PURPOSE: To update the 1999 American Society of Clinical Oncology guideline for antiemetics in oncology.
UPDATE METHODOLOGY: The Update Committee completed a review and analysis of data published from 1998 thru February 2006. The literature review focused on published randomized controlled trials, and systematic reviews and meta-analyses of published phase II and phase III randomized controlled trials.
RECOMMENDATIONS: The three-drug combination of a 5-hydroxytryptamine-3 (5-HT3) serotonin receptor antagonist, dexamethasone, and aprepitant is recommended before chemotherapy of high emetic risk. For persons receiving chemotherapy of high emetic risk, there is no group of patients for whom agents of lower therapeutic index are appropriate first-choice antiemetics. These agents should be reserved for patients intolerant of or refractory to 5-HT3 serotonin receptor antagonists, neurokinin-1 receptor antagonists, and dexamethasone. The three-drug combination of a 5-HT3 receptor serotonin antagonist, dexamethasone, and aprepitant is recommended for patients receiving an anthracycline and cyclophosphamide. For patients receiving other chemotherapy of moderate emetic risk, the Update Committee continues to recommend the two-drug combination of a 5-HT3 receptor serotonin antagonist and dexamethasone. In all patients receiving cisplatin and all other agents of high emetic risk, the two-drug combination of dexamethasone and aprepitant is recommended for the prevention of delayed emesis. The Update Committee no longer recommends the combination of a 5-HT3 serotonin receptor antagonist and dexamethasone for the prevention of delayed emesis after chemotherapeutic agents of high emetic risk.
CONCLUSION: The Update Committee recommends that clinicians administer antiemetics while considering patients' emetic risk categories and other characteristics.
Full Text at : http://jco.ascopubs.org/reports/mfr1.dtl
Friday, November 27, 2009
Tuesday, September 1, 2009
Sowing the Soil for Cure?
Sowing the Soil for Cure? Results of the ABCSG-12 Trial Open a New Chapter in the Evolving Adjuvant Bisphosphonate Story in Early Breast Cancer
Philippe L. Bedard
Department of Medical Oncology, Jules Bordet Institute, Brussels, Belgium
Jean-Jacques Body
Department of Medicine, Centre Hospitalier Universitaire Brugmann; Université Libre de Bruxelles, Brussels, Belgium
Martine J. Piccart-Gebhart
Department of Medical Oncology, Jules Bordet Institute; Université Libre de Bruxelles, Brussels, Belgium
Introduction
After their initial synthesis in 1865, bisphosphonates were largely used for industrial purposes to prevent calcium carbonate precipitation in the textile, agricultural, and oil sectors.1 More than 100 years later, bisphosphonates were shown to inhibit bone resorption in animal models.2 Since then, the role of bisphosphonates in the treatment of hypercalcemia, Paget's disease, and osteoporosis, as well as in the reduction of morbidity associated with bone metastases from breast,3–5 prostate,6 and plasma cell malignancies,7 has been established. The American Society of Clinical Oncology recommends "the extensive and early use of bisphosphonates" to prevent skeletal complications, such as pathologic fractures, surgery for fracture or impending fracture, radiation, spinal cord compression, and hypercalcemia, in women with metastatic bone disease from breast cancer.8,9 A more recent international panel of experts concluded that bisphosphonates reduce the frequency and severity of skeletal complications in patients with bone metastases from a variety of different cancers.10 In the setting of cancer treatment–induced bone loss, the panel advised considering the use of bisphosphonates in patients presenting with risk factors for fractures but did not endorse the use of bisphosphonates in the adjuvant setting.
Clinical trials with bisphosphonates in patients with metastatic breast cancer have failed to demonstrate an overall survival (OS) benefit.3–5 However, bisphosphonates might have an impact on long-term survival if used in earlier stages of disease. The dissemination of breast cancer cells to bone marrow instigates a vicious self-sustaining cycle of destruction, whereby individual tumor cells release growth factors that stimulate stromal cells and osteoblasts to produce the receptor activator for nuclear factor B ligand (RANKL), leading to the activation of osteoclasts. These activated osteoclasts resorb bone matrix–liberating potent growth factors that promote tumor cell colonization, inhibit apoptosis, and drive proliferation.11,12 Bisphosphonates are potent inhibitors of osteoclasts, thereby interrupting this self-perpetuating cycle.
