Common Site Of Distant Recurrence Research Articles

Recurrence patterns and postrecurrence survival after curative intent resection for pancreatic ductal adenocarcinoma

BackgroundPancreatic ductal adenocarcinoma has a high rate of recurrence after resection. We aimed to investigate patterns of recurrence of pancreatic ductal adenocarcinoma to identify opportunities for targeted intervention toward improving survival. MethodsThis was a retrospective analysis of consecutive patients that underwent curative-intent resection for pancreatic ductal adenocarcinoma between 2007 and 2015. Recurrence and survival were analyzed based on site of recurrence. Multiple clinicopathologic factors were calculated for likelihood of site-specific recurrence. ResultsThe study included 221 patients with median follow-up of 83 months. Median overall and recurrence-free survival was 19 and 13 months, respectively. Recurrence was observed in 71.9% patients. Local recurrence occurred in 16.4%, distant recurrence in 67.3%, and combined in 15.9%. The most common site of distant recurrence was the liver (49.7%) followed by lung (31.8%) and peritoneum (16.6%). Median time to liver recurrence was shortest (5 months, 95% confidence interval 1.7–8.3) and post recurrence survival was poor (4 months, 95% confidence interval 1.9–6.1). Patients with poorly differentiated tumors on pathology were 4.8 times more likely to recur in the liver (odds ratio 4.83, 95% confidence interval 1.7–13.9). ConclusionLiver metastasis after resection of pancreatic ductal adenocarcinoma occurs most frequently, earliest after surgery, and is rapidly fatal. Liver-directed therapies represent a target for future study.

SWOG S0307 phase III trial of bisphosphonates as adjuvant therapy in primary breast cancer: Comparison of toxicities and patient-stated preference for oral versus intravenous delivery.

558 Background: Bone metastases are a common site of distant recurrence in breast cancer. Evidence from randomized trials, including a recent meta-analysis, suggests that adjuvant bisphosphonates c...

Denosumab versus placebo as adjuvant treatment for women with early-stage breast cancer at high risk of disease recurrence (D-CARE): An international, placebo-controlled, randomized, double-blind phase III clinical trial.

TPS662 Background: In women with early-stage breast cancer, bone is a common site of distant recurrence and represents approximately 40% of all first recurrences. Preclinical studies demonstrated that inhibition of RANKL significantly delays skeletal tumor formation, reduces skeletal tumor burden, and prolongs survival of tumor-bearing mice. Denosumab is approved for the prevention of skeletal-related events (SREs) in patients with established bone metastases from solid tumors. The D-CARE trial is designed to assess if denosumab treatment prolongs bone metastasis-free survival (BMFS) and disease-free survival (DFS) in the adjuvant breast cancer setting. The primary endpoint of this event-driven trial is BMFS. Secondary endpoints include DFS and overall survival. Additional endpoints include safety, breast density, time to first on-study SRE (following the development of bone metastasis), patient reported outcomes, and biomarkers. Methods: In this international, randomized, double-blind, and placebo-controlled phase 3 trial, 4509 women with stage II or III breast cancer at high risk for recurrence and with known hormone and HERE2 receptor status were randomized. High risk was defined as biopsy evidence of breast cancer in regional lymph nodes, tumor size > 5 cm (T3), or locally advanced disease (T4). Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone or in combination, must be planned. Patients with a prior history of breast cancer (except DCIS or LCIS) or distant metastasis, oral bisphosphonate (BP) use within 1 year of randomization, or any intravenous BP use, were not eligible. Patients were randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 months, then every 3 months for a total of 5 years of treatment. Supplemental vitamin D (≥ 400 IU) and calcium (≥ 500 mg) were required. The trial, sponsored by Amgen Inc., began enrolling patients in June 2010 and completed enrollment in late 2012. Clinical trial information: NCT01077154.

Different recurrence pattern after neoadjuvant chemoradiotherapy compared to surgery alone in esophageal cancer patients.

