267Clinical Lung Cancer March 2004

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Rationale _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _• Bone metastases occur in 30%-40% ofpatients with lung cancer and are com-monly osteolytic in nature. Patients withlung cancer who develop bone metastaseshave a median survival of < 6 months, and55% of this subpopulation of patients willexperience ≥ 1 skeletal-related events(SREs) over a median follow-up of 6months.1,2 Hypercalcemia, pathologicfractures, spinal compression, and painare adverse SREs caused by bone metas-tases that increase morbidity and affectpatients mobility and quality of life. Treat-ments for SREs include radiation therapy,surgery, analgesics, and bisphosphonates.

• Bisphosphonates are stable analogues of py-rophosphate that have shown treatment ben-efit for bone metastases resulting from multi-ple myeloma, metastatic breast, and prostatecancers.3-6 Bisphosphonates bind to hydrox-yapatite on bone where they are internalizedby osteoclasts and induce apoptosis in thesecells with the result that tumor-induced boneresorption is decreased. Bisphosphonatessuch zoledronic acid, with an alkylamine (N)group at the bridging carbon atom betweenthe 2 phosphate atoms, are more potent thanother phosphonate moieties.

• N-bisphosphonates inhibit the enzymefarnesyl diphosphate (FPP) synthase in themevalonate pathway.7 The products down-stream of FPP in the mevalonate pathwayare farnesyl and geranylgeranyl moietiesthat are important for the prenylation ofsignaling molecules, including the pro-tooncogenes Ras and Rho. In vitro studiespoint to additional antitumor effects ofN-bisphosphonates that may or may not be

related to inhibition of the mevalonatepathway. N-bisphosponates reportedly in-hibit angiogenesis,8 cell adhesion,9 and ma-trix metalloproteases,10 and may also worksynergistically with cytotoxic agents.11

• Preclinical studies have compared variousbisphosphonates with regard to inhibitionof FPP synthase and induction of Apppiproduction. Inhibition by zoledronate wassuperior to the non–N-bisphosphonatesclodronate and alendronate, the primaryamine-containing ibandronate, and thetertiary amine-containing risedronate.When combined with chemotherapeuticagents, zoledronate enhanced the cytostaticeffect of docetaxel and gemcitabine on PC-3prostate cancer cells12 and synergisticallyinduced apoptosis with paclitaxel and dox-orubicin in MCF-7 breast cancer cells.11

• Bisphosphonates play an important rolein palliating the complications associatedwith bony metastases. N-bisphosphonateseffectively treat acute hypercalcemia of ma-lignancy and reduce the risk and incidenceof SREs in multiple myeloma, metastaticbreast cancer, and prostate cancer.3-6,13

• Older bisphosphonates like pamidronatehave demonstrated a durable objective ben-efit for patients with bone involvementfrom breast cancer or multiple myeloma.

Zoledronic acid, on the other hand, hasalso shown a benefit in patients with bonemetastases due to prostate cancer.

• A prospective trial (Trial 011) comparingthe efficacy of zoledronic acid to placebo inpatients with lung cancer and other solidtumors other than breast cancer hasdemonstrated promising results.14

Trial 011 DesignTrial 011 was designed as a prospective,

double-blinded, randomized, 3-arm phaseIII trial to examine the efficacy and safety ofzoledronic acid in patients with bonemetastases caused by lung cancer and othersolid tumors (Figure 1).14 The primary ob-jective was to determine whether zoledron-ic acid reduced the proportion of patientswith an SRE during 9 months of treatment.Hypercalcemia of malignancy was original-ly excluded as an SRE in this analysis be-cause the efficacy of zoledronic acid in thetreatment of this disorder had not been es-tablished. Skeletal-related events were limit-ed to pathologic fracture, spinal cord com-pression, radiation therapy or surgery tobone. Secondary objectives included timeto the first SRE, skeletal morbidity rate(SRE/year), and a multiple-event analysis.Patients were randomized to receive zole-dronate at a dose of 4 mg or 8 mg, or to re-ceive placebo every 3 weeks for 9 months.

Prepared by: Nancy Price, PhD Reviewed by: Chandra P. Belani, MD, Vinay K. Jain, MD

Bisphosphonates to Prevent Skeletal Morbidity in Patientswith Lung Cancer with Bone Metastases

Electronic forwarding or copying is a violation of US and International Copyright Laws.Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1525-7304, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.

Figure 1: Treatment Schema and Protocol Amendments for Trial 01114

*Amendment 1, June 1999: Infusion time increased from 5 minutes to 15 minutes.†Amendment 2, June 2000: 8-mg arm reduced to 4 mg.Abbreviations: NSCLC = non–small-cell lung cancer; SCLC = small-cell lung cancer

Zoledronic Acid* 4 mg every 3 weeks

Zoledronic Acid*† 8 mg every 3 weeks

Placebo every 3 weeks

Patients with NSCLC, SCLC, and other solid tumors were

stratified by tumor type

RANDOMIZE

268 Clinical Lung Cancer March 2004

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ief Eligible patients had at least one site of

bone metastases that was secondary tolung cancer or another solid tumor typeand an Eastern Cooperative OncologyGroup performance status of ≤ 2. Bonemetastases could be osteolytic, osteoblas-tic, or of mixed type. Patients were ex-cluded if they had liver metastases andbilirubin levels in excess of 2.5 mg/dL,creatinine levels > 3 mg/dL, or the pres-ence of symptomatic brain metastases. Pa-tients who had had more than one expo-sure to a bisphosphonate within 30 days,severe cardiovascular disease, hyperten-sion that was refractory to treatment,symptomatic coronary artery disease, orpregnancy within 6 months of random as-signment were also excluded.