Three clinical trials with the non–nitrogen-containing oral bisphosphonate clodronate in early breast cancer produced mixed results.13–15 A single-center German study involving 302 women with early breast cancer and detectable bone marrow metastases demonstrated a striking reduction in bone and visceral metastases and improvement in disease-free survival (DFS) and OS with two years of adjuvant clodronate therapy.13 With longer follow-up, the gain in OS persisted, although differences in DFS and bone metastasis–free and visceral metastasis–free survival were no longer apparent.16 A larger placebo-controlled multicenter study found that a similar schedule of oral clodronate for 2 years in conjunction with standard therapy for stage I to III breast cancer reduced the incidence of bone metastasis and improved OS with no observed difference in nonosseous metastasis.14,17 However, a small Finnish trial reported that three years of adjuvant clodronate did not improve overall survival and had no effect on bone recurrences and a negative impact on nonskeletal recurrences, particularly in women with estrogen receptor–negative disease.18,19 There are concerns that these results were skewed by imbalances between the clodronate and observation groups. On the basis of the data, which remained unconvincing when pooled in a meta-analysis, the US Food and Drug Administration announced that it would not consider approving clodronate in adjuvant breast cancer therapy until the results from the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-34 study—in which 3,323 women with stage I to II disease have been randomly selected to receive three years of clodronate or placebo—were available.20
There is reason to believe that newer generation bisphosphonates may deliver greater efficacy. Non–nitrogen-containing bisphosphonates, such as clodronate, can be metabolized to an adenosine triphosphate analog that is toxic for macrophages and osteoclasts. Nitrogen-containing bisphosphonates, including zoledronic acid and ibandronate, have a very different mechanism of action and are much more potent inhibitors of osteoclast-mediated bone resorption. They inhibit the mevalonate pathway that leads to the prenylation of key intracellular signaling proteins.21 Many of these proteins are guanosine triphosphate–binding peptides essential for signal transduction, including Rho and Ras, that regulate key osteoclast functions, including attachment and survival. Inhibition of prenylation alters cell membrane integrity and induces osteoclast apoptosis. Nitrogen-containing bisphosphonates have also been shown to directly induce tumor cell apoptosis, inhibit angiogenesis, and prevent tumor cell adhesion to bone and invasion of stroma, and in preclinical models, they have displayed antitumor synergy in combination with chemotherapy, endocrine therapy, and radiotherapy in a manner more potent than that of clodronate.22,23
There is also reason to believe that nitrogen-containing bisphosphonates may exert their antitumor effects outside of the bone milieu. In a murine model with breast cancer cells implanted into the mammary fat pad, zoledronic acid suppressed bone, liver, and lung metastases, prolonging the OS of treated mice.24 The combination of zoledronic acid and doxorubicin produced synergistic antitumor activity in a primary breast cancer murine model without any microscopic evidence of extra-skeletal disease.25 These findings are additionally supported by preliminary data from the AZURE (Adjuvant Zoledronic Acid Reduce Recurrence) trial demonstrating that the addition of zoledronic acid to neoadjuvant chemotherapy resulted in smaller residual tumor size and a higher proportion of patients achieving pathologic complete response when compared with chemotherapy alone.26
To our knowledge, the Austrian Breast and Colorectal Cancer Study Group ABCSG-12 trial reported by Gnant et al27 was the first study to suggest that the addition of a nitrogen-containing bisphosphonate improves long-term outcome in early-stage breast cancer. Building on the results of the prior ABCSG-5 trial from the same group,28 this study used a 2 x 2 factorial design to randomly assign 1,803 premenopausal women with stage I to II breast cancer to receive 3 years of monthly goserelin, a gonadotropin-releasing hormone agonist, in combination with either tamoxifen or anastrozole. In the second randomization, patients received either zoledronic acid every 6 months for 3 years or no additional therapy. Previously, Gnant et al29 had demonstrated that zoledronic acid could prevent bone loss during the 3 years of adjuvant therapy in both the anastrozole and tamoxifen groups. Two years after the completion of endocrine treatment, there was partial recovery of bone loss in patients who did not receive zoledronic acid. In contrast, patients treated with zoledronic acid had an increased bone mineral density at 5 years from baseline (+4.0%; P = .02).30 With a median follow-up of 48 months, 4-year DFS and 4-year OS for this entire cohort were 92% and 98%, respectively, even though 30% of women enrolled had node-positive disease, and adjuvant chemotherapy was not administered. The comparison between tamoxifen and anastrozole failed to show any difference in DFS or OS; however, the trial was underpowered to detect the size of effect reported in the postmenopausal aromatase inhibitor studies.31–33 The addition of zoledronic acid resulted in a statistically significant 36% reduction in risk of a DFS event (hazard ratio, 0.64; 95% CI, 0.46 to 0.91; P = .01), with a trend toward improvement in OS (hazard ratio, 0.60; 95% CI, 0.32 to 1.11; P = .11). Although only 137 DFS events had occurred at the time of reporting, zoledronic acid seemed to reduce all categories of breast cancer–related DFS events (eg, distant osseous and nonosseous recurrences, locoregional recurrences, and contralateral primary breast cancers) with minimal observed toxicity.
