|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 26, No 26 (September 10), 2008: pp. 4289-4295 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.4997
Ten-Year Follow-Up of 3 Years of Oral Adjuvant Clodronate Therapy Shows Significant Prevention of Osteoporosis in Early-Stage Breast Cancer
From the Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland Corresponding author: Tiina Saarto, MD, Department of Oncology, Helsinki University Hospital, PO Box 180, Helsinki FI-00029-HUS, Finland; e-mail: tiina.saarto{at}hus.fi
Purpose We have previously reported that 3-year adjuvant clodronate treatment prevents bone loss in breast cancer patients. Here we report the 10-year follow-up data of clodronate in the prevention of treatment-related osteoporosis in women with early-stage breast cancer. Patients and Methods Two hundred sixty-eight pre- and postmenopausal, node-positive breast cancer patients were randomly assigned to clodronate, 1.6 g orally administered daily, or to control groups for 3 years. Premenopausal women were treated with adjuvant CMF chemotherapy; and postmenopausal women were treated with antiestrogens, either 20 mg tamoxifen or 60 mg toremifene, for 3 years. The bone mineral density (BMD) of the lumbar spine and hip was measured before treatment and at 1, 2, 3, 5, and 10 years after therapy. Results Eighty-nine disease-free patients were included in the analyses of osteoporosis-free survival. During the 10-year period, 24 of 89 patients were diagnosed with osteoporosis. Fourteen patients developed spinal osteoporosis (three of 41 in the clodronate group, and 11 of 48 in the control group), and 14 of 89 patients were diagnosed with hip osteoporosis (seven of 41 in the clodronate group, and seven of 48 in the control group). The 10-year spinal, osteoporosis-free survival rate was 92.7% in the clodronate group, and 77.0% in the control group (P = .035). No difference was seen in the frequency of hip osteoporosis (85.4% v 82.9%; P = .92). Baseline BMD measurement had a predictive value of 18 of 24 patients (75%) who developed osteoporosis had osteopenia of the lumbar spine at baseline. Conclusion Three years of clodronate therapy significantly reduces the incidence of lumbar spine osteoporosis. Patients at risk of developing osteoporosis are among those who have pretreatment osteopenia, that is, baseline BMD measurement has predictive value.
Fractures caused by osteoporosis affect one in two women and one in five men older than 50 years; the risk of fractures increases steeply with age.1 Peak bone mass is attained in the third decade of life, and age-related bone loss starts around 40 years of age.2 The role of estrogen deficiency in menopause, and age-related bone loss in women is well documented.2 The withdrawal of sex steroids leads to bone loss because bone formation is unable to keep pace with osteoclastic bone resorption.3 Low-peak bone mass, increased bone loss at menopause, and greater longevity confer a greater risk of osteoporosis in women than in men.2 Epidemiologic studies show that the risk of breast cancer is greater in postmenopausal women with higher bone mineral density (BMD).4 Paradoxically, however, breast cancer survivors are at increased risk for osteoporosis and fracture compared with women in general.5-7 Recently, Chen et al7 reported a 15% increased rate of fractures in breast cancer survivors in the observational component of the Women Health Initiative (WHI) Study. The increased risk for clinical vertebral fracture was statistically significant only among survivors who had a breast cancer diagnosis before 55 years of age, probably due to chemotherapy-induced menopause. The rate of hip osteoporosis did not differ between breast cancer survivors and those without breast cancer diagnosis.7 It is likely that this paradox is explained by estrogen deficiency that develops in women treated for breast cancer. Thus, women who develop breast cancer may well have normal or high BMD at the time of diagnosis, but, due to estrogen deficiency induced by chemotherapy or aromatase inhibitors, for example, they have an increase in bone turnover, accelerated bone loss, and increased risk of fracture.8 Chemotherapy-induced early menopause causes rapid bone loss and may increase the risk of osteoporosis