prognostic factors. Both groups were compared for local control of MSCC within the irradiated region, overall control of MSCC (local and distant MSCC control), and survival. Results. The 1-year local control rates were 90% after radiotherapy plus zoledronic acid and 81%, after radiotherapy alone (p=0.042). The 1-year overall control rates were 87% and 75%, respectively (p =0.016), and the 1-year survival rates were 60% and 52%, respectively (p=0.17). Results were significant in the Cox proportional hazards model regarding local control (p=0.024) and overall control (p =0.008). Conclusion. According to the results of this study, zoledronic acid was associated with improved control of MSCC in irradiated patients. Keywords Zoledronic acid Metastatic spinal cord compression Radiotherapy Treatment outcomes Local control Einfluss von Zoledronsäure auf die Kontrolle der metastatisch bedingten Rückenmarkskompression Zusammenfassung Hintergrund. Zoledronsäure verringert die Rate von skelettassoziierten Ereignissen. Unter dem Begriff skelettassoziierte Ereignisse werden verschiedene Endpunkte bei Patienten mit Knochenmetastasen zusammengefasst. Im Gegensatz zu bisherigen Studien konzentriert sich die vorliegende Matched- Pair-Analyse auf den Endpunkt MSCC (metastatisch bedingte Rückenmarkskompression). Patienten und Methode. Im Rahmen einer Matched-Pair-Analyse (1:2) unter Berücksichtigung von 10 möglichen Prognosefaktoren wurden die Daten von 98 Patienten mit einer MSCC, die eine Strahlentherapie plus Zoledronsäure erhielten, mit 196 Patienten, die mit einer alleinigen Strahlentherapie behandelt wurden, verglichen. Untersuchte Endpunkte waren die lokale Kontrolle der MSCC innerhalb der bestrahlten Region, die Gesamt kontrolle der MSCC (innerhalb und außerhalb der bestrahlten Region) und das Gesamtüberleben. Ergebnisse. Die Raten für die lokale Kontrolle betrugen nach einem Jahr 90% nach Strahlentherapie plus Zoledronsäure sowie 81% nach alleiniger Strahlentherapie (p=0,042). Die Raten für die Gesamtkontrolle der MSCC nach einem Jahr betrugen 87% sowie 75% (p=0,016), die Raten für das Gesamtüberleben nach 1 Jahr 60% sowie 52% (p=0,17). Die Unterschiede für die lokale Kontrolle (p=0,024) und die Gesamtkontrolle der MSCC (p=0,008) waren auch in der Multivarianzanalyse signifikant. Schlussfolgerungen. Nach den Ergebnissen dieser Studie verbessert Zoledronsäure die Kontrolle der MSCC nach Strahlentherapie. Schlüsselwörter Zoledronsäure Metastatisch bedingte Rückenmarkskompression Strahlentherapie Behandlungsergebnisse Lokale Kontrolle with hormone-refractory prostate cancer who received either intravenous zoledronic acid at 4 mg (n=214), zoledronic acid at 8 mg subsequently reduced to 4 mg (8 mg/4 mg; n=221), or placebo (n=208) every 3 weeks for 15 months. The rates of skeletal related events were 33%, 39%, and 44%, respectively. The 4 mg regimen was significantly superior to placebo (p=0.021), whereas the 8 mg/4 mg regimen was not (p=0.22). In contrast to the 4 mg regimen, the 8 mg/4 mg regimen was associated with significant impairment of renal function. Therefore, the authors recommended zoledronic acid at 4 mg, which is consistent with the ASCO 912 Strahlentherapie und Onkologie 10 2012