These intriguing results raise as many open questions as they address. Namely, given the pluripotent preclinical effects of bisphosphonates, what is the underlying mechanism of action driving the observed differences in DFS? Or, to borrow from Paget's seminal theory of cancer metastasis,34 do bisphosphonates target the seed, soil, or both?
With regard to the soil, endocrine treatment alone resulted in a dramatic 14.4% reduction in overall bone mineral density at 36 months in the ABCSG-12 trial, an effect that was blunted by the addition of zoledronic acid.29 Combined use of an aromatase inhibitor with ovarian suppression for premenopausal women with early breast cancer is the most potent inducer of treatment-related bone loss.35 Elevated baseline markers of bone turnover may predict shorter bone metastasis–free survival.36 At the end of 3 years of endocrine therapy in the ABCSG-12 trial, in women who did not receive zoledronic acid, bone loss was significantly greater at the lumbar spine in the anastrozole plus goserelin group than it was in the tamoxifen plus goserelin group (–17.4% and –11.6%, respectively). Although not prospectively defined, subgroup analysis suggested that the observed benefit from the addition of zoledronic acid may have been driven by the anastrozole cohort, lending support to the idea that bisphosphonates may eliminate the fertile breeding ground induced by this form of cancer therapy. Another possible explanation is that the baseline condition of the bone matrix, rather than the rate of bone loss, determines whether circulating metastatic breast cancer cells are able to proliferate in the bone microenvironment. Unfortunately, baseline bone densitometry measurements were only performed in a subgroup of 400 women enrolled onto the ABCSG-12 study. Additional studies are required to address this important question.
Does the creation of a hostile soil for circulating breast cancer cells account for the reduction in all categories of DFS events observed with the addition of zoledronic acid in the ABCSG-12 trial?27 In preclinical studies, the antitumor activity of zoledronic acid was dose and schedule dependent.37 The administration of zoledronic acid in the ABCSG-12 trial (4 mg every 6 months for 3 years) may not have been intensive enough to invoke direct antitumor effects outside of the bone milieu as an explanation for the observed differences in clinical outcome.
Approximately 70% of patients with metastatic breast cancer develop bone metastases during the course of their illness. As Paget34 observed in his seminal studies of autopsy specimens, there are clear differences in tropism to distant metastatic sites according to the tissue of cancer origin. Even within the spectrum of primary breast cancers, the luminal (or estrogen receptor expressing) subtypes demonstrate a greater frequency of bone and pleural metastases, whereas the basal and human epidermal growth factor receptor 2 subtypes are more likely to relapse in brain, liver, and lung.38 Enrollment onto the ABCSG-12 trial was limited to premenopausal women with endocrine-sensitive disease, indicating that type of "seed" may be critical in selecting patients appropriate for a bone-directed metastasis eradication strategy. Soon to be reported studies with broader inclusion criteria, such as the NSABP B-34 and AZURE BIG (Breast International Group) 1-04 trials, should help clarify this issue. It may be possible to refine the prediction of patients with early disease at risk of subsequent bone metastasis using gene expression profiling.39 Early studies have suggested that genes linked to cellular adhesion and the fibroblast growth factor–mitogen-activated protein kinase pathway may be particularly important in the process of breast cancer metastasis to bone.39,40
If one presupposes that the effect of bisphosphonates is to create an unfavorable "soil" for a predisposed "seed," it is difficult to account for the reduction in nonosseous and locoregional recurrences seen in the ABCSG-12 trial.27 Although additional follow-up is needed to confirm these intriguing observations, the finding that a bone-directed therapy may reduce nonosseous and locoregional recurrences challenges our existing paradigm, in which systematic spread to distant sites is believed to be a late event in cancer progression. Elegant preclinical experiments with mouse models have suggested that cancer cells may disseminate early from premalignant lesions, and these early disseminated tumor cells are able to grow into detectable metastases before the transition to frankly invasive disease at the primary site occurs.41 Might bisphosphonates prevent the establishment of subsequent nonskeletal metastases and locoregional recurrences by eradicating dormant disseminated tumor cells in the bone microenvironment? Early clinical studies indicate that adjuvant zoledronic acid therapy may increase the rate of clearance of bone marrow disseminated tumor cells.42–44 This raises the tantalizing possibility that the early elimination of such minimal residual disease may have been a harbinger of the skeletal, nonskeletal, and locoregional recurrences observed in the ABCSG-12 trial.
