Patient Description

Ms. R, a 48-year-old white woman, has a history of stage 1, estrogen receptor (ER)-positive, HER2-positive breast cancer, which was diagnosed March 1998. At that time, she underwent modified radical mastectomy followed by adjuvant therapy with four cycles of doxorubicin/cyclophosphamide and then initiation of tamoxifen.

She remained well on tamoxifen until early December 2000, when she broke her arm swinging a golf club. Plain film x-ray suggested proximal right humerus pathologic fracture. Additional evaluation included computed tomography scan of the chest, abdomen, and pelvis as well as a bone scan, which revealed extensive bone, lung, and liver involvement. She subsequently underwent surgical repair and radiation of her pathologic fracture. The surgical specimen was consistent with a breast cancer primary, and ER and HER2 were both positive by immunostaining.

Following the surgery, Ms. R was asymptomatic. She was employed full time as a graphic designer. The patient was married and had two grown children. She was healthy, other than type 2 diabetes complicated by mild diabetic neuropathy and nephropathy. Her creatinine level was 0.7 mg/dL, but her history suggested that her creatinine levels were easily perturbed. Her medications included insulin, benazepril, and simvastatin. She had not menstruated since completing adjuvant chemotherapy.

Decision Point 1. First-Line Therapy for ER-Positive, HER2-Positive Metastatic Breast Cancer

If you were managing this case now, in addition to a bisphosphonate, what other therapies would you initiate as first-line treatment for metastatic breast cancer in this patient?

1. Paclitaxel plus trastuzumab administered weekly
2. Paclitaxel plus trastuzumab administered every 3 weeks
3. Paclitaxel/carboplatin/trastuzumab
4. An aromatase inhibitor plus trastuzumab
5. Lapatinib plus capecitabine
6. Enrollment in a clinical trial of trastuzumab-DM1 (T-DM1)

Answer: (a is probably the best choice, but c and d are also reasonable answers). Irrespective of hormone receptor status, clinicians should consider chemotherapy as first-line treatment for women whose tumors are refractory to hormone therapy and those with bulky visceral disease, severe tumor-related symptoms, or rapid progression.¹ Trastuzumab with a preferred single-agent chemotherapeutic agent, such as paclitaxel, is probably the best treatment strategy for Ms. R. However, use of trastuzumab with either combination chemotherapy (eg, paclitaxel/carboplatin) or with an aromatase inhibitor (eg, anastrozole, letrozole) is also an acceptable option.

Paclitaxel Plus Trastuzumab

Although Ms. R is asymptomatic and ER positive, her short disease-free interval while on tamoxifen and her bulky visceral metastases favor use of chemotherapy over endocrine therapy. Single chemotherapeutic agents that are recommended for use with trastuzumab in the National Comprehensive Cancer Network (NCCN) guidelines for breast cancer include paclitaxel (175 mg/m² intravenous [IV] day 1, cycled every 21 days or 80-90 mg/m² IV weekly), docetaxel (80-100 mg/m² IV day 1, cycled every 21 days or 35 mg/m² IV infusion weekly), vinorelbine (25 mg/m² IV weekly), and capecitabine (1000-1250 mg/m² PO twice daily days 1-14, cycled every 21 days).²

Ms. R was already exposed to anthracyclines in the adjuvant setting, but she is taxane-naive. Taxanes are the most commonly used chemotherapeutic agents for metastatic breast cancer in patients who were previously exposed to anthracyclines.¹ Thus, paclitaxel is a good choice for first-line chemotherapy in this patient.