Tab. 2 Univariate analysis of local control of metastatic spinal cord compression (MSCC) At 6 months (%) At 12 months (%) Treatment regimen RT alone (n=196) 95 81 0.042* RT +zoledronic acid (n=98) 100 90 64 years (n=150) 97 88 0.17 65 years (n=144) 97 80 Female (n=204) 99 88 0.017* Male (n=90) 91 71 1 2 (n=168) 98 85 0.91 3 4 (n=126) 94 85 Breast cancer (n=171) 99 88 0.002* Prostate cancer (n=36) 97 77 Myeloma/lymphoma (n=24) 100 84 Lung cancer (n=24) 100 92 Other tumors (n=39) 76 45 1 2 (n=63) 98 93 0.15 3 (n=231) 97 82 No (n=48) 96 79 0.27 Yes (n=246) 97 86 No (n=162) 99 85 0.43 Yes (n=132) 93 83 Not ambulatory (n=60) 100 96 0.09 Ambulatory (n=234) 96 83 1 7 days (n=72) 97 80 0.63 >7 days (n=222) 97 85 Short-course RT (n=66) 90 73 0.006* Longer-course RT (n=228) 99 88 *Value considered significantrt radiotherapy. clinical practice guideline update on the role of bone-modifying agents in breast cancer patients [8]. In 2004, Saad et al. [7] presented long-term results of 122 patients who had completed 24 months on study. The rates of skeletal related events were 38% in patients receiving zoledronic acid at 4 mg and 49% in the placebo group, respectively (p=0.028). The annual incidences of skeletal related events were 0.77 in the 4 mg zoledronic acid group and 1.47 in the placebo group, respectively (p=0.005). In 2004, Rosen et al. [4] presented a randomized trial of 773 patients with bone metastases from non-small cell lung cancer or other solid tumors who received either zoledronic acid (4 mg, n=257, or 8 mg/4 mg, n=266) or placebo (n=250) every 3 weeks for 21 months. In the placebo group, the rate of skeletal related events was 46% and higher than with 4 mg (39%; p=0.13) or 8 mg/4 mg of zoledronic acid (36%; p=0.023). In the 4 mg group, the median time to first skeletal related event was delayed when compared to the placebo group (236 vs. 155 days, p=0.009), and the annual incidence was reduced from 2.71 to 1.74 (p=0.012). In 2005, Kohno et al. [2] reported a randomized trial of 228 patients with bone metastases from breast cancer receiving 4 mg zoledronic acid (n=114) or placebo (n=114) every 4 weeks for 12 months. The rates of skeletal related events were 30% and 50%, respectively (p=0.003). A matched-pair analysis following strict matching criteria was performed. Both groups had to match for ten potential prognostic factors. We chose this design in order to control for as many potential sources of bias as possible. Because the data are retrospective in nature, hidden selection biases cannot be entirely excluded. This should be considered when interpreting the results of this study. This matched-pair analysis investigated whether zoledronic acid when added to radiotherapy could to improve control of MSCC in patients irradiated for this complication of bone metastasis. In the trials of Saad et al. [6] and Rosen et al. [4], zoledronic acid did not significantly reduce the rate of MSCC. The rates of MSCC in the trial of Saad et al. [6] were 4% (9/214) in the 4 mg group, 5% (11/221) in the 8 mg/4 mg group, and 7% (14/208) in the placebo group, respectively (p=0.26 for 4 mg vs. placebo; p=0.43 for 8 mg/4 mg vs. placebo). In the trial of Rosen et al. [4], the rates of MSCC were 3% (8/257) in the 4 mg group, 3% (7/266) in the 8 mg/4 mg group, and 4% (10/250) in the placebo group, respectively (not significant). This lack of a significant difference between zoledronic acid and placebo might have been due to the small number of MSCC events in patients with initially uncomplicated bone metastases. In the present study, only patients irradiated for MSCC were included. In a prospective study, the risk of developing a recurrence of MSCC in the irradiated regions of the spinal cord was 29% at 1 year [3]. If one includes the recurrences of MSCC outside the irradiated regions, this rate is higher. Therefore, a greater number of MSCC events could be expected in the present study when compared to the trials of Saad et al. [6] and Rosen et al. [4], leading to a greater probability of achieving a significant difference when comparing patients treated with radiotherapy alone to those who received radiotherapy plus zoledronic acid. And indeed, according to the findings of the present study, the addition of zoledronic acid to radiotherapy improved Strahlentherapie und Onkologie 10 2012 913