82 Background: Neoadjuvant chemoradiotherapy (CRT) is currently considered standard treatment in esophageal cancer patients who are eligible for surgical resection with curative intent. Objective was to evaluate the recurrence pattern after neoadjuvant CRT in patients with esophageal cancer. Methods: We analyzed the results and recurrence patterns from a single center (N=152) in a propensity score matched study between patients treated with neoadjuvant CRT (N=44) and surgery alone (44 from the 108),in the period 2002-2010. Patients treated with neoadjuvant (CROSS schedule) carboplatin/paclitaxel and 41.4 Gy radiotherapy, were compared with a historical cohort of patients with curative intended surgery alone. Surgery was performed through a transthoracic approach with 2-field lymphadenectomy. Results: After matching, the baseline characteristics were equally distributed between both groups (table 1). The response to CRT was 63%, with a pathological complete response of 26%. After a median follow-up of 23 months (7-74 months), lung was the most common site of distant recurrence (16%, N=7), followed by distant lymph nodes (11%, N=5) in the neoadjuvant CRT group, whereas skeletal metastases were the most common site of distant recurrence (18%, N=8), followed by skin or soft tissue (16%, N=7) in the surgical alone group. The estimated 3 and 5 year overall survival was 62% and 55% in the neoadjuvant CRT group, compared to 37% and 31% in the surgery group (Log-rank test: P=0.018). The estimated locoregional free recurrence survival (LRFS) after 3 and 5 years was 79% and 68% in the neoadjuvant CRT group, compared to 44% and 40% in the surgery alone group (Log-rank test: P=0.049). The estimated distant recurrence free survival (DRFS) was 63% and 54% after 3 and 5 years in the neoadjuvant CRT group, compared to 50% and 35% in the surgery alone group (Log-rank test: P=0.314). Conclusions: This neoadjuvant CRT regimen significantly improved oncological outcome compared to surgery alone. An important shift in recurrence pattern was observed from relatively high locoregional recurrences (LRFS) to relatively more distant recurrences (DRFS) in the CRT group compared to the surgery alone group.

Abstract OT2-3-03: Denosumab versus placebo as adjuvant treatment for women with early-stage breast cancer at high risk of disease recurrence (D-CARE): An international, randomized, double-blind, placebo-controlled phase 3 clinical trial

Abstract Bone represents approximately 40% of all first recurrences in women with early-stage breast cancer and is a common site of distant recurrence. In preclinical studies, RANKL inhibition significantly delays skeletal tumor formation, reduces skeletal tumor burden, and prolongs survival of tumor-bearing mice. Denosumab is approved for the prevention of skeletal-related events (SREs) in patients with established bone metastases from solid tumors. Purpose: The D-CARE trial is designed to assess if denosumab treatment prolongs bone metastasis-free survival (BMFS) and disease-free survival (DFS) in the adjuvant breast cancer setting. The primary endpoint of this event-driven trial is BMFS. Secondary endpoints include DFS and overall survival. Additional endpoints are safety, breast density, incidence of SREs (following the development of bone metastasis) patient reported outcomes, and biomarkers. Methods: In this international, randomized, double-blind, and placebo controlled phase 3 trial, approximately 4,500 women with stage II or III breast cancer, at high risk for recurrence and with known hormone and HER-2 receptor status, are eligible. High risk is defined as biopsy evidence of breast cancer in regional lymph nodes, tumor size > 5 cm, (T3), or locally advanced disease (T4). Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone or in combination, must be planned. Patients with a prior history of breast cancer (except ductal carcinoma in situ or lobular carcinoma in situ) or distant metastasis, oral bisphosphonate (BP) use within 1 year of randomization, or any intravenous BP use, are not eligible. Patients are randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 months, then every 3 months for a total of 5 years of treatment. Supplemental vitamin D (≥ 400 IU) and calcium (≥ 500 mg) will be administered. The trial, sponsored by Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154, began enrolling patients in June 2010 and is expected to complete enrollment in late 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-03.

