Anticancer evidence for zoledronic acid across the cancer continuum

Critical Reviews in Oncology/Hematology 77 S1 (2011) S31−S37

Anticancer evidence for zoledronic acid across the cancer continuum Luis Costaa , Peter Harperb , Robert E. Colemanc , Allan Liptond a Servi¸co de Oncologia, Hopital de Santa Maria and Instituto de Medicina Molecular, Lisbon, Portugal b Guy’s Hospital, London, United Kingdom c University of Sheffield, Weston Park Hospital, Cancer Research Centre, Sheffield, United Kingdom d Milton S. Hershey Medical Center, Penn State Cancer Institute, Hershey, PA, USA

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Evidence for zoledronic acid anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Zoledronic acid anticancer activity in the advanced cancer setting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Zoledronic acid anticancer activity in the early cancer setting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Direct anticancer effects of zoledronic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Keywords: Anticancer Bone metastasis Cancer Clinical trial Zoledronic acid

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summary Emerging evidence from clinical trials with zoledronic acid (ZOL) suggests that ZOL may have anticancer activity in a variety of cancer types. Retrospective studies and subset analyses as well as prospectively designed clinical trials have demonstrated that ZOL has survival benefits in patients with advanced cancers. Several studies have shown that ZOL improves disease-free survival, reduces the persistence of circulating and disseminated tumor cells, which are known to be predictive of disease recurrence, and decreases residual invasive tumor size in patients with early breast cancer. These data suggest that, in addition to providing skeletal-related event (SRE) benefits, ZOL also may potentially provide clinically meaningful benefits through anticancer activity. This article reviews the breadth of evidence supporting the anticancer activity of ZOL across the treatment continuum in patients with cancer. © 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Bisphosphonates (BPs) are a standard of care for maintaining bone health in patients with cancer [1]. All BPs are antiresorptive drugs that block pathologic bone resorption by inducing osteoclast apoptosis; however, only nitrogen-containing BPs (NBPs) also inhibit osteoclast function and activation [2,3]. Thus, BPs interrupt the vicious cycle of osteolytic bone lesions and reduce the tumor burden in bone [4]. Zoledronic acid (ZOL), * Corresponding author. Luis Costa, MD, PhD. Servi¸co de Oncologia, Hopital de Santa Maria, Lisbon, Portugal. Tel.: +351 21 780 5096/5257; fax: +351 21 780 5633/5097. E-mail address: [email protected] (L. Costa).

pamidronate, and clodronate (CLO) are BPs indicated for the treatment of patients with bone metastases from breast cancer (BC) or multiple myeloma, in conjunction with standard antineoplastic therapy, and ZOL also is indicated for the treatment of patients with bone metastases from all solid tumors, including prostate cancer (PC), lung cancer, and renal cell carcinoma (RCC) [5−7]. In addition to preserving bone health, preventing cancer therapy-induced bone loss (CTIBL) [8−12], and reducing the risk of skeletalrelated events (SREs), evidence from clinical trials suggests that BPs may have anticancer activity. In 2 clinical trials with the first-generation BP CLO, patients with early breast cancer (stages I−III) receiving CLO had improved overall survival (OS) compared with

1040-8428/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.

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Table 1 Summary of trials demonstrating anticancer benefits of ZOL Study (follow-up)

N Tumor type

ZOL (4 mg regimen)

Results

q3−4wk for 6 doses

↓ RITS by 44% (27.4 mm vs 15.5 mm; p = 0.006) ↑ pCR rate by nearly 2-fold ( p = 0.146)

Neoadjuvant setting Coleman et al. (6 months) [18]

205 BC

Adjuvant setting Lin et al. (24 months) [19]

45 BC

Monthly for 2 yr

↓ In persistent DTCs ( ↓ in 66% of patients at 1 yr; p = 0.0018) ( ↓ in 71% of patients at 2 yr; p = 0.01)

Solomayer et al. (12 months) [20]

76 BC

q4wk for 2 yr

↓ In persistent DTCs ( p = 0.066) ↑ DTC-free patients (67% vs 35%; p = 0.009)

Aft et al. (3 months) [21]

120 BC

q3wk for 1 yr

↓ In persistent DTCs (30% vs 47%; p = 0.054)

Rack et al. (39 months) [22]

172 BC

q4wk for 6 mo

↓ Proportion with persistent DTCs after ZOL (13% vs 27%; p = 0.099)

Eidtmann et al. (36 months) [23] (48 months) [24]

1,065 BC a

q6mo for 5 yr; ↑ DFS (HR = 0.588; p = 0.0314) with immediate vs delayed ZOL immediate vs delayed ↑ DFS (HR = 0.59; p = 0.0175)