later in life. The incidence of menopause with adjuvant polychemotherapy has been reported to range from 53% to 89%.9 The risk of chemotherapy-induced menopause is age dependent; most women in their 40s develop ovarian failure, while younger women often retain their menstruation.10,11 Previous studies have demonstrated a striking bone loss, reaching up to 8%, during the first year after chemotherapy-induced early menopause.12,13 Endocrine therapies for breast cancer have diverse effects on bone density. Selective estrogen receptor modulators, such as tamoxifen and toremifene, have estrogen agonistic effects on bone and decrease postmenopausal bone loss.14-17 While selective estrogen receptor modulators provide protection against bone loss in postmenopausal women, aromatase inhibitors seem to reduce BMD and increase the risk of fracture by decreasing estrogen levels.18,19 Bisphosphonates are effective in maintaining bone density in women receiving adjuvant therapy for breast cancer. Peroral clodronate and risedonate, as well as intravenous pamidronate, have been shown to reduce or even prevent bone loss in patients with chemotherapy-induced early menopause.12,20-23 Similarly, intravenous zoledronic acid has been shown to inhibit bone loss induced by the aromatase inhibitor letrozole.24 However, the follow-up periods of the studies examining prevention of therapy-induced bone loss are short, and no data exist on long-term efficacy of bisphosphonates in breast cancer patients. We previously reported that 3-year oral clodronate treatment significantly reduces bone loss in both pre- and postmenopausal breast cancer patients.12,16,25 This effect of clodronate treatment remains for at least 2 years after treatment termination.25 We present here the extended 10-year follow-up results of the efficacy of adjuvant clodronate treatment on BMD in breast cancer patients.
Patients The study population consisted of 268 pre- and postmenopausal women with newly diagnosed node-positive breast cancer who were treated between 1990 and 1993 at the Department of Oncology, Helsinki University Hospital, in Helsinki, Finland (Tables 1 and 2. Exclusion criteria were the following: (1) Karnofsky performance index below 70%, (2) other malignancies, (3) peptic ulcer, (4) creatinine over 150 umol/L, and (5) pregnancy. Premenopausal status at entry was defined as regular menstruation or last menstrual cycle within 3 months and serum follicle stimulating hormone levels less than 30 U/L.
The patients underwent surgery with total mastectomy or breast-conserving resection and axillary evacuation. All patients had postoperative radiotherapy with 50 Gy megavoltage irradiation in 25 fractions to regional lymph nodes, and to operative scar or remaining breast after breast-conserving resection, which was done concomitantly with adjuvant therapy. Premenopausal patients received six cycles of cyclophosphamide, methotrexate, and fluorouracil chemotherapy, consisting of 600 mg/m2 cyclophosphamide, 40 mg/m2 methotrexate, and 600 mg/m2 fluorouracil administered intravenously on day one and thereafter at 3-week intervals. Postmenopausal patients were randomly assigned to receive antiestrogens, either 20 mg tamoxifen or 60 mg/d toremifene, for 3 years. In addition, the patients were randomly assigned to either 1,600 mg oral clodronate (Bonefos; Oy Leiras Finland AB, Helsinki, Finland) daily for 3 years or to no further therapy. Data from 172 of the initial 268 patients were excluded from the current analyses, primarily because of breast cancer death (110 patients) and metastatic disease (26 patients). In addition, 10 patients were excluded because of noncancer death, nine patients discontinued follow-up, and six patients were diagnosed with other malignancies. Nine patients had diseases or were taking medications that could possibly affect bone metabolism; these patients were excluded from the analyses because of hormone replacement therapy (four patients), tamoxifen after chemotherapy (one patient), cortisone therapy (one patient), antiepileptic use (one patient), hyperparathyreosis (one patient), and hyperthyreosis (one patient). In addition, two patients were excluded because of pregnancy. Overall, 96 metastasis-free patients were eligible for analyses at 10 years of follow-up.