316TiP - Denosumab Versus Placebo as Adjuvant Treatment for Women With Early-Stage Breast Cancer at High Risk of Disease Recurrence (D-CARE): An in Progress, Phase 3 Clinical Trial

ABSTRACT Background Bone represents approximately 40% of all first recurrences in women with early-stage breast cancer and is a common site of distant recurrence. In preclinical studies, RANKL inhibition significantly delays skeletal tumour formation, reduces skeletal tumour burden, and prolongs survival of tumour-bearing mice. Denosumab is approved for the prevention of skeletal-related events (SREs) in patients with established bone metastases from solid tumours. Purpose The D-CARE trial is designed to assess if denosumab treatment prolongs bone metastasis-free survival (BMFS) and disease-free survival (DFS) in the adjuvant breast cancer setting. The primary endpoint of this event-driven trial is BMFS. Secondary endpoints include DFS and overall survival. Additional endpoints are safety, breast density, incidence of SREs (following the development of bone metastasis), patient reported outcomes, and biomarkers. Methods In this international, randomized, double-blind, and placebo controlled phase 3 trial, approximately 4,500 women with stage II or III breast cancer, at high risk for recurrence and with known hormone and HER-2 receptor status, are eligible. High risk is defined as biopsy evidence of breast cancer in regional lymph nodes, tumour size > 5 cm, (T3), or locally advanced disease (T4). Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone or in combination, must be planned. Patients with a prior history of breast cancer (except DCIS or LCIS) or distant metastasis, oral bisphosphonate (BP) use within 1 year of randomization, or any intravenous BP use, are not eligible. Patients are randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 months, then every 3 months for a total of 5 years of treatment. Supplemental vitamin D (≥ 400 IU) and calcium (≥ 500 mg) will be administered. The trial, sponsored by Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154, began enrolling patients in June 2010 and is expected to complete enrolment in late 2012. Disclosure R.E. Coleman: Other substantive relationships: Expert testimony - Novartis. R. Bell: Advisory Board Member : Amgen. M. Martin: Advisory Board Member amgen, roche, bayer, novartis, gsk, sanofi. A. Braun: Employee : Amgen Inc Stock : Amgen Inc. C. Ke: Employer : Amgen Inc. Stock ownership : Amgen Inc. T. Maniar: Employee :: Amgen Inc. Stock ownership :: Amgen Inc. P.E. Goss: Honoraria for Pfizer and Novartis. All other authors have declared no conflicts of interest.

Pulmonary Recurrence Predominates After Combined Modality Therapy for Rectal Cancer

To characterize patterns of recurrence in locally advanced rectal cancer treated with combined modality therapy (CMT): neoadjuvant chemoradiation + total mesorectal excision + adjuvant chemotherapy. A total of 593 consecutive rectal cancer patients (1998 to 2007) with locally advanced (stage II/III) disease (noted on endorectal ultrasound or magnetic resonance imaging) who received CMT were analyzed for patterns of recurrence. After median 44-month follow-up (interquartile range, 25 to 64 months), 119 patients (20%) recurred: 105 distant, 7 local, 7 local and distant, and 112 distant-only recurrence. Ninety-three (78%) had single-organ recurrence, and 26 (22%) had multiple-organ recurrence. The most common site of distant recurrence was lung (69% of all patients with distant relapse); 20% had liver recurrence. Fourteen patients (2.4%) recurred locally. Pulmonary metastases were most commonly identified by computed tomographic scan versus abnormal positron emission tomographic (PET) scan or carcinoembryonic antigen (CEA). Risk factors associated with pulmonary recurrence were the following: pathologic stage, tumor distance from anal verge, lymphovascular or perineural invasion. Five-year freedom from pulmonary recurrence for patients with 0, 1, 2, or 3 risk factors was 99%, 90%, 61%, and 42%, respectively. Thirty of 59 patents with pulmonary recurrence underwent lung metastasectomy; 3-year freedom from recurrence was 37%. Unlike colon cancer, which most frequently recurs in the liver, locally advanced rectal cancer treated with CMT relapses most frequently in the lung. Pulmonary metastasis was associated with advanced pathologic stage, low-lying tumor, lymphovascular invasion, or perineural invasion. Confirmation of pulmonary metastasis usually requires serial imaging because metastases are often small when initially detected, well below the resolution of PET, and not necessarily associated with elevated CEA. Individualized risk-based surveillance strategies are recommended in this patient population.

Denosumab versus placebo as adjuvant treatment for women with early-stage breast cancer who are at high risk of disease recurrence (D-CARE): An international, randomized, double-blind, placebo-controlled phase III clinical trial.