Gnant et al. (48 months) [25] (62 months) [26]

1,803 BC b

q6mo for 3 yr

↑ DFS (HR = 0.64; p = 0.01) ↑ DFS (HR = 0.68; p = 0.009)

Coleman et al. (~59 months) [27]

3,360 BC

q3−4wk for 6 mo; q3mo for 24 mo; q6 mo for 30 mo

Overall population: No ↑ DFS; trend toward ↑ OS (HR = 0.85; p = 0.07) In postmenopausal subset: ↑ DFS (HR = 0.76; p < 0.05)

Metastatic setting Mystakidou et al. (18 months) [28]

40 Advanced solid tumors (no BM)

Monthly

↑ BMFS at 12 months (60% vs 10%; p < 0.0005) ↑ BMFS at 18 months (20% vs 5%; p = 0.0002)

Zaghloul et al. (24 weeks) [29]

40 Bladder cancer

Monthly for 6 mo

↑ 1-yr OS (36.3% vs 0%; p = 0.004)

q21d

↑ OS by >6 mo (578 d vs 384 d; p < 0.001)

q28d

↑ 5-yr OS (80% vs 46%; p < 0.01) ↑ 5-yr EFS (80% vs 52%; p < 0.01)

q3−4wk

↑ PFS (HR = 0.883; p = 0.0179) ↑ OS (HR = 0.842; p = 0.0118)

Zarogoulidis et al. [30] Aviles et al. (49.6 months) [31] Morgan et al. (3.7 years) [32]

144 LC 94 MM 1,960 MM

a Postmenopausal women with early stage endocrine-responsive BC. b Premenopausal women with early stage endocrine-responsive BC.

Abbreviations: BC, breast cancer; BM, bone metastases; BMFS, bone metastasis-free survival; BP, bisphosphonate; DFS, disease-free survival; DTCs, disseminated tumor cells; EFS, event-free survival; HR, hazard ratio; LC, lung cancer; MM, multiple myeloma; OS, overall survival; PC, prostate cancer; pCR, pathologic complete response; PFS, progression-free survival; RITS, residual invasive tumor size; ZOL, zoledronic acid. Adapted from Gnant M. Curr Cancer Drug Targets [33]. Copyright 2009 by Bentham Science Publishers Ltd. Reproduced with permission of Bentham Science Publishers Ltd. in the format Journal via Copyright Clearance Center.

placebo or no CLO [13,14], although a third similar trial was reported as negative [15]. In one of these studies in patients with disseminated tumor cells (DTCs) present in the bone marrow, the improvement in survival was still evident after 8.5 years of follow-up [16]. These data suggest that BPs may effect a change in the bone marrow environment, and this change may be important for the prevention of disease relapse. Although a meta-analysis of the CLO studies found no statistically significant effects on the disease course for CLO [17], the data remained highly encouraging

and provided the rationale to investigate the potential anticancer activity of more active, later-generation BPs. Emerging evidence with the more potent third-generation NBP ZOL has demonstrated further anticancer benefits (Table 1) [18−33]. Much thought is being put into the possible mechanisms of action (MOA) responsible for the observed anticancer activity of ZOL. The metastatic process involves multiple steps, including tumor cell growth, migration, adhesion to extracellular matrix, extravasation into distant tissues,

