Bisphosphonates in oncology: Breast cancer and beyond

Bisphosphonates in oncology: Breast cancer and beyond

Bisphosphonates in Oncology: Debu Breast ciated cancer with frequently increased Bisphosphonates spreads osteoclastic exert osteoclast activi...

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Bisphosphonates

in Oncology: Debu

Breast ciated

cancer with

frequently increased

Bisphosphonates

spreads osteoclastic

exert

osteoclast

activity

frequency of breast cancer

to

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overall oncology

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REAST CANCER FREQUENTLY spreads to bone and is almost always associated with osteolysis caused by increased osteoclastic bone resorption. The molecular mechanisms by which tumor cells metastasize to bone are likely to involve invasion, cell adhesion to bone, and the release of soluble mediators from tumor cells that stimulate osteoclast-mediated bone resorption. The osteoclast is, therefore, a suitable site for therapeutic intervention in the bone metastatic process. Bisphosphonates are powerful inhibitors of osteoclast activity and are used in combination with standard chemotherapy or hormonal therapy for

From the Carol Franc Buck Breast Cancer Center, Department of Medicine and Cancer Center, University of California at Sun Francisco, CA. Dr Tripathy has sewed on the speakers’ bureau for F Hoffmann-la Roche. Address reprint requests to Debu Tripathy, MD, Associate Clinical Professor of Medicine, Carol Franc Buck Breast Cancer Center, Department of Medicine and Cancer Center, Box f714, University of California at San Francisco, CA 94930. Copyright 0 2001 by W.B. Saunders Company 0093-7754/01/2804-1116$35.00/O doi:l0.1053/sonc.2001.25443 86

Breast

Cancer

and

Beyond

Tripathy

the treatment of cancer-associated osteolytic metastases. The precise mechanism by which bisphosphonates inhibit osteoclast activity is still unclear; it may include inhibition of osteoclast formation as well as increased apoptosis in mature osteoclasts. Direct antineoplastic effects,i and poorly understood effects on bone pain may occur and animal models have shown that bisphosphonates are capable of suppressing the growth and spread of bone metastases, affecting the adhesion of tumor cells to bone matrix and delaying/decreasing bone complications from both malignant and nonmalig nant bone metastases.213 As a consequence of bisphosphonate-mediated inhibition of osteoclast activity, there is a marked reduction in the skeletal events associated with metastatic cancer to bone, such as pain, fracture, and hypercalcemia.4 However, and possibly even more importantly, there is also a reduction of tumor burden in bone.5 In experimental situations, this has been shown to affect not only morbidity but also survival.6 Nevertheless, studies have reported varying results with regard to the effect of bisphosphonates on survival rates in patients with breast cancer and bone metastases. It is thought that the nonconfirmatory nature of these results can largely be attributed to differences in study design, particularly the choice of primary and secondary outcome measures. This article discusses future prospects for the use of bisphosphonates in breast cancer and beyond. Methodologic problems that may present barriers (or opportunities) to research in this field are discussed based on experience from past studies. DEFINING ENDPOINTS IN BISPHOSPHONATE STUDIES

At present, bisphosphonatesare not used as antitumor agents, but rather as palliative treatment for the effects of cancer on the skeleton. Clinical endpoints used in the design of trials of bisphosphonatetherapy have to be sensitive to the perspective of patient care. Studiesmust be able to show that a reduction in the rate of osseousrecurrence translates into an improvement in overall survival, disease-freesurvival, or an improvement in quality of life through a reduction of adverse skeletal events.7 Seminon

in Oncology, Vol 28, No 4, Suppl I I (August),

200 I : pp 86-9 I

BISPHOSPHONATES

FOR

BREAST

CANCER

NO. Study Powles

AND

87

Metastases

(2-S

Patients

Clodronate

Versus

et allo

Bone

BEYOND

1,079

28 (5.2%)

versus

Die1 et al9

302

8% versus

17%

Saarto

299”

et al ’ ’

