Background Bisphosphonates are effective against the increasedbone resorption caused by certain diseases because they inhibitthe activity of osteoclasts. In patients who have breast cancerand metastatic bone disease, the bisphosphonate clodronate (clodronicacid) reduces the frequency of skeletal complications. Experimentsin animals and preliminary clinical observations indicate thatearly clodronate therapy reduces the incidence of new bony metastasesin breast cancer. We investigated the effects of clodronateon the incidence and extent of new metastases in patients withbreast cancer.
Methods Between 1990 and 1995, 302 patients with primary breastcancer and tumor cells in the bone marrow (the presence of whichis a risk factor for the development of distant metastases)were randomly assigned to receive clodronate at a dose of 1600mg per day orally for two years (157 patients) or standard follow-up(145 patients). The median length of observation was 36 months.All patients in both groups received standard surgical treatmentand customary hormonal therapy or chemotherapy.
Results Distant metastases were detected in 21 patients in theclodronate group and in 42 patients in the control group (P<0.001).The incidence of both osseous and visceral metastases was significantlylower in the clodronate group than in the control group (P=0.003for both osseous and visceral metastases). Six patients in theclodronate group died, as did 22 in the control group (P=0.001).The mean number of bony metastases per patient in the clodronategroup was roughly half that in the control group (3.1 vs. 6.3).
Conclusions Clodronate can reduce the incidence and number ofnew bony and visceral metastases in women with breast cancerwho are at high risk for distant metastases.
Bisphosphonates are pyrophosphate analogues that inhibit theformation and dissolution of calcium phosphate crystals in vitro.In vivo, bisphosphonates bind strongly to hydroxyapatite onthe bone surface. Used therapeutically, bisphosphonates inhibitosteoclast-mediated bone resorption by mechanisms that are notfully understood.1,2,3 Clinical trials have demonstrated theanti-osteolytic effect of bisphosphonates in patients with breastcancer and bone metastases. In such patients, bisphosphonatessignificantly reduced the incidence of hypercalcemia, bone pain,and pathologic fractures, but overall survival was not prolonged.4,5,6In experiments in animals, bisphosphonates have been shown toproduce a significant reduction in the appearance of new metastasesto bone.7,8 Clodronate (clodronic acid), a bisphosphonate, wasalso shown to reduce the number of new skeletal metastases inpatients with breast cancer who had advanced local or distantdisease without preexisting bony metastases.9
In the present study, we evaluated the effect of treatment withoral clodronate (Ostac, Boehringer Mannheim, Mannheim, Germany)during a period of two years in patients with primary breastcancer. The primary end points were the incidence and numberof new bony and visceral metastases and the length of time totheir appearance; skeletal complications were not included inthese end points. Only patients in whose bone marrow tumor cellswere found at the time of surgery were enrolled in the study.Even if there is no involvement of the axillary lymph nodes,the presence of tumor cells in the bone marrow (minimal residualcancer) portends a high risk of subsequent metastasis.10,11
Methods
Patients
This prospective, randomized, and non–placebo-controlledstudy was carried out at the University Hospital Heidelbergbetween February 1990 and April 1997 (enrollment of patientsended in November 1995). The criteria for inclusion were primarybreast cancer that was classified as being at stage T1, T2,T3, or T4 and histologically classified as stage N0, N1, orN2 (i.e., tumor size ranged from less than 2 cm to more than5 cm, and ipsilateral lymph-node metastases were either absentor present and, if present, either movable or fixed) (Table 1);immunocytochemical detection of at least one tumor cellin a bone marrow aspirate; and provision of written informedconsent. Criteria for exclusion were confirmed distant metastasis,previous or simultaneous secondary malignant disease, neoadjuvantchemotherapy or hormone therapy, skeletal disease, serious functionaldisorders of the liver or kidneys, and pregnancy. The studydesign was reviewed and approved by the ethics board of theFaculty of Clinical Medicine of the University of Heidelberg.
Table 1. Clinical and Pathological Factors in the 302 Patients with Breast Cancer in Whom Tumor Cells Were Detected in Bone Marrow.