Although the NCCN guidelines list both weekly dosing or every-3-week dosing of paclitaxel among the preferred single-agent regimens,² weekly dosing was found superior for HER2-positive patients in a randomized trial.³ In a combined analysis, 577 patients from Cancer and Leukemia Group B (CALGB) protocol 9840 and 158 patients from CALGB 9342 received paclitaxel 175 mg/m² every 3 weeks or 80 mg/m² weekly.³ Although HER2 assessment was not required for the first 171 patients, HER2 status was determined for all subsequent participants, and those who were HER2 positive also received trastuzumab.³ Weekly dosing of paclitaxel was associated with a higher response rate, longer time to progression, and longer overall survival (Table).³ However, grades 2 and 3 sensory neuropathy and motor neuropathy were more frequent with weekly paclitaxel (Table).³

Table. Efficacy and Safety of Weekly Versus Every-3-Week Paclitaxel.³

Abbreviations: CI, confidence interval; HR, hazard ratio; OR, odds ratio.

The addition of trastuzumab to chemotherapy augments both progression-free survival (PFS) and overall survival.⁴ Trastuzumab can be given either as 4 mg/kg IV day 1 followed by 2 mg/kg IV weekly, or as 8 mg/kg IV day 1 followed by 6 mg/kg IV every 3 weeks.² In a randomized trial, 469 women with HER2-overexpressing metastatic breast cancer were assigned to first-line treatment with chemotherapy alone or chemotherapy plus trastuzumab.⁴ Anthracycline-naive patients were treated with doxorubicin or epirubicin plus cyclophosphamide, and patients who had previously received adjuvant anthracycline were treated with paclitaxel.⁴ Compared with chemotherapy alone, chemotherapy plus trastuzumab increased median time to progression (4.6 versus 7.4 months; P <.001) and overall response rates (32% versus 50%; P <.001).⁴ Trastuzumab also reduced the rate of mortality in the first year to 22% compared with 33% with chemotherapy alone (P = .008), and increased median survival to 25.1 months versus 20.3 months respectively (P = .046).⁴ This 20% reduction in mortality—one of the largest ever reported in metastatic breast cancer from the addition of a single therapy—was observed despite the fact that two thirds of patients randomized to chemotherapy alone crossed over to treatment with trastuzumab after disease progression.⁴ In the paclitaxel-treated subgroup, median time to progression was 6.9 months with trastuzumab compared with 3.0 months without it (P <.001), and median overall survival was 22.1 versus 18.4 months (P = .17).⁴ Adverse effects associated with trastuzumab in this trial included infusion reactions (chills, fever, hypotension, bronchospasm), infections (mostly of the upper respiratory tract), and cardiac dysfunction (27% incidence in the anthracycline/trastuzumab group and 13% in the paclitaxel/trastuzumab group).⁴

Paclitaxel/Carboplatin/Trastuzumab

The NCCN guideline states that there is no compelling evidence that combination chemotherapy regimens are superior to sequential single agents, but nonetheless lists two combination chemotherapy regimens as appropriate options for use with trastuzumab:²

• PCH: Carboplatin area under the curve (AUC) of 6 IV day 1 and paclitaxel 175 mg/m² IV day 1, cycled every 21 days
• Weekly TCH: Paclitaxel 80 mg/m² IV on days 1, 8, and 15 and carboplatin AUC of 2 IV on days 1, 8, and 15, cycled every 28 days

Such regimens may improve response compared with single-agent therapy, but do not greatly increase overall survival and are associated with added toxicity.^1,2

In one randomized trial, women with HER2-positive metastatic breast cancer received weekly trastuzumab with either paclitaxel/carboplatin or paclitaxel alone every 3 weeks.⁵ The paclitaxel/carboplatin/trastuzumab group had a higher response rate (52% versus 36%; P = .04) and median PFS rate (10.7 versus 7.1 months; P = .03).⁵ In another randomized trial of 416 patients with metastatic breast cancer, median overall survival was 41.0 months with weekly paclitaxel—significantly longer (P = .037) than with paclitaxel/carboplatin (29.9 months) or docetaxel/gemcitabine (26.9 months) given every 3 weeks.⁶

Since Ms. R is asymptomatic, the added toxicities of a combination regimen likely outweigh the modest benefits.