L. Costa et al. / Critical Reviews in Oncology/Hematology 77 S1 (2011) S31−S37

angiogenesis, and avoidance of immune surveillance [4], and both preclinical and clinical evidence suggests that ZOL can inhibit many of these pathways. For example, preclinical and clinical studies demonstrated that ZOL inhibits factors involved in angiogenesis, such as vascular endothelial growth factor (VEGF) (see also Green and Guenther [34] in this supplement) [35]. In a small clinical trial (N = 26), ZOL (1 mg q1wk × 4, followed by 4 mg q4wk × 3) significantly and rapidly decreased VEGF levels compared with baseline ( p = 0.038) in patients with bone metastases from solid tumors, and the decreased VEGF levels were sustained throughout therapy ( p = 0.014) [35,36]. Moreover, some anticancer effects of ZOL have been shown to be dependent on inhibition of the mevalonate pathway [37,38], a mechanism of action not shared by early BPs such as CLO. In a preclinical study, ZOLinduced phosphoantigen accumulation in human BC cells correlated with gammadelta (gd) T-cell-mediated cancer cell death [37], indicating that ZOL may activate immunomodulatory gd T cells (see also Green and Guenther [34] in this supplement). Furthermore, in another preclinical study, ZOL significantly reduced the ability of mesenchymal stem cells to support migration of BC cells, suggesting an additional mechanism by which ZOL may impede tumor metastasis [39]. Moreover, ZOL has been shown to decrease the number and persistence of DTCs, cells known to promote disease recurrence [19−22]. Tumor cells can be detected in blood (circulating tumor cells [CTCs]) or in tissue other than the primary tumor type (DTCs) of patients with solid tumors, and persistence has been shown years after primary diagnosis [19−22]. These circulating tumor cells may act as “seeds” for subsequent local and distant relapse in supportive “soil”, and the sites of future tumor growth can be the primary tumor site (tumor “self-seeding”) or distant metastasis [4,40]. However, CTCs often adhere to the bone marrow microenvironment to become DTCs, presumably because it provides a secure niche for DTCs to survive for prolonged periods of time, and allows them to evade the cytotoxic effects of systemic anticancer therapy [4,41−43]. The captivating hypothesis for the anticancer activity of ZOL is that ZOL makes the “soil” (microenvironment) less suitable for growth of the “seed” (tumor cell) [44], suggesting that ZOL targets several steps involved in the metastatic process. Evidence continues to emerge that will likely provide further insight into this question. 2. Evidence for zoledronic acid anticancer activity 2.1. Zoledronic acid anticancer activity in the advanced cancer setting A number of retrospective studies and subset analyses have suggested that treatment with ZOL has survival benefits in patients with bone metastases from advanced

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cancers including BC, PC, RCC, and non-small cell lung carcinoma (NSCLC). In a retrospective subset analysis of patients with RCC (n = 74), ZOL (4 mg q3wk × 9 months) significantly increased the time to progression to bone metastases ( p = 0.014) compared with placebo [45]. Other retrospective subset analyses demonstrated that ZOL decreased levels of urinary N-telopeptide of type I collagen (NTX), a marker of bone resorption, in patients with metastases from BC, PC, or NSCLC (n = 1,669) when compared with placebo or pamidronate [46,47]. Moreover, normalization of NTX levels correlated with improved OS compared with persistently elevated NTX levels in this patient population [46,47]. Another retrospective analysis demonstrated that ZOL treatment significantly reduced the relative risk of death by 35% ( p = 0.024) compared with placebo in patients with NSCLC and high baseline NTX levels (n = 382) [48]. These data are further reinforced by a recent exploratory analysis of patients with complete bone marker data from the phase III trial database of ZOL (n = 1,126), wherein ZOL treatment was associated with a 30% relative decrease in the risk of death ( p = 0.003 vs placebo) in patients with elevated baseline NTX levels [49]. Interestingly, despite the correlation between SREs and mortality [50], further analyses demonstrated that the improvement in survival with ZOL treatment in the highNTX cohort was maintained in models adjusted for SRE incidence (25% decreased risk of death, p = 0.019, in the adjusted model vs 30% reduced risk of death, p = 0.003, in the unadjusted model) [49]. Moreover, a recent retrospective audit of an unrelated cohort of 114 patients with bone metastases from NSCLC treated with ZOL (n = 49) or without ZOL (n = 75) revealed a significant survival benefit (median OS of 34 weeks with ZOL vs 19 weeks without ZOL; p = 0.01) [51]. These retrospective studies suggest potential anticancer activity of ZOL against multiple tumor types. Similarly, several prospective studies have demonstrated the anticancer activity of ZOL in patients with advanced cancer. In a clinical trial in patients with bone metastases from NSCLC (N = 144) ZOL significantly increased OS compared with no ZOL ( p < 0.01), and persistence in ZOL therapy led to significantly improved survival and increased time to progression ( p < 0.01, both) [30]. In another randomized clinical trial ZOL improved 1-year survival rates in patients with bone metastases from bladder cancer (N = 40) [29]. A phase I clinical trial showed that metronomic administration of docetaxel followed by ZOL decreased prostate-specific antigen (PSA) levels in patients (N = 22) with bone metastases from hormoneresistant PC [52]. Furthermore, a randomized clinical study in patients with recurrent or advanced metastatic cancer without evidence of bone metastases (N = 40) demonstrated that ZOL reduced the risk of developing bone metastases [28].