Methods BMD (grams per square centimeter) was measured by dual-energy, x-ray absorptiometry using a Hologic QDR-1000 densitometer (Hologic Inc, Waltham, MA). BMD was measured at the lumbar vertebrae (L1-4) and at the femoral neck, femoral trochanter, and Ward's triangle, intertrochanteric and total femoral area in the right femoral area before therapy and at 1, 2, 3, 5 and 10 years thereafter. According to the WHO criteria, BMD T scores –2.5 standard deviation (SD) below normal peak-bone mass were classified as osteoporotic, T scores between –1 and –2.5 SD were considered osteopenic, and those over –1 SD were considered normal.26
Statistical Methods
Effect of Clodronate on BMD We previously reported that 3-year clodronate therapy significantly reduced bone loss in both the lumbar spine and femoral neck.12,16,25 After termination of clodronate therapy, no accelerated bone loss was found. The bone-loss rate did not differ between the groups within the next 7 years of follow-up. From 3 to 10 years, the bone-loss rate in the lumbar spine was –5.0% (SD, 6.7) in the control group v –4.1% (SD, 7.7) in the clodronate group (P = .81), and the bone-loss rate in the femoral neck was –4.7% (SD, 4.8) in the control group v –4.7% (SD, 5.0) in the clodronate group (P = .56). The total bone loss in the lumbar spine and the femoral neck during the10-year period was –10.3% (SD, 9.6) and –7.2% (SD, 6.1) in the control group, and –5.5% (SD, 10.7) and –5.2% (SD, 6.3) in the clodronate group (Fig 1).
Effect of Clodronate on Osteoporosis-Free Survival The effect of clodronate on 10-year cumulative OPFS was studied for those patients who had either normal or osteopenic BMD before adjuvant therapy. Seven patients already had osteoporotic BMD values (T score < –2.5 SD) before adjuvant therapy; four of these patients had osteoporotic T-scores at the femoral neck, two of these patients had osteoporotic T-scores at lumbar spine, and one patient had osteoporotic T-scores at all sites (lumbar spine, femoral neck, and total femoral area). These seven patients with osteoporosis at the start of the study were excluded, leaving 89 patients for the OPFS analyses. During the 10 years of follow-up, 24 of 89 patients were diagnosed with osteoporosis at any of the sites (lumbar spine, femoral neck, total femoral area) studied; these included 15 of 55 premenopausal women, and 9 of 33 postmenopausal women. Fourteen of 89 patients developed osteoporosis in the lumbar spine (11 of 48 patients in the control group v 3 of 41 patients in the clodronate group). Hip osteoporosis (femoral neck or total femoral area) was diagnosed in 14 of 89 patients (7 of 48 patients in the control group v 7 of 41 patients in the clodronate group. Ten-year T-score changes are presented in Fig 2 and Table 3.
Three years of clodronate therapy significantly reduced the incidence of lumbar spine osteoporosis. Ten-year spinal OPFS was 92.7% in the clodronate group v 77.0% in the control group (P = .035; Fig 3). However, no difference was observed in the frequency of femoral hip (femoral neck and total femoral area) osteoporosis; 10-year hip OPFS was 85.4% in the clodronate group v 82.9% in the control group (P = .92).
Baseline BMD measurement had predictive value as women with pretreatment osteopenia were at an increased risk of osteoporosis. Eighteen of 24 (75%) patients who developed osteoporosis at any site had osteopenia of the lumbar spine (T score between –1 and –2.5 SD) at baseline, while only five of 24 (20.8%) patients had pretreatment T-scores within the normal range (T scores above –1 SD). In one patient with femoral osteoporosis, baseline spinal T score was not available due to significant deformity of the lumbar spine. Patients who developed osteoporosis and those who did not had similar rates of bone loss during the 10 years of follow-up. To avoid the confounding of 3 years of clodronate therapy, the rates of bone loss were compared only for the control patients. Osteoporotic patients had lost an average –1.04 (SD 0.65) of their lumbar-spine baseline T-score values, while the nonosteoporotic patients had lost –0.95 (SD 0.96), respectively (P = .68).