The inclusion criteria were met by 302 patients, who were randomlyassigned either to treatment with clodronate or to the controlgroup. Randomization was carried out postoperatively after theresults of the histologic examination, assessment of prognosticfactors, and tumor-cell immunocytologic studies had been received,but before a decision was made regarding adjuvant systemic treatment.No stratification according to the type of adjuvant treatmentwas undertaken. The control group consisted of 145 patients,3 of whom refused to undergo follow-up examinations, leaving142 patients who could be evaluated. Of the 157 patients inthe bisphosphonate group, 13 were excluded because therapy wasstopped for unknown reasons (4 patients), because of side effects(7), or because there was insufficient compliance with therapyin the first two to three months (2). Two additional patientswere lost to follow-up, leaving 142 patients in the bisphosphonategroup who could be evaluated. All 302 patients were includedin the intention-to-treat analysis.
Therapy
The primary surgical therapy consisted of either mastectomyor breast-conserving surgery (lumpectomy or segmental resectionplus 50 Gy of radiotherapy to the breast). Axillary lymphadenectomy(levels I and II) and iliac-crest bone marrow aspiration werecarried out in all patients. The marrow was processed, stained,and evaluated according to a standardized procedure, as describedelsewhere.10,11 Tumor cells in bone marrow were identified immunocytologicallyby the presence of the tumor-associated glycoprotein TAG 12.
Adjuvant systemic therapy was based on the recommendations ofthe German Adjuvant Breast Cancer Group and the guidelines ofthe St. Gallen Consensus Conferences. All patients with axillary-lymph-nodeinvolvement and all node-negative patients with other factorsindicating a poor prognosis received adjuvant systemic treatment.Menopausal status, steroid hormone–receptor status, andtumor size were taken into account in making therapeutic decisions,but the presence or absence of tumor cells in bone marrow wasnot a factor in the decision. Patients were treated with 30mg of tamoxifen daily for 2 years (92 patients); standard cyclophosphamide(500 mg per square meter of body-surface area), methotrexate(40 mg per square meter), and fluorouracil (600 mg per squaremeter) on day 1 and day 8 of every 28-day cycle for six cycles(63 patients); six cycles of cyclophosphamide (600 mg per squaremeter) and epirubicin (90 mg per square meter) every 21 days,with or without 600 mg of fluorouracil per square meter (17patients); 3.6 mg of goserelin monthly for 2 years (27 patients);or a combination of tamoxifen plus cyclophosphamide, methotrexate,and fluorouracil (47 patients). Fifty-six patients receivedno further systemic treatment.
Patients assigned to the clodronate group received 1600 mg oforal clodronate per day for two years. They were instructedto take four capsules of clodronate (400 mg each) every morningat least one hour before breakfast and were instructed to takethe capsules only with water and never with meals containingcalcium.
Various endocrine therapies (antiestrogen agents, luteinizinghormone–releasing hormone analogues, aromatase inhibitors,and progestins) were used in patients with confirmed metastases.Antineoplastic agents were given in the event of rapid progressionor extensive metastases. Clodronate therapy was continued inall patients with metastatic disease in the clodronate groupand was started in patients in the control group in whom metastasesto bone were identified. Osteolytic lesions were irradiatedin the event of bone pain or the threat of pathologic fractures.Intravenous clodronate (1500 mg over a period of two hours)was administered to patients with hypercalcemia.
Follow-Up
Follow-up investigations were carried out in the UniversityWomen's Hospital for all patients according to a standard protocol.The interval between investigations was three to four monthsduring the first two years. At every visit, a history was takenand a physical examination was performed; chest radiography,bone scanning, ultrasonographic examination of the liver, andmammography were performed yearly. Laboratory tests (blood countsand measurements of tumor antigens in serum) were carried outevery three months. If there was evidence of metastases to bone,additional x-ray films were obtained of the affected areas.The pattern of metastasis was analyzed at the end of the study.Bone lesions seen on radiographs were assessed by two independentradiologists. Skeletal complications were recorded as events,but they were not included in the statistical analysis.
Statistical Analysis
The initial statistical projection was that, after 36 monthsof follow-up, there would be a difference of 10 percent betweenthe groups in the rate of bony metastasis. This assumption wasbased on our previous studies of tumor-cell detection. The plannedsize of the sample was 300 patients. The data were last updatedin March 1997. The chi-square test was used to assess differencesin the frequency of individual prognostic factors between thegroups. Kaplan–Meier analyses and the log-rank test wereused to investigate differences in overall and metastasis-freesurvival. All P values were two-sided. Statistical data processingwas carried out with SAS software (SAS Institute, Cary, N.C.)and Systat software (Systat, Evanston, Ill.).