Of the six acquired capabilities of cancer cells proposed by Hanahan et al45 as the "hallmarks of cancer," tissue invasion and metastasis are the most poorly understood. It is now possible to detect and molecularly characterize subpopulations of rare circulating tumor cells in patients without clinically apparent metastatic disease.46 The ABCSG-12 trial illustrates how much remains to be understood about the process of cancer metastasis. There is a wide array of emerging therapies directed against the bone microenvironment, such as inhibitors of the receptor activator for nuclear factor B ligand, Src, cathepsin K, and vβ3 integrins, which will form the foundation of future clinical trials in early-stage breast cancer. To capitalize on the promise of the ABCSG-12 trial, such studies must integrate new technologies to accelerate biomarker development and expand our understanding of the biology of cancer metastasis.
While waiting for this new and exciting knowledge to emerge, should clinicians routinely incorporate bisphosphonates into adjuvant therapy? A single randomized trial contingent on 137 DFS events is insufficient to change the current standard of care. The open-label design of the ABCSG-12 trial may have introduced bias favoring the earlier detection of bone metastases in the standard therapy arm, and longer follow-up is required to establish the stability of these early efficacy results. Moreover, concerns that the effect of zoledronic acid treatment may have been driven by the experimental anastrozole and goserelin arm—and concerns about the administration of endocrine therapy for only the nonstandard duration of 3 years—in this study suggest that it is too early to treat all patients with early-stage breast cancer with adjuvant bisphosphonate therapy. Reserving final judgment until the results of the NSABP B-34 and AZURE trials are available is prudent, although the delay in presentation of the efficacy analyses raises concern that the event rates may be lower than anticipated, or there may not be significant differences in outcome with the addition of a bisphosphonate. Nevertheless, on the basis of the striking treatment effect and minimal toxicity observed in the ABCSG-12 trial,27 it is certainly reasonable to discuss the benefits of early rather than late administration of zoledronic acid every 6 months in premenopausal women receiving adjuvant ovarian suppression to prevent treatment-related bone loss and subsequent fractures and possibly reduce the risk of breast cancer relapse.
From: http://jco.ascopubs.org
Philippe L. Bedard
Department of Medical Oncology, Jules Bordet Institute, Brussels, Belgium
Jean-Jacques Body
Department of Medicine, Centre Hospitalier Universitaire Brugmann; Université Libre de Bruxelles, Brussels, Belgium
Martine J. Piccart-Gebhart
Department of Medical Oncology, Jules Bordet Institute; Université Libre de Bruxelles, Brussels, Belgium
Introduction
After their initial synthesis in 1865, bisphosphonates were largely used for industrial purposes to prevent calcium carbonate precipitation in the textile, agricultural, and oil sectors.1 More than 100 years later, bisphosphonates were shown to inhibit bone resorption in animal models.2 Since then, the role of bisphosphonates in the treatment of hypercalcemia, Paget's disease, and osteoporosis, as well as in the reduction of morbidity associated with bone metastases from breast,3–5 prostate,6 and plasma cell malignancies,7 has been established. The American Society of Clinical Oncology recommends "the extensive and early use of bisphosphonates" to prevent skeletal complications, such as pathologic fractures, surgery for fracture or impending fracture, radiation, spinal cord compression, and hypercalcemia, in women with metastatic bone disease from breast cancer.8,9 A more recent international panel of experts concluded that bisphosphonates reduce the frequency and severity of skeletal complications in patients with bone metastases from a variety of different cancers.10 In the setting of cancer treatment–induced bone loss, the panel advised considering the use of bisphosphonates in patients presenting with risk factors for fractures but did not endorse the use of bisphosphonates in the adjuvant setting.