Tumor assessment, bone scan, andbone survey were performed before thecommencement of treatment and at 3, 6,and 9 months after starting treatment.The Brief Pain Inventory composite painscore was assessed every 6 weeks. Howev-er, SREs and adverse events were assessedat every 3-week treatment visit.

Patient CharacteristicsA majority of patients had lung cancer

(57%; Table 1). Patients were stratified bytumor type before randomization into 1 of3 treatment arms. Sixty-nine percent of pa-tients had ≥ 1 prior SRE. Of 254 patientsin the 4-mg arm, 158 were male, as were186 of 265 in the 8-mg arm, and 159 of247 in the placebo arm.

ResultsThe protocol was amended twice (Fig-

ure 1). Initially, patients received zoledron-ic acid in a 50-mL volume over a 5-minuteinfusion. Because of renal safety concerns,the protocol was modified in June 1999 toincrease the infusion time to 15 minutes.Patients were to receive zoledronic acid ata dose of 4 mg or 8 mg, or to receive place-bo every 3 weeks for 9 months. A secondprotocol amendment occurred in June2000 because of concerns about the renaltolerability of the 8-mg dose of zoledronicacid. Patients originally assigned to the 8-mg arm continued treatment thereafter atthe 4-mg dose, and this arm becameknown as the 8/4-mg arm. Since all pa-

tients were enrolled before the date of thesecond protocol amendment, 198 of thepatients in this arm had already completedor discontinued their treatment at the 8-mg dose; however, 67 patients were still re-ceiving treatment and were switched to thelower dose. Serum creatinine was moni-tored for the remainder of the trial, and allpatients received supplements includingvitamin D and calcium.

When patients with hypercalcemia ofmalignancy were excluded in the assess-

ment of SREs, there was a numerical im-provement in the primary endpoint of re-ducing the proportion of SREs but this didnot reach statistical significance in the 4-mg arm when compared to placebo, with38% of patients in the 4-mg arm having anSRE compared with 44% in the placeboarm (Table 2). However, only 35% of pa-tients in the 8/4-mg arm had an SRE,which did reach statistical significancecompared with the placebo arm (P = 0.023).When patients with hypercalcemia of malig-

Table 2: Efficacy

ParameterTime to Progression

of Bone Lesions SREs/YearProportion

of SREsExcluding HCM

Median Timeto First SRE

Excluding HCM

Zoledronic Acid

4 mg

8/4 mg*

Placebo

*Patients in this group were initially given 8 mg of zoledronic acid, but dose was decreased to 4 mg.†Not including HCM.P values are comparing zoledronate acid dose (either 4 mg or 8/4 mg) with placebo.Abbreviations: HCM = hypercalcemia of malignancy; SRE = skeletal-related events

38%(P = 0.127)

35%(P = 0.023)

44%

230 Days(P = 0.023)

219 Days(P = 0.034)

163 Days

145 Days(P = 0.109)

238 Days(P = 0.009)

109 Days

2.24†

(P = 0.069)

1.55†

(P = 0.005)

2.52†

Table 1: Patient Characteristics by Treatment Arm

CharacteristicZoledronic Acid

8 mg(n = 265)

Placebo(n = 247)

Zoledronic Acid4 mg

(n = 254)

Cancer Type (Number of Patients)

NSCLC

SCLC

Renal cell

Head and neck

Thyroid

Other

Unknown primary

Median Age (Years)

Previous Skeletal-Related Events

Yes

No

BPI Pain Score

134

22

28

7

5

53

16

62

180

85

3.3

120

19

19

4

4

64

17

64

179

68

3.3

Abbreviations: BPI = brief pain inventory; NSCLC = non–small-cell lung cancer; SCLC = small-cell lung cancerAdapted with permission from Rosen LS et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial--the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 2003; 21:3150-3157.

124

17

27

6

2

60

18

64

166

88

3.5

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nancy were included in the analysis, the 4-mg arm did reach statistical significancewith 38% SREs compared with 47% in theplacebo arm (P = 0.039). Zoledronic aciddecreased the proportion of patients experi-encing each category of SRE (ie, fractures,etc.), but only hypercalcemia of malignancy

showed a statistically significant decreasecompared with placebo (Table 3).