TPS670 Background: Bone is a common site of distant recurrence in women with early-stage breast cancer, and represents approximately 40% of all first recurrences. Tumor cells in bone release growth factors and cytokines that stimulate osteoclast-mediated bone resorption through the RANK ligand (RANKL) pathway. In preclinical studies, RANKL inhibition significantly delays skeletal tumor formation, reduces skeletal tumor burden, and prolongs survival of tumor-bearing mice. Denosumab is a fully human monoclonal antibody that binds to RANKL with high affinity and specificity. It is approved for the prevention of skeletal-related events in patients with established bone metastases from a variety of solid tumors. The purpose of the D-CARE trial is to evaluate the ability of denosumab to prolong bone metastasis-free survival (BMFS) and disease-free survival (DFS) in the adjuvant breast cancer setting. Methods: Approximately 4,500 women with stage II or III breast cancer, at high risk for recurrence and with known hormone and HER-2 receptor status, are eligible. Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone or in combination must be planned. Exclusion criteria include: a prior history of breast cancer (except DCIS or LCIS) or distant metastasis, oral bisphosphonate (BP) use within 1 year of randomization or any intravenous BP use. Patients are randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 months, then every 3 months for a total of 5 years of treatment. All patients receive vitamin D (≥ 400 IU) and calcium (≥ 500 mg) supplements. Primary endpoint of this event-driven trial is BMFS. Secondary endpoints include DFS and overall survival. Safety, quality of life assessments, breast density, and biomarkers are additional endpoints. The trial, sponsored by Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154, began enrolling patients in June 2010 and is expected to complete in October 2016. Paul Goss and Dianne Finkelstein supported in part by the Avon Foundation New York.

Pattern of distant recurrence according to the molecular subtypes in Korean women with breast cancer

BackgroundDistant recurrence is one of the most important risk factors in overall survival, and distant recurrence is related to a complex biologic interaction of seed and soil factors. The aim of the study was to investigate the association between the molecular subtypes and patterns of distant recurrence in patients with breast cancer.MethodsIn an investigation of 313 women with breast cancer who underwent surgery from 1994 and 2000, the expressions of estrogen and progestrone receptor (ER/PR), and human epithelial receptor-2 (HER2) were evaluated. The subtypes were defined as luminal-A, luminal-HER2, HER2-enriched, and triple negative breast cancer (TNBC) according to ER, PR, and HER2 status.ResultsBone was the most common site of distant recurrence. The incidence of first distant recurrence site was significantly different among the subtypes. Brain metastasis was more frequent in the luminal-HER2 and TNBC subtypes. In subgroup analysis, overall survival in patients with distant recurrence after 24 months after surgery was significantly different among the subtypes.ConclusionsOrgan-specific metastasis may depend on the molecular subtype of breast cancer. Tailored strategies against distant metastasis concerning the molecular subtypes in breast cancer may be considered.

OT1-01-03: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Multicenter Study Comparing Denosumab with Placebo as Adjuvant Treatment for Women with Early-Stage Breast Cancer Who Are at High Risk of Disease Recurrence (D-CARE).

Abstract Background Bone is a common site of distant recurrence in women with early-stage breast cancer. Cancer cells are thought to stimulate osteoclast-mediated bone resorption, which releases growth factors and cytokines that promote tumor growth. RANK Ligand (RANKL) is the key mediator of osteoclast-induced bone destruction. In preclinical studies, RANKL inhibition reduced the incidence of bone and lung metastases, suppressed tumor progression, and prolonged survival of tumor-bearing mice. Effects were additive with hormonal, chemotherapy, or targeted therapies. Denosumab is a fully human monoclonal antibody against RANKL, approved in the U.S. for the prevention of skeletal-related events in patients with bone metastases from solid tumors. In patients with castrate-resistant prostate cancer, denosumab significantly improved bone metastasis-free survival (BMFS) compared to placebo. The D-CARE trial evaluates BMFS effects of denosumab in women with stage II or III breast cancer. Methods: Women with node-positive or locally advanced (T3 or T4) disease, and known hormone and HER-2 receptor status are eligible. Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone or in combination must be planned with curative intent. Women with a prior history of breast cancer (other than ductal carcinoma in situ [DCIS] or lobular carcinoma in situ [LCIS]) or distant metastasis, oral bisphosphonate (BP) use within 1 year or any intravenous BP use are excluded. Patients are randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 mos, then every 3 mos, for a total of 5 yrs treatment. All patients receive vitamin D (≥ 400 IU) and calcium (≥ 500 mg) supplements. Primary endpoint of this event-driven trial is BMFS. Secondary endpoints include disease-free (DFS) and overall survival. The study is powered for both, BMFS and DFS. Safety, quality of life assessments and biomarkers are additional endpoints. The trial, sponsored by Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154 began enrolling patients in June 2010. PG and DF are supported in part by the Avon Foundation, NY. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT1-01-03.