To our knowledge, this is the longest prospective follow-up report of adjuvant bisphosphonate treatment in the prevention of osteoporosis in women with breast cancer. In the current study, 3-year oral clodronate treatment significantly reduced the incidence of spinal osteoporosis in patients who received adjuvant chemotherapy or antiestrogens as an adjuvant therapy for breast cancer. The reduction of osteoporosis was still evident 7 years after the termination of clodronate treatment. In the present study, 10-year OPFS was 92.7% in the clodronate group compared with 77.0% in the control group. This was in line with bone density findings. During the 3-year clodronate treatment, the bone-loss rate in lumbar spine decreased significantly and the effect of clodronate remained for at least 7 years without any signs of accelerated bone loss after treatment termination. However, no difference was seen in the frequency of hip osteoporosis in the two groups. This is consistent with the findings in earlier studies where clodronate has demonstrated beneficial effects on BMD, especially in the lumbar spine.27-29 In osteoporotic patients, clodronate has been shown to reduce the risk of vertebral-only fracture,28,29 whereas alendronate and risedronate reduce the risk of both vertebral and nonvertebral fracture.30 Even though there is significant evidence of prevention of treatment-related bone loss with bisphosphonates,12,16,20-25 little data exist for the prevention of treatment-related osteoporosis. In addition to the present data, there is only one study with adjuvant zoledronic acid, which demonstrated prevention of spinal osteoporosis in breast cancer patients (ABCSG-12 trial).31 In that study, 401 premenopausal breast cancer patients were treated with goserelin, and with anastrozole or tamoxifen for 3 years. In addition, patients were randomly assigned to 4 mg zoledronic acid administered intravenously every 6 months for 3 years, or to no further treatment. Endocrine treatment without zoledronic acid led to significant overall bone loss. The bone-loss rate was significantly more severe in patients receiving goserelin and anastrozole (3-year BMD decrease was –17.3% from the lumbar spine, and –11.3% from the trochanter), compared with goserelin and tamoxifen (–11.6% and –5.1%, respectively). In contrast, BMD remained stable in zoledronic acid-treated patients. Twenty-five percent of the patients treated with goserelin and anastrozole developed spinal osteoporosis, while no osteoporosis was seen in patients in the tamoxifen or zoledronic-acid groups. However, no data exist for the prevention of hip osteoporosis or osteoporotic fractures in cancer survivors. The absence of fracture data is a limitation of the present study as well. In the current study, the risk of osteoporosis was, as expected, associated with low baseline BMD levels. Nearly 80% of the patients who became osteoporotic during the 10 years of follow-up had osteopenia at baseline. This is in agreement with results of aromatase inhibitor studies. In the bone subgroup analyses of the ATAC trial (Arimidex and Tamoxifen, Alone or in Combination), the 5-year anastrozole adjuvant therapy induced significant bone loss in the lumbar spine (–6.1%) as tamoxifen caused a slight improvement in spinal BMD (+2.8%). Osteoporosis was diagnosed in five patients with anastrozole (3%). Furthermore, in the Intergroup Exemestane (IES) trial, the occurrence of osteoporosis was significantly greater in women who had switched to exemestane after tamoxifen than in those who continued with tamoxifen for up to 5 years.33 In the MA.17 trial-bone substudy, osteoporosis was detected by BMD measurement in 3% of women while receiving letrozole, and in 0% of women while on placebo; however, this difference was not statistically significant.34 Interestingly, no women with BMD in the normal range at trial entry developed osteoporosis in any of the studies. All the women who did develop osteoporosis had osteopenia to begin with.32-34 The rate of bone loss in the current study did not differ between those patients who eventually developed osteoporosis and those who did not. Thus, baseline BMD has predictive value for the risk of osteoporosis in patients receiving adjuvant therapy for breast cancer.32,33 Breast cancer patients with normal BMD before the initiation of adjuvant cancer treatments have a minimal risk of osteoporosis at least within the next five to 10 years. Because it appears that long-term breast cancer survivors are at a higher than average risk for osteoporosis, initial dual-energy x-ray absorptiometry bone scan is recommended to determine those individuals with low baseline BMD who should have their BMD monitored during follow-up. In summary, clodronate significantly prevents treatment-related bone loss and spinal osteoporosis in breast cancer patients treated with adjuvant chemotherapy or endocrine therapy. Osteopenia before adjuvant therapy predicts increased risk of osteoporosis during the following five to 10 years, whereas women with normal initial BMD have only a minor risk of developing osteoporosis. To select patients at a risk of treatment-related osteoporosis initial dual-energy x-ray absorptiometry bone-scan measurement before adjuvant treatments is recommended.