Year

Follow-up)

Disease-Free

Placebo

state

Overall

(%)

-

44 (8. I %)* -

Survival 6) NS

87% versus

7 I%

96% versus

85%

52% versus

69%

86% versus

8 I%

"P = ,054. *Patients

received

therapy

SURVIVAL: THE CLINICAL

with

cyclophosphamide,

methotrexate,

GOLD STANDARD ENDPOINT

Improvements in survival time of certain subgroups of patients have been found in several phaseIII studieswith bisphosphonates.8However, these studieswere not powered to detect survival time as a primary or secondary outcome measure, thus, these results can only be seen as important indicators for future research.8 To date, only three major trials have examined the effect of the bisphosphonate clodronate on survival rates as a primary efficacy parameter of adjuvant therapy in patients with early stagebreast cancer. The first, an open-label controlled trial by Die1 et aI,9 investigated the effects of clodronate on the incidence and extent of new metastasesin patients with breast cancer who were at high risk for developing distant metastaseson the basisof the presenceof bone marrow micrometastases.In total, 302 patients with primary breastcancer were randomized to 2 years’ oral treatment with clodronate (1,600 mg/d) or a control treatment arm of standard follow-up. The study was conducted over a 5year period with a median length of follow-up of 36 months. Patients received standard care (surgical, hormonal, or chemotherapy) during this time. Overall, an increasewasseenin diseasefree and overall survival in patients taking the bisphosphonate therapy (Table 1).9 Significantly fewer women in the clodronate group developed distant metastasesand osseousand visceral metastasescompared with the control group.g Furthermore, the number of bony metastasesper patient in the clodronate group wasroughly half of that in the control group. An interim analysisfrom a larger, multicenter, double-blind, placebo-controlled trial involving 1,079 women with primary operablebreast cancer

fluorouracil

(CSF)

(pretreatment),

or antiestrogens.

reported a significant reduction in osseousmetastasesafter treatment with clodronate (1,600 mg/d) for 2 years (Table l).lO However, disease-freeand overall survival were unchanged compared with the placebo group. In contrast, a third open-label trial, conducted in Finland in 299 patients with lymph node-positive breast carcinoma, did not find clodronate (1,600 mg/d) to have a significant effect on the relapseof bone metastases(Table 1).ll The investigators reported a deleterious effect on relapse rates of nonosseouslmetastases and a deterioration in overall survival after 3 years’ treatment with clodronate. Taken together, the resultsof these studiesare clearly equivocal with regard to the effect of adjuvant clodronate on overall survival rates in patients with breastcancer. The differing effects seen are likely to be attributable to random or methodologic factors, such asdiversity in inclusion criteria and patient populati.ons,use of alternative assessment techniques, and differences in sample size (methodo 1og’ICd’ff 1 erencesbetween thesethree key studiesare discussedin detail by Die1 elsewherein this supplement). It is clear that the bisphosphonateshave a role in the treatment of breastcancer and further investigation of their effects is warranted. Well-designed confirmatory clinical trials are now required to elucidate the true benefits of these agents. MAINTENANCE

OF BONE

HEALTH

Lowering the risk of diseaseprogression,either in the adjuvant setting or in the metastatic setting, preserving bone mineral density, and reducing the risk of osteoporosiscomplications are the key clinical endpoints in breast cancer that are important with regard to bone health.