Results
Characteristics of the Patients
The median age of the patients was 51 years (range, 24 to 78).Tumors in stage T2 were most common (46 percent of patients),followed by tumors smaller than 2 cm (37 percent) and stageT3 or T4 tumors (17 percent) (Table 1). The nodal status wasnegative in 143 patients (47 percent), whereas the axillarylymph nodes were involved in 159 (53 percent). Of 257 primarytumors tested, 188 (73 percent) were estrogen-receptor–positive;157 of 250 tumors tested (63 percent) were progesterone-receptor–positive.A total of 113 patients (37 percent) were premenopausal, and189 (63 percent) were postmenopausal. With regard to grading,185 of the 263 primary tumors we assessed were grade I or II(70 percent) and 78 were grade III (30 percent) (Table 1). Thechi-square test showed that there were no significant differencesin the distribution of the individual characteristics and prognosticfactors between the clodronate and control groups.
Adjuvant Systemic Treatment
Of the 302 patients who were initially enrolled, 246 (81 percent)received adjuvant systemic treatment (Table 2). There was nosignificant difference in the proportion of patients receivingadjuvant therapy between the control and clodronate groups.
Table 2. Adjuvant Systemic Treatment in Patients with Breast Cancer.
Follow-Up and Pattern of Metastasis
During the median observation period of 36 months, distant metastases(bone or visceral) were detected in 21 women in the clodronategroup and in 42 women in the control group (Table 3). In theclodronate group, metastases to bone developed in 12 women andvisceral metastases in 13 women, whereas in the control groupthere were 25 women with bony metastases and 27 with visceralmetastases. Twenty-two patients (15 percent) in the controlgroup died, as compared with six patients (4 percent) in theclodronate group. Furthermore, the mean number of bony metastasesper patient was about twice as high in the control group (6.3)as in the clodronate group (3.1, P=0.004).
Table 3. Incidence of Metastatic Disease and Death in the Clodronate and Control Groups after a Median Follow-up of 36 Months.
The Kaplan–Meier curves showed significant differencesbetween the two groups in metastasis-free survival (P<0.001)and overall survival (P=0.001) Figure 1). The differences werealso significant with regard to the proportion of patients withbony metastases (P=0.003) and visceral metastases (P=0.003)(Figure 2).
Figure 1. Kaplan–Meier Curves for Metastasis-free Survival and Overall Survival after Primary Surgery among 157 Patients Treated with Clodronate and 145 Controls.
P values were derived with the log-rank test. The numbers of patients below the panels are the numbers at risk.
Figure 2. Kaplan–Meier Curves for Survival Free of Bony Metastases and Survival Free of Visceral Metastases among 157 Patients Treated with Clodronate and 145 Controls.
P values were derived with the log-rank test. The numbers of patients below the panels are the numbers at risk.
Discussion
In this study of women with breast cancer, we found that oraltreatment with 1600 mg of clodronate per day for two years inaddition to standard surgical and systemic therapy significantlyreduced the incidence of osseous and nonosseous metastases.There was an even distribution of possible confounding factorssuch as the receipt of chemotherapy, endocrine therapy, or notherapy, in the two groups of patients, perhaps because of therandomization procedure. After a median follow-up of 36 months,the number of metastatic bony lesions per woman was twice ashigh in the control group as in the clodronate group. All thewomen in this study had a high risk of distant metastases, asindicated by the presence of tumor cells in the bone marrow.We and others have shown that the presence of tumor cells inthe bone marrow is a strong predictor of early hematogenic metastasis.11,12,13Tumor cells were found in the bone marrow in 55 percent of node-positivepatients with breast cancer and 31 percent of node-negativepatients, and their presence was significantly associated withlarger tumors, positive lymph nodes, and other unfavorable prognosticfactors. There was a strong correlation between the presenceof tumor cells in the bone marrow and the subsequent detectionof distant metastasis. Indeed, the presence of tumor cells inthe marrow was found to be the most powerful predictor of outcome,superior even to nodal status in predictive value.11
In about three quarters of women who eventually die of breastcancer, bony metastases develop. Patients with skeletal metastaseshave relatively favorable survival times, but the course oftheir diseases is complicated by bone pain, pathologic fractures,spinal cord compression, and hypercalcemia.14,15,16
Bisphosphonates such as clodronate are potent inhibitors ofbone resorption. They have been used for years to reduce skeletalcomplications of manifest bony metastasis, both in patientswith breast cancer and in those with other types of solid tumor.Although only 4 to 5 percent of clodronate is absorbed whenit is given orally, the efficacy of the drug in disease withmetastases to bone is very good. Furthermore, oral therapy issafe and has a low rate of side effects.6,17,18,19