The author(s) indicated no potential conflicts of interest.
Conception and design: Inkeri Elomaa Financial support: Inkeri Elomaa Administrative support: Inkeri Elomaa Provision of study materials or patients: Tiina Saarto, Leena Vehmanen, Inkeri Elomaa Collection and assembly of data: Tiina Saarto, Leena Vehmanen Data analysis and interpretation: Tiina Saarto, Carl Blomqvist Manuscript writing: Tiina Saarto, Leena Vehmanen, Carl Blomqvist, Inkeri Elomaa Final approval of manuscript: Tiina Saarto
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Cummings SR, Melton LJ III: Epidemiology and outcomes of osteoporotic fractures. Lancet 359:1761-1767, 2002[CrossRef][Medline] 2. Poole KE, Compston JE: Osteoporosis and its management. BMJ 333:1251-1256, 2006 3. Manolagas SC, Jilka RL: Bone marrow, cytokines, and bone remodeling. N Engl J Med 332:305-311, 1995 4. Ramaswamy B, Shapiro CL: Osteopenia and osteoporosis in women with breast cancer. Semin Oncol 30:763-775, 2003[CrossRef][Medline] 5. Mincey BA, Moraghan TJ, Perez EA: Prevention and treatment of osteoporosis in women with breast cancer. Mayo Clin Proc 75:821-829, 2000[Abstract] 6. Kanis JA, McCloskey EV, Powles T, et al: A high incidence of vertebral fracture in women with breast cancer. Br J Cancer 79:1179-1181, 1999[CrossRef][Medline] 7. Chen Z, Maricic M, Bassford TL, et al: Fracture risk among breast cancer survivors: Results from the Women's Health Initiative Observational Study. Arch Intern Med 165:552-558, 2005 8. Eastell R: Breast Cancer and the Risk of Osteoporotic Fracture: A Paradox. J Clin Endocrinol Metab 92:42-43, 2007 9. Del Mastro L, Venturini M, Sertoli MR, et al: Amenorrhea induced by adjuvant chemotherapy in early breast cancer patients: Prognostic role and clinical implications. Breast Cancer Res Treat 43:183-190, 1997[CrossRef][Medline] 10. Bonadonna G, Valagussa P, Rossi A, et al: Ten-year experience with CMF-based adjuvant chemotherapy in resectable breast cancer. Breast Cancer Res Treat 5:95-115, 1985[CrossRef][Medline] 11. Padmanabhan N, Wang DY, Moore JW, et al: Ovarian function and adjuvant chemotherapy for early breast cancer. Eur J Cancer Clin Oncol 23:745-748, 1987[CrossRef][Medline] 12. Saarto T, Blomqvist C, Välimäki 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. Shapiro CL, Manola J, Leboff M: Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol 19:3306-3311, 2001 14. Love RR, Mazess RB, Barden HS, et al: Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 326:852-856, 1992[Abstract] 15. Powles TJ, Hickish T, Kanis JA, et al: Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 14:78-84, 1996[Abstract] 16. Saarto T, Blomqvist C, Välimäki M, et al: Clodronate improves bone mineral density in postmenopausal breast cancer patiens treated with adjuvant antioestrogens. Br J Cancer 75:602-605, 1997[Medline] 17. Marttunen MB, Hietanen P, Tiitinen A, et al: Comparison of effects of tamoxifen and toremifene on bone biochemistry and bone mineral density in postmenopausal breast cancer patients. J Clin Endocrinol Metab 83:1158-1162, 1998 18. Eastell R, Adams J: Results of the ‘Arimidex’ (anastrozole, A), tamoxifen (T), alone