Clinical trials with bisphosphonates in patients with metastatic breast cancer have failed to demonstrate an overall survival (OS) benefit.3–5 However, bisphosphonates might have an impact on long-term survival if used in earlier stages of disease. The dissemination of breast cancer cells to bone marrow instigates a vicious self-sustaining cycle of destruction, whereby individual tumor cells release growth factors that stimulate stromal cells and osteoblasts to produce the receptor activator for nuclear factor B ligand (RANKL), leading to the activation of osteoclasts. These activated osteoclasts resorb bone matrix–liberating potent growth factors that promote tumor cell colonization, inhibit apoptosis, and drive proliferation.11,12 Bisphosphonates are potent inhibitors of osteoclasts, thereby interrupting this self-perpetuating cycle.
Three clinical trials with the non–nitrogen-containing oral bisphosphonate clodronate in early breast cancer produced mixed results.13–15 A single-center German study involving 302 women with early breast cancer and detectable bone marrow metastases demonstrated a striking reduction in bone and visceral metastases and improvement in disease-free survival (DFS) and OS with two years of adjuvant clodronate therapy.13 With longer follow-up, the gain in OS persisted, although differences in DFS and bone metastasis–free and visceral metastasis–free survival were no longer apparent.16 A larger placebo-controlled multicenter study found that a similar schedule of oral clodronate for 2 years in conjunction with standard therapy for stage I to III breast cancer reduced the incidence of bone metastasis and improved OS with no observed difference in nonosseous metastasis.14,17 However, a small Finnish trial reported that three years of adjuvant clodronate did not improve overall survival and had no effect on bone recurrences and a negative impact on nonskeletal recurrences, particularly in women with estrogen receptor–negative disease.18,19 There are concerns that these results were skewed by imbalances between the clodronate and observation groups. On the basis of the data, which remained unconvincing when pooled in a meta-analysis, the US Food and Drug Administration announced that it would not consider approving clodronate in adjuvant breast cancer therapy until the results from the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-34 study—in which 3,323 women with stage I to II disease have been randomly selected to receive three years of clodronate or placebo—were available.20
There is reason to believe that newer generation bisphosphonates may deliver greater efficacy. Non–nitrogen-containing bisphosphonates, such as clodronate, can be metabolized to an adenosine triphosphate analog that is toxic for macrophages and osteoclasts. Nitrogen-containing bisphosphonates, including zoledronic acid and ibandronate, have a very different mechanism of action and are much more potent inhibitors of osteoclast-mediated bone resorption. They inhibit the mevalonate pathway that leads to the prenylation of key intracellular signaling proteins.21 Many of these proteins are guanosine triphosphate–binding peptides essential for signal transduction, including Rho and Ras, that regulate key osteoclast functions, including attachment and survival. Inhibition of prenylation alters cell membrane integrity and induces osteoclast apoptosis. Nitrogen-containing bisphosphonates have also been shown to directly induce tumor cell apoptosis, inhibit angiogenesis, and prevent tumor cell adhesion to bone and invasion of stroma, and in preclinical models, they have displayed antitumor synergy in combination with chemotherapy, endocrine therapy, and radiotherapy in a manner more potent than that of clodronate.22,23
There is also reason to believe that nitrogen-containing bisphosphonates may exert their antitumor effects outside of the bone milieu. In a murine model with breast cancer cells implanted into the mammary fat pad, zoledronic acid suppressed bone, liver, and lung metastases, prolonging the OS of treated mice.24 The combination of zoledronic acid and doxorubicin produced synergistic antitumor activity in a primary breast cancer murine model without any microscopic evidence of extra-skeletal disease.25 These findings are additionally supported by preliminary data from the AZURE (Adjuvant Zoledronic Acid Reduce Recurrence) trial demonstrating that the addition of zoledronic acid to neoadjuvant chemotherapy resulted in smaller residual tumor size and a higher proportion of patients achieving pathologic complete response when compared with chemotherapy alone.26