DEBU

88

Women with breast cancer have an increased risk of developing osteoporosis; those older than 40 years are at particularly high risk.12 A number of factors are involved: (1) the majority of premenopausal breast cancer patients are likely to undergo early menopause because of chemotherapy-induced ovarian failure or oophorectomy, known to be a strong predictor of osteoporosisls; (2) chemotherapy may have a direct adverse effect on bone mineral density, and osteoclastic activity may increase from the breast cancer itself; and (3) though estrogen therapy is considered standard for the prevention and treatment of osteoporosis, use of estrogen in women with a history of breast cancer is usually contraindicated because of its associated risk of breast cancer. Men undergoing androgen deprivation therapy for advanced prostate cancer, a frequently diagnosed condition in the aging male population, are also at increased risk for developing osteoporosis; androgen deprivation has been associated with the loss of bone mineral density in these patientsr4J5 Steroid therapy is occasionally used in patients with breast and prostate cancer. It can also accelerate the loss of bone mineral density and therefore constitutes a risk factor for osteoporosis. Most women in whom early stage breast cancer is detected and treated appropriately will survive. Furthermore, in breast cancer patients with bone metastases, those responding to systemic therapy for their metastases have a good chance of being alive at 3 years, and 20% will be alive at 5 years.16 The bisphosphonates have been shown to decrease chemotherapy-induced bone loss in women with breast cancer.12 Combined with their potential benefits on bone metastases, there is, therefore, a rationale for using the bisphosphonates early in the treatment of this disease. Current standard procedure for postmenopausal women recommends waiting until bone mineral density is below normal before commencing adjuvant therapy. SURROGATE MARKERS FOR BISPHOSPHONATE

TRIPATHY

confidence for an agent to be adopted into clinical practice, these studies require larger samplesizes and longer study durations than those assessing surrogate markers (Table 2). Surrogate biological endpoints may alsoprovide insight into the mechanismsof action underlying the effects of bisphosphonates in the diseaseprocess;knowledge that in itself would permit further refinement of research methodology. DESIGNING

THE OPTIMAL SURROGATE MARKER STUDY

Current knowledge of the effects of bisphosphonates in the metastatic setting indicates that these agents hold much promise for patients with early stage breast cancer and in the adjuvant setting. Clinical studiesare urgently required to check the preliminary, but encouraging, results that have been obtained to date. Defining the optimal population at risk is important to obtain results quickly. A planned study by the National Surgical Adjuvant Breast and Bowel Project (NSABP), and other studies currently in progress,have attempted to maximize the event rate seenin their studiesby selectingsmaller sample sizesconsisting of patients with specific characteristics that put them at high risk for early metastasis(eg, regional lymph node involvement, local progression or tumor cells present in the bone marrow, or patients with elevated concentrations of specific prognostic factors for bone metastasis). Figure 1 is a schematicfor a pilot study designed to assess the feasibility of measuringeradication/ modulation of micrometastasesas a surrogate marker for the assessment of bisphosphonatetherapy. Several lines of evidence suggestthat micrometastasespredict metastatic potential. The larg

AS ENDPOINTS STUDIES

It is possible that surrogate markers, such as circulating micrometastases,bone turnover markers, and bone mineral density may become valuable adjuncts to clinical endpoints in studies of bisphosphonates.Although clinical endpoints are unquestionably required for the drug approval process,to show clinical benefit and to provide the

Smaller

sample

Shorter

study

Biological explain action

size

endpoints mechanisms

More Larger may of

Linkage

definitive sample

(and approvable) size

of markers

endpoints

to clinical

BISPHOSPHONATES

FOR

BREAST

CANCER

AND

89

BEYOND

Primary surgery:

An example of surrogate pilot marker analysis study

Node-positive disease 1 Chemo Rx Radiation Rx Hormonal Rx

Endpoint: BM micrometastases in immediate vs delayed bisphosphonate l

Bone marrow aspirate: ‘PCR . Flow . ICC

1 year

0+

Fig I. Methodologic design for a pilot surrogate marker study to analyze the effect of bisphosphonates in breast cancer.