Aromatase Inhibitor Plus Trastuzumab

The NCCN guidelines indicate that women with ER- and/or progesterone receptor-positive recurrent or metastatic disease are appropriate candidates for first-line endocrine therapy, and recommends an aromatase inhibitor as the choice of endocrine therapy in postmenopausal women.²

Two phase III studies of trastuzumab added to endocrine therapy in women with ER-positive, HER2-positive breast cancer suggest significant improvement in PFS.^7,8 In an open-label randomized study (N = 208), median PFS was twice as long with trastuzumab/anastrozole (4.8 months) compared with anastrozole alone (2.4 months; HR 0.63; 95% CI 0.47-0.84; P = .0016).⁷ Overall survival did not differ significantly between groups (28.5 versus 23.9 months respectively, P = .325), but this may have been confounded by the fact that 70% of patients in the anastrozole-alone arm received trastuzumab after progression.⁷ Adding trastuzumab to anastrozole increased the incidence of fatigue, vomiting, diarrhea, and cardiac events.⁷

In a subgroup of 219 ER-positive, HER2-positive patients in a double-blind randomized study, median PFS was 8.2 months with trastuzumab/letrozole compared with 3.0 months with placebo/letrozole (HR 0.71; 95% CI 0.53-0.96; P = .019).⁸ As in the anastrozole trial, overall survival did not significantly differ (33.3 months with trastuzumab/letrozole versus 32.3 months with placebo/letrozole; P = .113),⁸ but only half of survival events had occurred at the time of reporting. Adding trastuzumab to letrozole increased the incidence of diarrhea, rash, symptomatic left ventricular ejection fraction decline, and liver enzyme elevations.⁸

Thus, there is a benefit to adding trastuzumab when endocrine therapy is being considered. However, it should be noted that PFS improvements in these two clinical trials were more modest than those seen in the trial of trastuzumab/chemotherapy described above. In addition, aromatase inhibitors have been associated with accelerated bone loss and increased risk of pathologic fracture.⁹ Therefore, the choice of chemotherapy versus endocrine therapy should take these factors into account.

Audio Commentary by Dr. Burstein

Lapatinib Plus Capecitabine

Lapatinib/capecitabine is recommended in the NCCN guidelines for patients with advanced breast cancer that has progressed after treatment with an anthracycline, a taxane, and trastuzumab.² In that population (N = 324), the addition of trastuzumab to capecitabine improved PFS over capecitabine alone (median 8.4 versus 4.4 months), reducing the risk of disease progression by 51% (HR 0.49; 95% CI 0.34-0.71; P <.001).¹⁰ However, lapatinib/capecitabine combination therapy has not been comprehensively examined in patients such as Ms. R who have no prior exposure to taxanes or trastuzumab.

Clinical Trial of T-DM1

T-DM1 is not a good option for Ms. R at this point because it has not been tested in first-line therapy. T-DM1 is an investigational therapy that links trastuzumab to a derivative of maytansine 1, thereby allowing intracellular delivery of the cytotoxic agent to cells expressing HER2. In a phase 1 study of heavily pretreated patients with HER2-positive breast cancer, T-DM1 produced response in 44% of the nine patients with measurable disease who were treated with the maximally tolerated dose of 3.6 mg/kg every 3 weeks.¹¹ Thrombocytopenia was the dose-limiting side effect, and other adverse events included liver enzyme elevations, fatigue, anemia, and nausea.¹¹

Bisphosphonates

Because of Ms. R's established bone disease and ongoing risk of fracture, she should also be treated with a bisphosphonate. The NCCN guidelines recommend that a bisphosphonate be added to either chemotherapy or endocrine therapy for women with bone metastases, especially if the lesions are lytic, and if the patient has an expected survival of at least 3 months and creatinine level <3.0 mg/dL.² Bisphosphonates should be accompanied by calcium citrate 1200 to 1500 mg/day and vitamin D 400 to 800 IU/day.²