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Data from these retrospective analyses and small prospective clinical studies suggest that ZOL may have anticancer activity in patients with advanced cancers. Furthermore, evidence for the anticancer activity of ZOL in the adjuvant cancer setting is emerging. 2.2. Zoledronic acid anticancer activity in the early cancer setting Data from translational clinical studies show that ZOL decreases the number and persistence of DTCs in the bone marrow of women with early BC [19−22]. This may be of clinical significance, as higher numbers of DTCs in bone marrow are predictive of disease recurrence in patients with early BC [19]. In a phase II randomized clinical trial, 120 women with early BC received either ZOL (4 mg q3wk × 1 year) or no ZOL in addition to standard neoadjuvant and adjuvant chemotherapy [21]. At 3 months, DTCs were detected in the bone marrow of 30% of patients treated with ZOL compared with 47% of patients who did not receive ZOL ( p = 0.054) [21]. In another clinical trial in women with early BC (N = 172), DTCs were detected in the bone marrow of 13% of women treated with ZOL (n = 31) compared with 27% of those not treated with ZOL (n = 141; p = 0.099) [22]. Moreover, an ongoing clinical trial in women with early BC (n = 76) showed that of the patients who had DTC-positive bone marrow at baseline, significantly more patients treated with ZOL (4 mg q4wk) became DTC-negative after 12 months compared with no ZOL (66.7% vs 35.1%, respectively; p = 0.009) [20]. Because high baseline DTCs in bone marrow are predictive for early disease recurrence [19], reducing the number of DTCs or preventing the persistence of DTCs in bone marrow may decrease the risk of disease recurrence and improve OS. These studies suggest that acting on DTCs may be a mechanism for the anticancer activity of ZOL. The Zometa® –Femara® Adjuvant Synergy Trials (Z-/ ZO-/E-ZO-FAST) are companion trials in postmenopausal women receiving adjuvant hormonal therapy for early BC. The Z- and ZO-FAST trials initially demonstrated that ZOL preserves bone mineral density (BMD) in this setting [8,23]. Notably, the benefits observed in these trials extend beyond the maintenance of bone health. A 24-month integrated analysis of the Z-/ZO-FAST trials (N = 1,667) demonstrated that upfront ZOL increased disease-free survival (DFS) by 43% (hazard ratio [HR] = 0.573, p = 0.0183) compared with delayed ZOL [53]. Moreover, the ZO-FAST trial (N = 1,065) showed a 41% improvement in DFS ( p = 0.0175) at 48 months’ median follow-up [24] and demonstrated a decrease in local and distant disease recurrence in and outside of bone at 36 months’ median follow-up [23]. Early reports from the E-ZO-FAST study (N = 527) have not supported the results of the Z-/ZO-FAST studies, and further analyses are underway [24].

In addition to the Z-/ZO-FAST trials, the Austrian Breast and Colorectal Cancer Study Group trial 12 (ABCSG-12) in premenopausal women with early BC (N = 1,803) demonstrated that ZOL plus endocrine therapy reduced the risk of DFS events by 36% ( p = 0.01), decreased the relative risk of disease progression by 33% ( p = 0.02), and decreased the risk of recurrence in and outside of bone by 32% ( p = 0.03) compared with endocrine therapy alone [25]. Furthermore, at a median follow-up of 62 months, more than 2 years after therapy completion, ZOL continued to reduce the risk of DFS events by 32% (HR = 0.68, p = 0.009) [26]. In another large, randomized trial (AZURE), women with stage II/III BC (N = 3,360) received standard therapy alone or standard therapy plus ZOL (4 mg every 3−4 weeks × 6; 4 mg every 3 months × 8; 4 mg every 6 months × 5). Standard therapy included endocrine therapy, chemotherapy, or the combination, and was prescribed by the treating physicians per their standard practices. Adjuvant use of ZOL did not improve DFS in the overall patient population. Although the primary endpoint, DFS, did not reach statistical significance, there was a trend toward improved OS for ZOL compared with placebo in the overall population (HR = 0.85; p = 0.07) [27]. Furthermore, prospective subgroup analyses based on menopausal status (protocol-defined secondary endpoint) showed that ZOL significantly improved DFS (HR = 0.76; p not reported) and OS (HR = 0.71; p = 0.017) in patients who were at least 5 years postmenopausal at baseline. Additionally, ZOL significantly reduced each type of DFS event and reduced recurrences both in and outside of bone (HR and p value were not reported) compared with placebo in this subset [27]. These data suggest that ZOL has the greatest potential for anticancer benefits in patients who have been menopausal for >5 years, which may at first seem inconsistent with data showing significant DFS benefits from ZOL in premenopausal women in ABCSG-12. However, ovarian ablation with goserelin therapy plus either anastrozole or tamoxifen resulted in amenorrhea in all patients in ABCSG-12, and residual estrogen levels in these patients were likely similar to those in the AZURE postmenopausal population. Safety data were consistent with the known tolerability profile of ZOL in patients with BC, and no renal issues were reported with ZOL, which is consistent with reports from ZO-FAST [23] and ABCSG-12 [25]. The data from these large, prospective clinical trials suggest that ZOL may have anticancer activity in postmenopausal women in the adjuvant cancer setting. Ongoing trials Several ongoing trials are evaluating the role of ZOL as anticancer therapy. The SWOG 0307 (N = 4,500), SUCCESS (N = 3,754), and NATAN (N = 654) trials are examining the effects of ZOL on DFS (at 3 to 5 years) in patients with early BC. In patients with nonmetastatic PC,