est body of evidence supports a relationship between bone marrow micrometastases and poorer disease survival.i7Js The presence of micrometastases in patients with primary breast cancer has also been shown to be a useful predictor of early relapse in bone, indicating the clonogenic potential of bone marrow micrometastases.19 Information on bone marrow status may serve as a complement to axillary lymph node status in assessing the prognosis of breast cancer patients and may help in selecting patients for subsequent systemic treatment. The surrogate marker study proposed in Fig 1 will be conducted over 3 years, in patients with breast cancer who test positive for micrometastases by flow cytometry, immunohistochemistry, or reverse transcriptase polymerase chain reaction. Study participants will be randomized to bisphosphonate therapy or a control group who will receive no adjuvant treatment for a period of 1 year, then switch to bisphosphonate for the remainder of the study. The study endpoint will be to assess the difference in bone marrow micrometastases in immediate versus delayed bisphosphonate therapy assessed by an initial bone marrow biopsy at the time of surgery and repeat bone marrow aspirates after 1 and 2 years. The reduction in micrometas

2 years

I

I Start bisphosphonate

Recheck bone marrow aspirate

3 years

Ib Recheck bone marrow aspirate

tases over time is not a validated surrogate of recurrence-free or overall survival, but is a reasonable and testable hypothesis. Although the design of this pilot study will permit the analysis of the surrogate endpoint of micrometastases, it will not be powered to assess the ultimate endpoints of recurrence. The advantages of this type of study design clearly include the longitudinal nature of the fole low-up, which, in addition to enabling assessment of the impact of prolonged therapy, also permits the assessment of the clinical significance of micrometastases over time. Phenotypic and gene, typic characterization of these micrometastatic cells may have some implications on the basic biology of metastases and provide insights into the mechanism of action underlying these disease processes. The design would also allow the comparison; of the effects of different therapies such as the bisphosphonates and hormonal agents, if a two-by: two approach were incorporated. Furthermore, the inclusion of a second treatment arm, in which patients receive bisphosphonate therapy 1 year postdiagnosis, enables the comparison of immediate versus delayed therapy. Retrospective analyses of previous studies with bisphosphonates show

90

DEBU

that therapy was often started long after the diag nosis of osseous lesions; in one study with ibandronate the difference was approximately 200 days.20 This delay may be a contributing factor to some of the differences observed in overall survival outcome. ENDPOINTS

OF TRUE

CLINICAL

USE

In the future, pharmacoeconomic considerations are likely to become increasingly important in making decisionsfrom a clinical practice standpoint, particularly given the number and associated cost of bone health-related disorders.A recent cost-utility study conducted in Canada looked specifically at the bisphosphonate,pamidronate.21 The investigators concluded that the drug provided patients with a substantial quality+ adjustedsurvival benefit at a reasonablecost to the Canadian health care system. Further research is warranted to better determine the cost-benefit consequencesof bisphosphonates. CONCLUSIONS

The gold standardendpoint for oncology studies is clearly overall survival. However, the bisphosphonates have not yet been shown to have a conclusive impact on this critical outcome measure.These agentsgained approval basedon their quality of life merit in terms of beneficial reductions in skeletal complications in cancer patients (ie, the ability to reduce the incidence of pathologic fractures, surgery for fracture or impending fracture, radiation, spinal cord compression,and hypercalcemia). To detect an effect of bisphospho, nates on disease-freeor overall survival it is likely that clinical studies will need to select specific groupsof patients at high risk for diseaseprogression, particularly skeletal. The study by Die1 et al9 suggeststhat patients with histologically detectable bone marrow involvement, but without radiologic evidence of bone metastasis,may be an appropriate group for such studies. The newer bisphosphonates,with more patient-friendly oral and intravenous administration regimens,offer the potential for long-term adjuvant use with good patient compliance. Quality of life outcomesare undoubtedly crucial endpoints from the patient’s perspective and bisphosphonateshave been shown to provide a meaningful supportive benefit to many patients with bone metastasesarising from breast cancer.