A randomized, double-blind, placebo-controlled multicenter phase III study comparing denosumab with placebo as adjuvant treatment for women with early-stage breast cancer who are at high risk of disease recurrence (D-CARE).

TPS152 Background: Bone is a common site of distant recurrence in women with early-stage breast cancer. Cancer cells are thought to stimulate osteoclast-mediated bone resorption, which releases growth factors and cytokines that promote tumor growth. RANK Ligand (RANKL) is the key mediator of osteoclast-induced bone destruction. In preclinical studies, RANKL inhibition reduced the incidence of bone and lung metastases, suppressed tumor progression, and prolonged survival of tumor-bearing mice. Effects were additive with hormonal, chemotherapy, or targeted therapies. Denosumab is a fully human monoclonal antibody against RANKL, approved in the U.S. for the prevention of skeletal-related events in patients with bone metastases from solid tumors. In patients with castrate-resistant prostate cancer, denosumab significantly improved bone metastasis-free survival (BMFS) compared to placebo. The D-CARE trial evaluates BMFS effects of denosumab in women with stage II or III breast cancer. Methods: Women with node-positive or locally advanced (T3 or T4) disease, and known hormone and HER-2 receptor status are eligible. Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone or in combination must be planned with curative intent. Women with a prior history of breast cancer (other than DCIS or LCIS) or distant metastasis, oral bisphosphonate (BP) use within 1 year or any intravenous BP use are excluded. Patients are randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 mos, then every 3 mos, for 5 yrs. Supplemental vitamin D and calcium are required at standard doses. Primary endpoint of this event-driven trial is BMFS. Secondary endpoints include disease-free (DFS) and overall survival. The study is powered for both BMFS and DFS. Safety, quality of life assessments, and biomarkers are additional endpoints. The trial, sponsored by Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154, began enrolling patients in June 2010. PG and DF are supported in part by the Avon Foundation, NY.

Pamidronate as adjuvant treatment for prevention of bone metastasis in breast cancer

888 Background: Bone is the most common site of distant recurrence in breast cancer. The primary mechanism of metastatic bone disease is stimulation of osteoclastic bone resorption by factors produced by the cancer cells. Bisphosphonates are potent inhibitors of osteoclastic bone resorption with proven efficacy in reducing tumor-associated skeletal complications. Several studies have investigated the adjuvant, or preventive, use of these drugs in breast cancer. Laboratory experiments have shown that the development of bone metastases can be inhibited by Bisphosphonates. Pamidronate is an easy to use potent inhibitor of osteolysis, given in conjunction with standard anticancer therapies. We evaluated the efficacy of adjuvant pamidronate therapy for prevention of bone metastasis in women with breast cancer. Methods: We analyzed the data of 429 patients with primary operable stage I-III breast cancer that were treated at KNUH during the period January 1999-December 2002. All patients had radical local therapy and systemic therapy performed according to our guidelines at that time. 258 patients were received adjuvant pamidronate therapy(parmidronate 15mg iv every 4 weeks and oral parmidronate 100mg daily during adjuvant chemotherapy). 171 patients had no bisphosphonate therapy. The patients were perimenopausal women. The mean age of patients was 53 years and the median follow-up period was 3.5 years. The clinicopathological characteristics of the patients were well balanced. Results: The incidence of bone metastasis was 2.3% in the parmidronate group and 8.7% in control group. The incidence of other sites metastasis in pamidronate group was lower than control group but no statistically significant. Overall survival and disease-free survival rate were equal in the both groups. Bone metastasis free survival was significantly higher in the pamidronate group compared to the control group. Conclusions: In the parmidronate group, the incidence of bone metastases was significantly reduced and bone metastasis free survival was significantly higher. We conclude that adjuvant parmidronate therapy significantly reduced the development of bone metastases in perimenopausal women with primary breast cancer. No significant financial relationships to disclose.