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Metastatic

Adjuvant

Chemotherapy Bladder (N = 40) Ç OS (p = 0.004) RCC (n = 46) Ç Time to bone lesion progression (p = 0.014) Lung (N = 144) Ç OS (p < 0.001)

AZUREa (pre- /perimenopausal n = 2,258) DFS not significantly different from placebo HR = 1.01 (p = 0.93) Trend toward OS HR = 0.85 (p = 0.07)

MM (N = 1,960) Ç OS (p = 0.012) Ç DFS (p = 0.018)

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Neoadjuvant

Endocrine Therapy

Z-FAST/ZO-FAST (N = 1,667) Ç DFS 43% (p = 0.0183) ABCSG-12 (N = 1,803) Ç DFS 36% (p = 0.01) AZUREa (> 5 yr postmenopausal or > 60 yr, n = 1,101) Ç DFS 24% (p = NR) Ç OS 29% (p = 0.017)

AZURE neoadjuvant (n = 205) È RITS 44% (p = 0.006) Ç Pathologic CR rates Aft 2010 BC (N = 120) È % of patients with persistent DTC (p = 0.054) Rack 2010 BC (N = 172) È % of patients who remained DTC+ at 6 mo (p = 0.099)

MM (N = 94) Ç 5-yr OS (p < 0.01)

Fig. 1. Zoledronic acid anticancer activity − evidence across the disease continuum [18,21,22,25,27,29−32,53,57]. Abbreviations: ABCSG, Austrian Breast and Colorectal Cancer Study Group; BC, breast cancer; CR, complete response; DFS, disease-free survival; DTC, disseminated tumor cell; MM, multiple myeloma; NR, not reported; OS, overall survival; RCC, renal cell carcinoma; RITS, residual invasive tumor size. a In the AZURE trial most pre-/ perimenopausal women received chemotherapy; most postmenopausal women who were endocrine receptor-positive had treatment regimens that included endocrine therapy.

the ZEUS study (N = 1,433) will investigate the proportion of patients with bone metastases at 4 years, and the RADAR study (N = 1,071) is studying prostate-specific antigen recurrence-free survival at 5 years [54]. Other studies are being conducted in patients with NSCLC (2419 study, N = 446) and multiple myeloma (DAZZLE, N = 53) with endpoints of time to disease recurrence and survival, respectively. Data from these studies are eagerly awaited. 2.3. Direct anticancer effects of zoledronic acid In addition to improving survival, decreasing disease recurrence, and decreasing DTC persistence in bone marrow, ZOL has demonstrated possible direct anticancer effects in tumors. In the neoadjuvant substudy of the AZURE trial (n = 205) ZOL in combination with chemotherapy decreased the residual invasive tumor size by 44% ( p = 0.006) and increased pathologic complete response almost 2-fold compared with neoadjuvant therapy alone [18]. In addition to decreasing tumor size, ZOL has demonstrated synergy with chemotherapy agents to directly kill cancer cells in preclinical studies (see Green and Guenther [34] in this supplement). Furthermore, two small translational studies in patients with BC (N = 23) or PC (N = 9) demonstrated that ZOL activated gd T cells [35,55], which can kill cancer cells that have internalized ZOL (see Green and Guenther [34] in this supplement). These data suggest that ZOL directly affects cancer cells and may be an additional mechanism responsible for the potential anticancer activity of ZOL. 3. Conclusions Therapies directed against cancer cells have been the foundation of chemotherapy in oncology. However, some newer