To our knowledge, the Austrian Breast and Colorectal Cancer Study Group ABCSG-12 trial reported by Gnant et al27 was the first study to suggest that the addition of a nitrogen-containing bisphosphonate improves long-term outcome in early-stage breast cancer. Building on the results of the prior ABCSG-5 trial from the same group,28 this study used a 2 x 2 factorial design to randomly assign 1,803 premenopausal women with stage I to II breast cancer to receive 3 years of monthly goserelin, a gonadotropin-releasing hormone agonist, in combination with either tamoxifen or anastrozole. In the second randomization, patients received either zoledronic acid every 6 months for 3 years or no additional therapy. Previously, Gnant et al29 had demonstrated that zoledronic acid could prevent bone loss during the 3 years of adjuvant therapy in both the anastrozole and tamoxifen groups. Two years after the completion of endocrine treatment, there was partial recovery of bone loss in patients who did not receive zoledronic acid. In contrast, patients treated with zoledronic acid had an increased bone mineral density at 5 years from baseline (+4.0%; P = .02).30 With a median follow-up of 48 months, 4-year DFS and 4-year OS for this entire cohort were 92% and 98%, respectively, even though 30% of women enrolled had node-positive disease, and adjuvant chemotherapy was not administered. The comparison between tamoxifen and anastrozole failed to show any difference in DFS or OS; however, the trial was underpowered to detect the size of effect reported in the postmenopausal aromatase inhibitor studies.31–33 The addition of zoledronic acid resulted in a statistically significant 36% reduction in risk of a DFS event (hazard ratio, 0.64; 95% CI, 0.46 to 0.91; P = .01), with a trend toward improvement in OS (hazard ratio, 0.60; 95% CI, 0.32 to 1.11; P = .11). Although only 137 DFS events had occurred at the time of reporting, zoledronic acid seemed to reduce all categories of breast cancer–related DFS events (eg, distant osseous and nonosseous recurrences, locoregional recurrences, and contralateral primary breast cancers) with minimal observed toxicity.
These intriguing results raise as many open questions as they address. Namely, given the pluripotent preclinical effects of bisphosphonates, what is the underlying mechanism of action driving the observed differences in DFS? Or, to borrow from Paget's seminal theory of cancer metastasis,34 do bisphosphonates target the seed, soil, or both?
With regard to the soil, endocrine treatment alone resulted in a dramatic 14.4% reduction in overall bone mineral density at 36 months in the ABCSG-12 trial, an effect that was blunted by the addition of zoledronic acid.29 Combined use of an aromatase inhibitor with ovarian suppression for premenopausal women with early breast cancer is the most potent inducer of treatment-related bone loss.35 Elevated baseline markers of bone turnover may predict shorter bone metastasis–free survival.36 At the end of 3 years of endocrine therapy in the ABCSG-12 trial, in women who did not receive zoledronic acid, bone loss was significantly greater at the lumbar spine in the anastrozole plus goserelin group than it was in the tamoxifen plus goserelin group (–17.4% and –11.6%, respectively). Although not prospectively defined, subgroup analysis suggested that the observed benefit from the addition of zoledronic acid may have been driven by the anastrozole cohort, lending support to the idea that bisphosphonates may eliminate the fertile breeding ground induced by this form of cancer therapy. Another possible explanation is that the baseline condition of the bone matrix, rather than the rate of bone loss, determines whether circulating metastatic breast cancer cells are able to proliferate in the bone microenvironment. Unfortunately, baseline bone densitometry measurements were only performed in a subgroup of 400 women enrolled onto the ABCSG-12 study. Additional studies are required to address this important question.
Does the creation of a hostile soil for circulating breast cancer cells account for the reduction in all categories of DFS events observed with the addition of zoledronic acid in the ABCSG-12 trial?27 In preclinical studies, the antitumor activity of zoledronic acid was dose and schedule dependent.37 The administration of zoledronic acid in the ABCSG-12 trial (4 mg every 6 months for 3 years) may not have been intensive enough to invoke direct antitumor effects outside of the bone milieu as an explanation for the observed differences in clinical outcome.