Of note, zoledronic acid significantly ex-tended the median time to the first SRE bymore than 2 months (P = 0.009) and de-creased the skeletal morbidity rate per yearin the 8/4 mg arm (P = 0.005) as shown inTable 2. The multiple-event analysisshowed that zoledronate significantly de-creased the risk of multiple events by 31%in the overall group of patients (P = 0.003),33% in patients with non–small-cell lungcancer (P = 0.016), and 58% in patientswith renal cell carcinoma (P = 0.01; Table4). Zoledronate did not affect overall dis-ease progression or survival.

The most frequently reported toxicitieswere bone pain and nausea and occurredwith similar frequency in all 3 arms.

ConclusionsSkeletal metastases complicate the clini-

cal course of many patients with lung can-cer. Zoledronic acid effectively reduced theproportion of SREs and reduced the risk ofdeveloping multiple SREs in patients withlung cancer and other solid tumors with asafety profile similar to the placebo. Theability of zoledronic acid to produce an ob-jective benefit for patients with lung cancerfills a significant unmet medical need inthis patient population.

References _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _1. Coleman RE. Skeletal complications of malignancy.

Cancer 1997; 80:1588-1594.2. Tchekmedyian S, Rosen LS, Gordon D., et al. Long-

term efficacy and safety of zoledronic acid in reducing

skeletal complications in patients with bone metas-tases from solid tumors. Proc Am Soc Clin Oncol2003; 22:630 (Abstract #2532).

3. Saad F, Gleason DM, Murray R, et al. A randomized,placebo-controlled trial of zoledronic acid in patientswith hormone-refractory metastatic prostate carcino-ma. J Natl Cancer Inst 2002; 94:1458-1468.

4. Rosen LS, Gordon DH, Dugan W, Jr, et al. Zoledron-ic acid is superior to pamidronate for the treatment ofbone metastases in breast carcinoma patients with atleast one osteolytic lesion. Cancer 2004; 100:36-43.

5. Rosen LS, Gordon D, Kaminski M, et al. Long-term ef-ficacy and safety of zoledronic acid compared withpamidronate disodium in the treatment of skeletal com-plications in patients with advanced multiple myelomaor breast carcinoma: a randomized, double-blind, multi-center, comparative trial. Cancer 2003; 98:1735-1744.

6. Berenson JR, Rosen LS, Howell A, et al. Zoledronicacid reduces skeletal-related events in patients with os-teolytic metastases. Cancer 2001; 91:1191-1200.

7. Dunford JE, Thompson K, Coxon FP, et al. Structure-activity relationships for inhibition of farnesyl diphos-phate synthase in vitro and inhibition of bone resorp-tion in vivo by nitrogen-containing bisphosphonates.J Pharmacol Exp Ther 2001; 296:235-242.

8. Wood J, Bonjean K, Ruetz S, et al. Novel antiangiogeniceffects of the bisphosphonate compound zoledronicacid. J Pharmacol Exp Ther 2002; 302:1055-1061.

9. Pickering LM, Mansi JL, Colston KW, et al. Adhesion ofbreast cancer cells to extracellular matrices is inhibited byzoledronic acid and enhanced by aberrant Ras signalling.Proc Amer Soc Clin Oncol 2003; 22:863 (Abstract #3468).

10. Valleala H, Hanemaaijer R, Mandelin J, et al. Regula-tion of MMP-9 (gelatinase B) in activated humanmonocyte/macrophages by two different types of bis-phosphonates. Life Sci 2003; 73:2413-2420.

11. Jagdev SP, Coleman RE, Shipman CM, et al. The bis-phosphonate, zoledronic acid, induces apoptosis ofbreast cancer cells: evidence for synergy with paclitax-el. Br J Cancer 2001; 84:1126-1134.

12. Ullen AL, Lennartsson M, Hjelm-Eriksson M, et al.Additive/synergistic anti-tumoral effects on prostatecancer cells in vitro following treatment with a combi-nation of gemcitabine and zoledronic acid. Proc AmSoc Clin Oncol 2003; 22:432 (Abstract #1737).

13. Lipton A, Small E, Saad F, et al. The new bisphosphonate,Zometa (zoledronic acid), decreases skeletal complicationsin both osteolytic and osteoblastic lesions: a comparison topamidronate. Cancer Invest 2002; 20(suppl 2):45-54.

14. Rosen LS, Gordon D, Tchekmedyian S, et al. Zole-dronic acid versus placebo in the treatment of skeletalmetastases in patients with lung cancer and other solidtumors: a phase III, double-blind, randomized trial--theZoledronic Acid Lung Cancer and Other Solid TumorsStudy Group. J Clin Oncol 2003; 21:3150-3157.

Table 3: Proportion of Patients Experiencing Individual Skeletal-Related Events*

Skeletal-Related Events

Placebo P ValueZoledronateAcid 4 mg

BoneRadiation

PathologicFractures

Surgery to Bone

Spinal CordCompression

Hypercalcemiaof Malignancy

34%

22%

5%

4%

4%

NS

NS

NS

NS

0.05

*21-Month data.Abbreviation: NS = not significant

29%

16%

4%

3%

0

Table 4: Risk Reduction by Patient Population14

Cancer P ValueRisk Reduction

Solid Tumors

Lung Cancer

Renal Cell Carcinoma

0.003

0.016

0.01

31%

33%

58%