anticancer approaches also mediate indirect cancer effects through the cancer environment, such as blocking tumorsupporting angiogenesis or increasing anticancer immune responses. Bisphosphonates, such as ZOL, are important therapeutic agents in patients with cancer, particularly the elderly [56], and are used in various treatment regimens, depending upon the indication [56]. Specifically, ZOL can have both direct anticancer effects and indirect effects on the cancer microenvironment, especially within the bone marrow. Indeed, clinical trial evidence supports the anticancer activity of ZOL in solid tumors across the disease continuum (Fig. 1) [18,21,22,25,27,29−32,53,57]. Furthermore, in addition to solid tumors, compelling evidence for the anticancer activity of ZOL has been reported in multiple myeloma. The recently completed Myeloma IX trial (N = 1,960) demonstrated that patients with multiple myeloma who were treated with ZOL had significantly increased overall survival (by 5.5 months; p = 0.04) compared with CLO (see also the article by Morgan [58] in this supplement) [32]. Because ZOL affects cancer cells directly (the seed) and the bone marrow microenvironment (the soil), and is generally well tolerated, it represents an important component in the therapeutic repertoire to prevent cancer recurrence. Conflict of interest statement Dr. Luis Costa has received honoraria and consulting fees from Novartis, Amgen, and Roche, and has received research funding from Novartis and Amgen. Dr. Peter Harper has received honoraria from Eli Lilly, Roche, Pfizer, GSK, and Novartis. Dr. Robert Coleman has received honoraria and consulting fees from Novartis, Amgen, Roche, AstraZeneca, and Pfizer; has received research

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funding from Novartis; and has previously given expert testimony on behalf of Novartis. Dr. Lipton has served as a consultant for Amgen and Novartis; has received honoraria from Amgen, Novartis, and Genentech; has received research funding from Novartis, Monogram Biosciences, and Oncogene Sciences; and has given expert testimony for Novartis. Funding

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Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.

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Acknowledgements

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Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. We thank Duprane Pedaci Young, PhD, ProEd Communications, Inc.® , for her medical editorial assistance with this manuscript.

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References [1] Aapro M, Abrahamsson PA, Body JJ, Coleman RE, Colomer R, Costa L, et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol 2008;19:420−32. [2] Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337−42. [3] Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, et al. Cellular and molecular mechanisms of action of bisphosphonates. Cancer 2000;88:2961−78. [4] Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002;2:584−93. [5] Zometa (zoledronic acid) injection [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2008. [6] Bonefos (disodium clodronate) [package insert]. Oy, Turku, Finland: Bayer Schering Pharma; 2008. [7] Aredia (pamidronate disodium) injection [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2008. [8] Brufsky AM, Bosserman LD, Caradonna RR, Haley BB, Jones CM, Moore HC, et al. Zoledronic acid effectively prevents aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: Z-FAST study 36-month follow-up results. Clin Breast Cancer 2009;9:77−85. [9] Gnant M, Mlineritsch B, Luschin-Ebengreuth G, Kainberger F, Kassmann H, Piswanger-Solkner JC, et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with earlystage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy. Lancet Oncol 2008;9:840−9. [10] Hines SL, Mincey B, Dentchev T, Sloan JA, Perez EA, Johnson DB, et al. Immediate versus delayed zoledronic acid for prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen-N03CC. Breast Cancer Res Treat 2009;117:603−9. [11] Llombart A, Frassoldati A, Paija O, Sleeboom HP, Jerusalem G, Mebis J, et al. Zoledronic acid prevents aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: E-ZO-FAST 36-month follow-up. Poster presented at American Society of Clinical Oncology Breast Cancer Symposium, 2009 [abstract 213]. [12] Shapiro CL, Halabi S, Gibson G, Weckstein DJ, Kirshner J, Sikov WM, et al. Effect of zoledronic acid (ZA) on bone mineral