Approximately 70% of patients with metastatic breast cancer develop bone metastases during the course of their illness. As Paget34 observed in his seminal studies of autopsy specimens, there are clear differences in tropism to distant metastatic sites according to the tissue of cancer origin. Even within the spectrum of primary breast cancers, the luminal (or estrogen receptor expressing) subtypes demonstrate a greater frequency of bone and pleural metastases, whereas the basal and human epidermal growth factor receptor 2 subtypes are more likely to relapse in brain, liver, and lung.38 Enrollment onto the ABCSG-12 trial was limited to premenopausal women with endocrine-sensitive disease, indicating that type of "seed" may be critical in selecting patients appropriate for a bone-directed metastasis eradication strategy. Soon to be reported studies with broader inclusion criteria, such as the NSABP B-34 and AZURE BIG (Breast International Group) 1-04 trials, should help clarify this issue. It may be possible to refine the prediction of patients with early disease at risk of subsequent bone metastasis using gene expression profiling.39 Early studies have suggested that genes linked to cellular adhesion and the fibroblast growth factor–mitogen-activated protein kinase pathway may be particularly important in the process of breast cancer metastasis to bone.39,40
If one presupposes that the effect of bisphosphonates is to create an unfavorable "soil" for a predisposed "seed," it is difficult to account for the reduction in nonosseous and locoregional recurrences seen in the ABCSG-12 trial.27 Although additional follow-up is needed to confirm these intriguing observations, the finding that a bone-directed therapy may reduce nonosseous and locoregional recurrences challenges our existing paradigm, in which systematic spread to distant sites is believed to be a late event in cancer progression. Elegant preclinical experiments with mouse models have suggested that cancer cells may disseminate early from premalignant lesions, and these early disseminated tumor cells are able to grow into detectable metastases before the transition to frankly invasive disease at the primary site occurs.41 Might bisphosphonates prevent the establishment of subsequent nonskeletal metastases and locoregional recurrences by eradicating dormant disseminated tumor cells in the bone microenvironment? Early clinical studies indicate that adjuvant zoledronic acid therapy may increase the rate of clearance of bone marrow disseminated tumor cells.42–44 This raises the tantalizing possibility that the early elimination of such minimal residual disease may have been a harbinger of the skeletal, nonskeletal, and locoregional recurrences observed in the ABCSG-12 trial.
Of the six acquired capabilities of cancer cells proposed by Hanahan et al45 as the "hallmarks of cancer," tissue invasion and metastasis are the most poorly understood. It is now possible to detect and molecularly characterize subpopulations of rare circulating tumor cells in patients without clinically apparent metastatic disease.46 The ABCSG-12 trial illustrates how much remains to be understood about the process of cancer metastasis. There is a wide array of emerging therapies directed against the bone microenvironment, such as inhibitors of the receptor activator for nuclear factor B ligand, Src, cathepsin K, and vβ3 integrins, which will form the foundation of future clinical trials in early-stage breast cancer. To capitalize on the promise of the ABCSG-12 trial, such studies must integrate new technologies to accelerate biomarker development and expand our understanding of the biology of cancer metastasis.
While waiting for this new and exciting knowledge to emerge, should clinicians routinely incorporate bisphosphonates into adjuvant therapy? A single randomized trial contingent on 137 DFS events is insufficient to change the current standard of care. The open-label design of the ABCSG-12 trial may have introduced bias favoring the earlier detection of bone metastases in the standard therapy arm, and longer follow-up is required to establish the stability of these early efficacy results. Moreover, concerns that the effect of zoledronic acid treatment may have been driven by the experimental anastrozole and goserelin arm—and concerns about the administration of endocrine therapy for only the nonstandard duration of 3 years—in this study suggest that it is too early to treat all patients with early-stage breast cancer with adjuvant bisphosphonate therapy. Reserving final judgment until the results of the NSABP B-34 and AZURE trials are available is prudent, although the delay in presentation of the efficacy analyses raises concern that the event rates may be lower than anticipated, or there may not be significant differences in outcome with the addition of a bisphosphonate. Nevertheless, on the basis of the striking treatment effect and minimal toxicity observed in the ABCSG-12 trial,27 it is certainly reasonable to discuss the benefits of early rather than late administration of zoledronic acid every 6 months in premenopausal women receiving adjuvant ovarian suppression to prevent treatment-related bone loss and subsequent fractures and possibly reduce the risk of breast cancer relapse.
From: http://jco.ascopubs.org
Men with prostate cancer can live long lives without surgery
Men who are diagnosed with prostate cancer will probably live a full and long life without needing surgery, a new study has found.
Only those who have very aggressive cancers should consider a radical prostatectomy, say researchers from the Memorial Sloan-Kettering Cancer Center.
Those diagnosed with the cancer can expect to live for at least a further 15 years, especially if the cancer is slow-growing, without needing to have any treatment.
In a study of 12,677 men who had a radical prostatectomy, most lived for 15 years or longer afterwards.