In the early phase of the metastasis of breast cancer to bone,osteolytic factors produced by the metastatic cells, such asparathyroid hormone–related protein, activate osteoclasts.There is evidence that growth factors, such as transforminggrowth factor and insulin-like growth factor, are released whenbone matrix is degraded. These growth factors may promote theproliferation of tumor cells.20,21 Bisphosphonates can influencethis interaction between tumor cells and bone cells at a veryearly stage. Like other bisphosphonates, clodronate inhibitsbone destruction by inhibiting the activity of osteoclasts.The therapeutic effect of the bisphosphonates is more likelyto be due to a protective effect on uninvolved skeleton thanto recalcification of existing lytic lesions.19,22
In experiments in animals, the timely use of etidronate, clodronate,pamidronate, and risedronate markedly reduced both the extentof tumor-induced osteolysis and the metastatic tumor burden.23,24,25,26,27,28In rats that were simultaneously inoculated with tumor cellsand treated with risedronate, significantly fewer bony metastasesdeveloped than was the case in untreated control animals.7
Elomaa et al.17 reported that the use of clodronate in patientswith breast cancer who already had metastases to bone led toa reduction in the number of new metastases. This observationwas confirmed by Kanis et al.9 in a study of patients with advancedlocal or distant breast cancer but without skeletal involvement.In their study, Kanis et al. found that oral treatment with1600 mg of clodronate per day for three years significantlyreduced the number of new bony metastases.
Our results also show that clodronate significantly reducesthe incidence of new skeletal metastases in women with breastcancer. The mechanism of this effect is uncertain. There areno reports of cytotoxic effects of bisphosphonates at therapeuticdoses, but these compounds can induce apoptosis, at least inosteoclasts and macrophage-like cells, and they can suppressthe paracrine activity of macrophages.29,30,31 There are alsoreports that adhesion molecules on breast-cancer cells and thesurface of the bone matrix are altered by bisphosphonates.32,33Yoneda et al.34 showed that the combination of the bisphosphonateibandronate (ibandronic acid) and the tissue inhibitor of matrixmetalloproteinase 2 reduced bony metastases when human breast-cancercells were inoculated into immunodeficient mice.
Because the observation period was only 36 months in the presentstudy, the results may simply have been due to a drastic reductionin the growth of bony metastases, rendering them undetectableby conventional means. Later follow-up will show whether clodronatemerely prolonged bony-metastasis–free survival or whetherbony metastases were actually prevented from developing.
The reduction in nonosseous metastases in the group of womengiven clodronate was unexpected. This effect has never beenseen in experiments in animals. In fact, some investigatorsfeared that bisphosphonates could lead to a shift in the patternof metastasis toward a greater frequency of visceral metastases.The processes relevant to osseous metastasis (apoptosis andalteration of adhesion molecules and proteases) could, however,also have a role in the development of visceral metastasis.Another factor may be synergy between cytotoxic agents and bisphosphonates.There is little evidence of such synergy, but investigationsin animal models have shown that combinations of paclitaxeland alendronate35 and of ibandronate and doxorubicin (YonedaT, Mundy GR: personal communication) are more effective thanthe compounds given individually in preventing the occurrenceand development of new osseous and nonosseous metastases. Weassume that bisphosphonates interfere with the adhesion andinvasiveness of tumor cells by changing the microenvironment,whereas cytotoxic drugs suppress cell proliferation. We suggestthat by attacking tumor cells and changing the microenvironmentat the metastatic site, the combination of bisphosphonates andcytotoxic agents produces a "two-hit" effect that reduces thedevelopment of metastases in patients with breast cancer.
Supported by a grant from Boehringer Mannheim.
Source Information
From the Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg (I.J.D., E.-F.S., C.G., R.G., D.W., G.B.); and the Department of Obstetrics and Gynecology, University of Frankfurt, Frankfurt (S.D.C., M.K.) — both in Germany.
Address reprint requests to Dr. Diel at the Department of Obstetrics and Gynecology, University Hospital, Voss Strasse 9, 69115 Heidelberg, Germany.
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Clodronate in Metastatic Breast Cancer
Meli M., Rausa L., Panasci L. C., Sandor V., Melnychuk D., Atkins C. D., Diel I. J., Costa S. D., Kaufmann M.
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N Engl J Med 1998;
339:1940-1941, Dec 24, 1998.
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