In a meta-analysis of 21 randomized trials, bisphosphonates showed clear palliative benefits for women with advanced breast cancer and existing bone metastases, despite a lack of effect on overall survival.¹² Bisphosphonates reduced the risk of skeletal events by 17% (relative risk [RR] 0.83; 95% CI 0.78-0.89; P <.00001), significantly prolonged the median time to skeletal event, and significantly reduced bone pain.¹² Risk of skeletal events was 41% lower with zolendronate IV 4 mg (RR 0.59; 95% CI 0.42-0.82), 23% lower with pamidronate IV 90 mg (RR 0.77; 95% CI 0.69-0.87), and 16% lower with oral clodronate 1600 mg (pooled RR 0.84; 95% CI 0.72-0.98).¹² Side effects are generally mild, but long-term use of bisphosphonates has been associated with cases of osteonecrosis of the jaw (ONJ)¹² and renal toxicity.¹³ Given the risk of ONJ, patients should maintain good oral hygiene before and during use of bisphosphonates.¹²

Case Continues

Ms. R underwent surgery, with placement of an intramedullary rod in the right (fractured) humerus and custom hemiarthroplasty of the left humerus for impending fracture. After healing from surgery, Ms. R began treatment with zoledronic acid and a paclitaxel-based trastuzumab-containing regimen. She remained on this regimen from December 2000 through August 2001, at which point her peripheral neuropathy worsened, manifested by foot drop. Her treatment was changed to vinorelbine plus trastuzumab, which was well tolerated except for intermittent absolute neutrophil counts <1000/mm³ requiring supplementation with granulocyte colony-stimulating factor. Because of Ms. R's history of a pathologic fracture, she was started on bisphosphonate therapy. Her creatinine level was carefully monitored due to the potential for renal toxicity with bisphosphonates. She was able to take the bisphosphonate for 3 years before creatinine rise prompted discontinuation.

Audio Commentary by Dr. Burstein

In June 2003, Ms. R developed seizures. Magnetic resonance imaging revealed an isolated 3-cm left frontal lobe metastasis. She was started on dexamethasone at a loading dose of 10 mg and then 4 mg four times daily.

Decision Point 2. Management of Brain Metastases

In addition to the systemic steroids, appropriate management of brain metastases in HER2-positive breast cancer includes:

1. Surgical resection or sterotactic radiosurgery (SRS)
2. Whole brain radiation therapy (WBRT)
3. Change to capecitabine/lapatinib
4. An antiepileptic drug

Answer: a and d, and then possibly b. Since she has had a seizure, an antiepileptic drug would be appropriate. Surgery or SRS should be considered for local treatment of a single isolated brain metastasis. WBRT is known to be beneficial, but local treatment (ie, with surgery or SRS) should be prioritized. WBRT may then be given either immediately thereafter or upon intracranial progression.

Surgery or SRS

Surgery for brain metastases involves removal of the tumor and a minimal amount of the adjacent normal tissue, and the surgeon should attempt to minimize disruption of blood vessels that perfuse distal brain tissue.¹⁴ Resection prior to WBRT improves outcome compared with WBRT alone. In one prospective study, patients with a single resectable brain lesion were randomly assigned to surgery plus WBRT or WBRT alone.¹⁵ Among 48 evaluable patients, the surgical group had a lower risk of local recurrence (20% versus 52%; P <.02), a longer time to recurrence (median >59 versus 21 weeks; P <.0001), and longer overall survival (median 40 versus 15 weeks; P <.01).¹⁵ Furthermore, Karnofsky Performance Status scores remained ≥70 for a significantly longer time in the surgery group (median 38 versus 8 weeks; P <.005).¹⁵

Surgery is generally well tolerated, with morbidity in less than 5% of cases and mortality in less than 3%.¹⁶ Complications can include seizures, edema, venous thromboembolic disease, hematoma, wound infections, pseudomeningocele, and neurologic impairment.^14,16 Risks can be minimized by use of intraoperative ultrasound and frameless stereotaxy.¹⁶ Some patients may not be candidates for surgery due to advanced age, comorbidities, unresectable lesions, poor performance status, or the unstable extracranial metastases.^14,16,17