(Source: Journal of Clinical Oncology, 2009: published online July 27, 2009, DOI:10.1200/JCO.2008.18.2501).
Only those who have very aggressive cancers should consider a radical prostatectomy, say researchers from the Memorial Sloan-Kettering Cancer Center.
Those diagnosed with the cancer can expect to live for at least a further 15 years, especially if the cancer is slow-growing, without needing to have any treatment.
In a study of 12,677 men who had a radical prostatectomy, most lived for 15 years or longer afterwards.
(Source: Journal of Clinical Oncology, 2009: published online July 27, 2009, DOI:10.1200/JCO.2008.18.2501).
Thursday, January 1, 2009
Dehydration
What's The Big Sweat About Dehydration
When it's hot outside and you've been sweating, you get thirsty. Why? Thirst is a sign of dehydration (say: dee-hye-dray-shun). Dehydration means that your body doesn't have enough water in it to keep it working right. A person gets water by drinking and eating. You lose water when you sweat, urinate (pee), have diarrhea, or throw up. You even lose a little water when you breathe.
Our bodies need water to work properly. Usually, you can make up for the water you lose — like when you come in from outside and have a long, cool drink of water. If you don't replace the water your body has lost, you might start feeling sick. And if you go too long without the water you need, you can become very ill and might need to go to the hospital.
Why Am I Dehydrated?
Many times kids get dehydrated when they are playing hard and having fun. Have you ever gotten really sweaty and red-faced when you've been playing? This often happens when it's hot outside, but it can happen indoors, too, like if you're practicing basketball in a gym.
Kids also can get dehydrated when they're sick. If you have a stomach virus (say: vye-rus), you might throw up or have diarrhea (say: dye-uh-ree-uh). On top of that, you probably don't feel very much like eating or drinking. If you have a sore throat, you might find it hard to swallow food or drink. And if you have a fever, you can lose fluids because water evaporates from your skin in an attempt to cool your body down. That's why your mom or dad tells you to drink a lot of fluids when you're sick.
Signs of Dehydration
In addition to being thirsty, here are some signs that a person might be dehydrated:
- feeling lightheaded, dizzy, or tired
- rapid heartbeat
- dry lips and mouth
Another sign of dehydration is not peeing as much. Normally, urine should be a pale yellow color. Dark or strong-smelling pee can be a sign of dehydration.
What to Do
If you can, try not to get dehydrated in the first place. If you're going to be going outside, it's a good idea to drink water before, during, and after you play, especially if it's hot. Dehydration can happen along with heat-related illnesses, such as heat exhaustion (say: ig-zos-chun) and heat stroke. In addition to drinking water, it's smart to dress in cool clothes and take breaks indoors or at least in the shade.
If you're sick, keep taking small sips of drinks and soups, even if you're not that thirsty or hungry. Eating an icepop is a great way to get fluids. How is an icepop a liquid? Well, it's basically frozen water and flavoring. The warmth in your mouth and stomach turns it from a solid to a liquid. Other foods, such as fruits and vegetables, contain water, too.
Do I Need a Doctor?
Some cases of dehydration can be handled at home. But sometimes, that isn't enough to get a kid feeling better. A kid may need to go to the doctor or emergency department if he or she has a heat-related illness or a virus with vomiting or diarrhea that just won't quit.
At the hospital, the good news is that an intravenous (say: in-truh-vee-nus) (IV) line can get fluids into your body fast. An IV line is a special tube (like a very thin straw) that goes right into your veins, so the liquid goes right to where your body needs it most. It may pinch a little when the nurse is inserting it, but it often helps a person feel much better.
Thirst-Quenching Tips
So do you have to drink eight glasses of water a day? No, but you do need to drink enough to satisfy your thirst, and maybe a little extra if you're sick or if you're going to be exercising. The best drink is water, of course, but milk is another great drink for kids. Juice is OK, but choose it less often than water and milk. Sports drinks are fine once in a while, but water should be considered the drink of champions.
Limit soda and other sugary drinks, such as fruit punches, lemonades, and iced teas. These drinks contain a lot of sugar that your body doesn't need. Some of them also contain caffeine, which is a diuretic (say: dye-yuh-reh-tik). This means that caffeinated drinks cause you to urinate (pee) more often than normal. In other words, they tell your body to get rid of fluids. And as you now know, that's the opposite of what you need to do if you're dehydrated!
From: http://kidshealth.org/kid/stay_healthy/fit/dehydration.html
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