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

density (BMD) in premenopausal women who develop ovarian failure (OF) due to adjuvant chemotherapy (AdC): first results from CALGB trial 79809. J Clin Oncol 2008;26(Suppl):9s [abstract 512]. Diel IJ, Solomayer EF, Costa SD, Gollan C, Goerner R, Wallwiener D, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998;339:357−63. Powles T, Paterson A, McCloskey E, Schein P, Scheffler B, Tidy A, et al. Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res 2006;8:R13. Saarto T, Vehmanen L, Virkkunen P, Blomqvist C. Ten-year followup of a randomized controlled trial of adjuvant clodronate treatment in node-positive breast cancer patients. Acta Oncol 2004;43:650−6. Diel IJ, Jaschke A, Solomayer EF, Gollan C, Bastert G, Sohn C, et al. Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up. Ann Oncol 2008;19:2007−11. Ha TC, Li H. Meta-analysis of clodronate and breast cancer survival. Br J Cancer 2007;96:1796–801. Coleman RE, Winter MC, Cameron D, Bell R, Dodwell D, Keane MM, et al. The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer. Br J Cancer 2010;102:1099–105. Lin AY, Park JW, Scott J, Melisko M, Goga A, Moasser MM, et al. Zoledronic acid as adjuvant therapy for women with early stage breast cancer and disseminated tumor cells in bone marrow. J Clin Oncol 2008;26(Suppl):20s [abstract 559]. Solomayer EF, Gebauer G, Hirnle P, Janni W, Luck HJ, Becker S, et al. Influence of zoledronic acid on disseminated tumor cells (DTC) in primary breast cancer patients. Presented at 31st Annual San Antonio Breast Cancer Symposium, 2008 [abstract 2048]. Aft R, Naughton M, Trinkaus K, Watson M, Ylagan L, ChavezMacgregor M, et al. Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol 2010;11:421−8. Rack B, Juckstock J, Genss EM, Schoberth A, Schindlbeck C, Strobl B, et al. Effect of zoledronate on persisting isolated tumour cells in patients with early breast cancer. Anticancer Res 2010;30:1807−13. Eidtmann H, de Boer R, Bundred N, Llombart-Cussac A, Davidson N, Neven P, et al. Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST study. Ann Oncol 2010;21:2188−94. Coleman R, Bundred N, de Boer R, Llombart A, Campbell I, Neven P, et al. Impact of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: Z-FAST, ZO-FAST, and E-ZO-FAST. Presented at 32nd Annual San Antonio Breast Cancer Symposium, 2009 [abstract 4082]. Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Postlberger S, Menzel C, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009;360:679−91. Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengrueth G, Poestlberger S, Dubsky PC, et al. Mature results from ABCSG-12: Adjuvant ovarian suppression combined with tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with endocrine-responsive early breast cancer. J Clin Oncol 2010;28(Suppl):74s [abstract 533]. Coleman RE, Thorpe HC, Cameron D, Dodwell D, Burkinshaw R, Keane M, et al. Adjuvant treatment with zoledronic acid in stage II/III breast cancer. The AZURE trial (BIG 01/04). Presented at 33rd Annual San Antonio Breast Cancer Symposium, 2010 [abstract S4-5]. Mystakidou K, Katsouda E, Parpa E, Kelekis A, Galanos A, Vlahos L. Randomized, open label, prospective study on the effect of zoledronic acid on the prevention of bone metastases in patients with recurrent solid tumors that did not present with bone metastases at baseline. Med Oncol 2005;22:195–201.

L. Costa et al. / Critical Reviews in Oncology/Hematology 77 S1 (2011) S31−S37 [29] Zaghloul MS, Boutrus R, El-Hossieny H, Kader YA, El-Attar I, Nazmy M. A prospective, randomized, placebo-controlled trial of zoledronic acid in bony metastatic bladder cancer. Int J Clin Oncol 2010;15:382−9. [30] Zarogoulidis K, Boutsikou E, Zarogoulidis P, Eleftheriadou E, Kontakiotis T, Lithoxopoulou H, et al. The impact of zoledronic acid therapy in survival of lung cancer patients with bone metastasis. Int J Cancer 2009;125:1705−9. [31] Aviles A, Nambo MJ, Neri N, Castaneda C, Cleto S, HuertaGuzman J. Antitumor effect of zoledronic acid in previously untreated patients with multiple myeloma. Med Oncol 2007;24:227−30. [32] Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, et al. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet 2010;376:1989−99. [33] Gnant M. Bisphosphonates in the prevention of disease recurrence: current results and ongoing trials. Curr Cancer Drug Targets 2009;9: 824−33. [34] Green JR, Guenther A. The backbone of progress − preclinical studies and innovations with zoledronic acid. Crit Rev Oncol Hematol 2011;77(1):S3−12. [35] Santini D, Martini F, Fratto ME, Galluzzo S, Vincenzi B, Agrati C, et al. In vivo effects of zoledronic acid on peripheral gammadelta T lymphocytes in early breast cancer patients. Cancer Immunol Immunother 2009;58:31−8. [36] Santini D, Vincenzi B, Galluzzo S, Battistoni F, Rocci L, Venditti O, et al. Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients. Clin Cancer Res 2007;13:4482−6. [37] Benzaid I, Monkkonen H, Stresing V, Bonnelye E, Green J, Monkkonen J, et al. Zoledronic acid-induced IPP/ApppI (phosphoantigen) accumulation in human breast cancer cells correlates with Vg9Vd2 T cell-mediated cancer cell death in vitro and in vivo. Presented at International Bone and Mineral Society Meeting, 2010 [abstract 93]. [38] Clezardin P, Ebetino FH, Fournier PGJ. Bisphosphonates and cancerinduced bone disease: beyond their antiresorptive activity. Cancer Res 2005;65:4971−4. [39] Normanno N, Gallo M, Lamura L, De Luca A. Effect of zoledronic acid acts on the interaction between mesenchymal stem cells and breast cancer cells within the bone microenvironment. J Clin Oncol 2010;28(Suppl):748s [abstract 10602]. [40] Norton L, Massague J. Is cancer a disease of self-seeding? Nat Med 2006;12:875−8. [41] Clines GA, Guise TA. Molecular mechanisms and treatment of bone metastasis. Expert Rev Mol Med 2008;10:e7. [42] Meads MB, Hazlehurst LA, Dalton WS. The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance. Clin Cancer Res 2008;14:2519−26. [43] Shiozawa Y, Havens AM, Pienta KJ, Taichman RS. The bone marrow niche: habitat to hematopoietic and mesenchymal stem cells, and unwitting host to molecular parasites. Leukemia 2008;22:941−50. [44] Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1889;1:571−3. [45] Lipton A, Zheng M, Seaman J. Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer 2003;98:962−9. [46] Lipton A, Cook R, Saad F, Major P, Garnero P, Terpos E, et al. Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid. Cancer 2008;113:193–201. [47] Lipton A, Cook RJ, Major P, Smith MR, Coleman RE. Zoledronic acid and survival in breast cancer patients with bone metastases and elevated markers of osteoclast activity. Oncologist 2007;12: 1035−43. [48] Hirsh V, Major PP, Lipton A, Cook RJ, Langer CJ, Smith MR, et al. Zoledronic acid and survival in patients with metastatic bone disease