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 P=0.042 RT + ZOL RT alone 0 10 20 30 40 time to local recurrence (months) 8. Van Poznak CH, Temin S, Yee GC et al (2011) American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol 29:1221 1227 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 P=0.016 RT + ZOL RT alone 0 10 20 30 40 time to any recurrence (months) Fig. 1 9 Comparison of radiotherapy plus zoledronic acid (RT+ZOL) to radiotherapy alone (RT alone) with respect to local control and overall control of MSCC local control and overall control of MSCC in patients irradiated for this complication of bone metastasis. Corresponding address D. Rades, M.D. Department of Radiation Oncology, University of Lubeck Ratzeburger Allee 160, 23538 Lubeck Germany Rades.Dirk@gmx.net Conflict of interest. On behalf of all authors, the corresponding author states the following: DR: study grant (Novartis Oncology), speaker s honoraria (Amgen). References 1. Kaplan EL, Meier P (1958) Non parametric estimation from incomplete observations. J Am Stat Assoc 53:457 481 2. Kohno N, Aogi K, Minami H et al (2005) Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol 23:3314 3321 3. Rades D, Lange M, Veninga T et al (2011) Final results of a prospective study comparing the local control of short-course and long-course radiotherapy for metastatic spinal cord compression. Int J Radiat Oncol Biol Phys 79:524 530 4. Rosen LS, Gordon DH, Dugan W et al (2004) Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 100:36 43 5. Rosen LS, Gordon D, Tchekmedyian S et al (2003) Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase II, double-blind, randomized trial The Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 21:3150 3157 6. Saad F, Gleason DM, Murray R et al (2002) A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94:1458 1468 7. Saad F, Gleason DM, Murray R et al (2004) Longterm efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 96:879 882 914 Strahlentherapie und Onkologie 10 2012
Tab. 3 Univariate analysis of overall control of metastatic spinal cord compression (MSCC) At 6 months (%) At 12 months (%) p Treatment regimen RT alone (n=196) 91 75 0.016* RT +zoledronic acid (n=98) 99 87 64 years (n=150) 93 83 0.15 65 years (n=144) 93 74 Female (n=204) 96 84 0.003* Male (n=90) 86 62 1 2 (n=168) 95 80 0.52 3 4 (n=126) 91 77 Breast cancer (n=171) 95 83 0.053 Prostate cancer (n=36) 90 70 Myeloma/lymphoma (n=24) 95 70 Lung cancer (n=24) 100 92 Other tumors (n=39) 76 45 1 2 (n=63) 91 81 0.89 3 (n=231) 94 78 No (n=48) 91 72 0.18 Yes (n=246) 94 81 No (n=162) 94 78 0.72 Yes (n=132) 91 82 Not ambulatory (n=60) 91 77 0.74 Ambulatory (n=234) 94 79 1 7 days (n=72) 93 77 0.99 >7 days (n=222) 93 79 Short-course RT (n=66) 87 68 0.009* Longer-course RT (n=228) 95 83 *Value considered significantrt radiotherapy. Strahlentherapie und Onkologie 10 2012 915
Tab. 4 Univariate analysis of survival At 6 months (%) At 12 months (%) p Treatment regimen RT alone (n=196) 69 52 0.17 RT +zoledronic acid (n=98) 71 60 64 years (n=150) 73 60 0.005* 65 years (n=144) 67 49 Female (n=204) 75 61 <0.001* Male (n=90) 57 39 1 2 (n=168) 84 69 <0.001* 3 4 (n=126) 51 35 Breast cancer (n=171) 77 63 <0.001* Prostate cancer (n=36) 67 48 Myeloma/lymphoma (n=24) 83 52 Lung cancer (n=24) 58 58 Other tumors (n=39) 41 24 1 2 (n=63) 79 62 0.012* 3 (n=231) 67 52 No (n=48) 88 64 0.051 Yes (n=246) 66 53 No (n=162) 90 74 <0.001 Yes (n=132) 45 31 Not ambulatory (n=60) 45 28 <0.001* Ambulatory (n=234) 76 62 1 7 days (n=72) 42 26 <0.001* >7 days (n=222) 79 64 Short-course RT (n=66) 74 54 0.38 Longer-course RT (n=228) 68 55 *Value considered significantrt radiotherapy. 916 Strahlentherapie und Onkologie 10 2012