TRIPATHY

However, further researchinto the useof markers of bone turnover and micrometastasesassurrogate endpoints will help to provide insight into the clinical predictors of bisphosphonatesand provide guidance on when to start and stop therapy and appropriate dosing regimes.Good data from randomized trials currently being designedor already in progressare awaited with interest. REFERENCES 1. Fromigue 0, Lagneaux L, Body JJ: Bisphosphonates induce breast cancer cell death in vitro. J Bone Miner Res 15:2211-2221, 2000 2. Boissier S, Ferreras M, Peyruchaud 0, et al: Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 60:2949-2954, 2000 3. Boissier S, Magnetto S, Frappart L, et al: Bisphosphonates inhibit prostate and breast carcinoma cell adhesion to unmineralized and mineralized bone extracellular matrices. Cancer Res 57:3890-3894, 1997 4. Body JJ, Bard R, Burckhardt P, et al: Current use of bisphosphonates in oncology. J Clin Oncol 16:3890-3899, 1998 5. Mundy GR: Bisphosphonates as anticancer drugs. N Engl J Med 339:398400, 1998 6. Mundy GR: Mechanisms of bone metastasis. Cancer 80: 1546.1556, 1997 (suppl 8) 7. Paterson AH: The potential role of bisphosphonates as adjuvant therapy in the prevention of bone metastases. Cancer 88:3038-3046, 2000 8. Die1 IJ, Solomayer EF, Bastert G: Bisphosphonates and the prevention of metastasis. First evidences from preclinical and clinical studies. Cancer 88:3080-3088, 2000 (suppl 12) 9. Die1 IJ, Solomayer EF, Costa SD, et al: Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 339:357,363, 1998 10. Powles TJ, Paterson AHG, Nevantaus A, et al: Adju. vant clodronate reduces the incidence of bone metastases in patients with primary operable breast cancer. Proc Am Sot Clin Oncol 17:468A, 1998 (abstr) 11. Saarto T, Blomqvist C, Virkkunen, et al: No reduction of bone metastases with adjuvant clodronate treatment in node-positive breast cancer patients. Proc Am Sot Clin Oncol 18:128A, 1999 (abstr) 12. Saarto T, Blomqvist C, Valimaki M, et al: Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: A randomized study in premenopausal breast cancer patients. J Clin.Oncol 15:1341-1347, 1997 13. Mincey BA, Moraghan TJ, Perez EA: Prevention and treatment of osteoporosis in women with breast cancer. Mayo Clin Proc 75:821-829, 2000 14. Daniel1 HW, Dunn SR, Ferguson DW, et al: Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 163:181-186, 2000 15. Wei JT, Gross M, Jaffe CA, et al: Androgen deprivation therapy for prostate cancer results in significant loss of bone density. Urology 54:607-611, 1999

BISPHOSPHONATES

FOR

BREAST

CANCER

AND

BEYOND

16. British Association of Surgical Oncology Guidelines: The management of metastatic bone disease in the United Kingdom. The Breast Specialty Group of the British Association of Surgical Oncology. Bur J Sung Oncol 25:3,23, 1999 17. Simmons R, Hoda S, Osborne M: Bone marrow micrometastases in breast cancer patients. Am J Surg 180:309-312, 2000 18. Yeatman TJ, Cox CE: The significance of breast cancer lymph node micrometastases. Surg Oncol Clin N Am 8:481496, 1999 19. Mansi JL, Berger U, Easton D, et al: Micrometastases in

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bone marrow in patients with primary breast cancer: Evaluation as an early predictor of bone metastases. Br Med J 295:10931096, 1987 20. Die1 IJ, Lichinister MR, Body JJ, et al: Improvement of bone pain, quality of life and survival time of breast cancer patients with metastatic bone disease treated with intravenous ibandronate. Eur J Cancer 35:A269, 1999 (suppl 4) (abstr) 21. Dranitsaris G, Hsu T: Cost utility analysis of prophylactic pamidronate for the prevention of skeletal related events in patients with advanced breast cancer. Support Care Cancer 7:271-279, 1999