or in combination (C) (ATAC) trial: Effects on bone mineral density (BMD) and bone turnover (ATAC Trialists’ Group). Ann Oncol 13:Suppl 5:32, 2002 19. Thürlimann B, Keshaviah A, Coates AS, et al: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747-2757, 2005 20. Delmas PD, Balena R, Confravreux E, et al: Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: A double-blind, placebo-controlled study. J Clin Oncol 15:955-962, 1997 21. Powles TJ, McCloskey E, Paterson AH, et al: Oral clodronate and reduction in loss of bone mineral density in women with operable primary breast cancer. J Natl Cancer Inst 90:704-708, 1998 22. Fuleihan Gel-H, Salamoun M, Mourad YA, et al: Pamidronate in the prevention of chemotherapy induced bone loss in premenopausal women with breast cancer. J Clin Endocrinol Metab 90:3209-3214, 2005 23. Greenspan SL, Bhattacharya RK, Sereika SM, et al: Prevention of bone loss in survivors of breast cancer: A randomized, double-blind, placebo-controlled clinical trial. J Clin Endocrinol Metab 92:131-136, 2007 24. Brufsky A, Harker WG, Beck JT, et al: Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol 25:829-836, 2007 25. Vehmanen L, Saarto T, Elomaa I, et al: Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment. Eur J Cancer 37:2373-2378, 2001[CrossRef][Medline] 26. WHO Study Group: Assessment of fracture risk and its application to postmenopausal osteoporosis. Geneva, Switzerland, World Health Organ Tech Ser 843, 1984 27. Välimäki MJ, Laitinen K, Patronen A, et al: Prevention of bone loss by clodronate in early postmenopausal women with vertebral osteopenia: A dose-finding study. Osteoporos Int 13:937-947, 2002[CrossRef][Medline] 28. Filipponi P, Cristallini S, Rizzello E, et al: Cyclical intravenous clodronate in postmenopausal osteoporosis: Results of a longterm clinical trial. Bone 18:179-184, 1996[CrossRef][Medline] 29. McCloskey E, Selby P, Davies M, et al: Clodronate reduces vertebral fracture risk in women with postmenopausal or secondary osteoporosis: Results of a double-blind, placebo-controlled 3-year study. J Bone Miner Res 19:728-736, 2004[CrossRef][Medline] 30. Cranney A, Guyatt G, Griffith L, et al: Metaanalyses of therapies for postmenopausal osteoporosis. IX: Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 23:570-578, 2002 31. Gnant MF, Mlineritsch B, Luschin-Ebengreuth G, et al: Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: A report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol 25:820-828, 2007 32. Coleman RE, ATAC Trialists’ Group: Effect of anastrozole on bone mineral density: 5-year results from the ‘Arimidex,’ Tamoxifen Alone or in Combination (ATAC) trial. J Clin Oncol 24:5s, 2006 (suppl; abstr 511) 33. Coleman RE, Banks LM, Girgis SI, et al: Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): A randomised controlled study. Lancet Oncol 8:119-127, 2007[CrossRef][Medline] 34. Perez EA, Josse RG, Pritchard KI, et al: Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: A companion study to NCIC CTG MA.17. J Clin Oncol 24:3629-3635, 2006 Submitted November 26, 2007; accepted January 24, 2008.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