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

S37

from lung cancer and elevated markers of osteoclast activity. J Thorac Oncol 2008;3:228−36. Body J-J, Cook R, Costa L, Brown J, Terpos E, Saad F, et al. Possible survival benefits from zoledronic acid treatment in patients with bone metastases from solid tumors and poor prognostic features. Presented at XI International Meeting on Cancer Induced Bone Disease, 2009 [abstract 71]. Saad F, Lipton A, Cook R, Chen Y-M, Smith M, Coleman R. Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer 2007;110:1860−7. Calderone RG, Nimako K, Leary AN, Popat S, Kipps E, O’Brien MN. Use of zoledronic acid in lung cancer. J Thorac Oncol 2010;5(Suppl 1):S99–S100 [abstract 253P]. Facchini G, Caraglia M, Morabito A, Marra M, Piccirillo MC, Bochicchio AM, et al. Metronomic administration of zoledronic acid and taxotere combination in castration resistant prostate cancer patients: phase I ZANTE trial. Cancer Biol Ther 2010;10:543−8. Frassoldati A, Brufsky A, Bundred N, Lambert-Falls R, Hadji P, Schenk N, et al. Effect of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: a 24month integrated follow-up of the Z-FAST/ZO-FAST trials. Presented at Primary Therapy of Early Breast Cancer 11th International Conference, 2009 [abstract 132]. Neville-Webbe HL, Gnant M, Coleman RE. Potential anticancer properties of bisphosphonates. Semin Oncol 2010;37(Suppl 1):S53– S65. Dieli F, Vermijlen D, Fulfaro F, Caccamo N, Meraviglia S, Cicero G, et al. Targeting human gd T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer. Cancer Res 2007;67:7450−7. Santini D, Fratto ME, Galluzzo S, Vincenzi B, Tonini G. Are bisphosphonates the suitable anticancer drugs for the elderly? Crit Rev Oncol Hematol 2009;69:83−94. Saad F, Lipton A. Zoledronic acid is effective in preventing and delaying skeletal events in patients with bone metastases secondary to genitourinary cancers. BJU Int 2005;96:964−9. Morgan GJ. Can bisphosphonates improve outcomes in patients with newly diagnosed multiple myeloma? Crit Rev Oncol Hematol 2011; 77(1):S24−30.

Biography Luis Costa, MD, PhD, is Professor of Medicine at the Faculdade de Medicina de Lisboa at the University of Lisbon, Portugal, and Director of the Oncology Division at the University Hospital de Santa Maria in Lisbon. Professor Costa is a certified member of the European Society for Medical Oncology and Head of the Clinical Translational Oncology Research Unit of the Molecular Medicine Institute at the University of Lisbon, and has also served as a visiting Professor at The University of Texas MD Anderson Cancer Center. Professor Costa’s clinical research, publications, and scientific presentations have focused on bone metastases and breast cancer. Professor Costa was nominated head of the Breast Unit at Hospital de Santa Maria. He is a member of the Portuguese Board of Internal Medicine, the Portuguese Board of Medical Oncology, the American Society of Clinical Oncology, and the European Association for Cancer Research. Professor Costa is an FP7 expert for the European Commission.