Malignant mixed müllerian tumors of the uterus: Analysis of patterns of failure, prognostic factors, and treatment outcome

PurposeTo determine the survival outcomes, prognostic factors, and patterns of failure in patients with malignant mixed Müllerian tumor (MMMT) of the uterus. Methods and materialsBetween 1954 and 1998, 300 patients with clinical Stage I–III MMMT of the uterus were treated with curative intent at The University of Texas M. D. Anderson Cancer Center. Their hospital records were reviewed to obtain patient and tumor characteristics; details of surgery, radiotherapy (RT), and chemotherapy; and long-term outcome. Surviving patients were followed for a median of 109 months (range 15–138). Survival rates were calculated using the Kaplan-Meier method, with differences assessed by log–rank tests. ResultsOf the 300 patients, 113 (38%) were treated with surgery alone, 160 (53%) with surgery plus adjuvant EBRT or ICRT, and 27 (9%) with RT alone. Forty-eight patients received adjuvant chemotherapy. At 5 years, the overall rates of survival and cause-specific survival were 31% and 33%, respectively. Women who were postmenopausal or had a history of prior pelvic RT, pain at presentation, clinical Stage II-III disease, uterine enlargement (≥12 weeks), or an abnormal Papanicolaou smear finding had a significantly poorer prognosis than the other patients in the series. Of the 273 patients who underwent surgery, those who had positive abdominal washings, uterine length >10 cm, or extrauterine spread of disease to the cervix, adnexa, or peritoneum had a significantly worse prognosis than the other patients. Factors found on multivariate analysis to have an independent adverse influence on cause-specific survival included postmenopausal status (p = 0.0007, relative risk [RR] 3.3), uterine length >10 cm (p = 0.0001, RR 2.2), cervical involvement (p = 0.002, RR 1.8), and peritoneal involvement (p = 0.0001, RR 4.3). At 5 years, the rates of pelvic and distant disease recurrence for the entire group of 300 patients were 38% and 57%, respectively. The most common site of distant recurrence was the peritoneal cavity. Patients treated with pelvic RT had a lower rate of pelvic recurrence than patients treated with surgery alone (28% vs. 48%, p = 0.0002), but the overall survival rates (36% vs. 27%, p = 0.10) and distant metastasis rates (57% vs. 54%, p = 0.96) were not significantly different. However, patients treated with pelvic RT had a longer mean time to any distant relapse (17.3 vs. 7.0 months, p = 0.001) than patients treated with surgery alone. The use of adjuvant chemotherapy did not correlate with the survival rate or rate of distant metastasis. ConclusionAdjuvant pelvic RT decreased the risk of pelvic recurrence and may delay the appearance of distant metastases after hysterectomy for MMMT. However, the survival rates remain poor because of a high rate of distant recurrence. As more effective systemic chemotherapy is developed to control microscopic distant disease, the role of RT in controlling locoregional disease in the pelvis and abdomen may become more important. Future research should consider programs that integrate surgery, RT, and chemotherapy to maximize the probability of cure.

The role of bisphosphonates as adjuvant therapy for breast cancer.

Bone is the most common site of distant recurrence in breast cancer. The development of skeletal metastases involves complex interactions between the cancer cells and the bone microenvironment. The presence of tumor in bone is associated with activation of osteoclasts, resulting in excessive bone resorption. Bisphosphonates are potent inhibitors of osteoclastic bone resorption with proven efficacy in reducing tumor-associated skeletal complications. Several studies have investigated the adjuvant, or preventive, use of these drugs in breast cancer. Laboratory experiments have shown that the development of bone metastases can be inhibited by bisphosphonates. Three randomized clinical trials of bisphosphonates in nonmetastatic breast cancer patients have yielded conflicting results with respect to development of osseous and visceral metastases and survival. Defining the potential role of these agents in adjuvant breast cancer treatment requires further investigation in randomized, large-scale, multicenter clinical trials. The data available to date provide a strong impetus for continued clinical and laboratory work with bisphosphonates in breast cancer.