Recent guidelines suggest similar benefit from SRS compared with surgery in appropriate patients.^18,19 SRS combines stereotaxy with focal delivery of high radiation doses to a conformally mapped target while minimizing exposure of normal brain tissue.¹⁷ In general, SRS can be considered in lesions <3 cm when sampling of tissue for diagnosis or receptor confirmation is not crucial. Compared with surgery, this procedure is minimally invasive and can be performed on an outpatient basis.¹⁷ Complications can include headaches, nausea, vomiting, edema, seizures, radiation necrosis, and worsening of neurologic deficits.^16,17

WBRT

WBRT helps prevent both local and distal recurrences of CNS metastases,¹⁶ reduces neurologic symptoms, and improves quality of life.²⁰ WBRT is given as stand-alone therapy to patients who are not candidates for surgery or SRS because of the location, size, or number of metastases.²⁰ However, local treatment with surgery or SRS is preferred for eligible patients.

Adjuvant use and timing of WBRT following surgery or SRS are controversial,¹⁶ despite the high rate of relapse (70%) after cranial resection if WBRT is not performed compared with 18% when it follows SRS.²¹ WBRT reduces the likelihood of dying from neurologic causes but does not prolong overall survival or functional independence.²¹ Therefore, WBRT may be given either immediately after directed therapy or delayed until subsequent progression, and the decision should be made on a case-by-case basis. Complications of WBRT may include nausea, vomiting, alopecia, hearing loss, skin reactions, somnolence, necrosis, personality changes, memory loss, and neurocognitive deficits.²⁰

Capecitabine/Lapatinib

Ms. R has symptomatic brain metastases amenable to local therapy, which should be tried before systemic salvage treatment.

Use of chemotherapy and HER2-targeted therapies for treatment of brain metastases is limited, in part because the blood-brain barrier restricts entry of most systemic anticancer therapies.²² Because of its size, lapatinib may cross the blood-brain barrier more effectively than trastuzumab. It has shown activity against breast cancer brain metastases in preclinical models.²³ In an open-label phase II study, 242 patients with HER2-positive breast cancer and new or progressive brain metastases after WBRT or SRS and prior exposure to trastuzumab were treated with lapatinib.²⁴ The CNS objective response rate was about 6% (15 partial and no complete responses); median PFS was 2.4 months and median overall survival was 6.4 months.²⁴ Those who had a ≥50% reduction in volume of CNS lesions had a median PFS of 3.38 months.²⁴

Participants in the lapatinib trial were given the option of enrolling in an extension in which they received lapatinib plus capecitabine after they developed progression of extra-CNS or CNS disease.²⁴ Among the 50 patients who enrolled in this extension, 10 (20%) had a CNS response (all partial responses) and median PFS was 3.65 months.²⁴ Among those in the extension who had a ≥50% reduction in CNS lesion volume, median PFS was 6.21 months.²⁴ The modest benefits seen with lapatinib/capecitabine in this trial warrant further investigations in prospective studies, as this combination may be beneficial to patients who have failed local therapies.

Antiepileptic Drugs

Seizures are a common manifestation of CNS metastases. Antiepileptic drugs, such as phenytoin, carbamazepine, and valproic acid, have a high risk of side effects, such as cognitive impairment, myelosuppression, liver dysfunction, and dermatologic reactions.²⁵ In addition, antiepileptic drugs have potential for drug interactions that can reduce the efficacy of corticosteroids and chemotherapy.²⁵ Therefore, they should be used only if necessary to control seizures. Since Ms. R had a seizure, she was an appropriate candidate for an antiepileptic drug. If an antiepileptic drug is needed, the patient should receive a single agent at the lowest effective dose.¹⁶

Audio Commentary by Dr. Burstein

Case Outcome

Ms. R was started on an antiepileptic drug, which she took for about a year. During that time, she was seizure-free and the antiepileptic drug was then tapered and discontinued.

The patient elected to enroll in a clinical trial in which her brain metastasis was resected and carmustine (BCNU) wafers were placed in the resection cavity. She did not receive WBRT. BCNU wafers are still considered investigational. This strategy circumvents the difficulty of getting chemotherapeutic agents across the blood-brain barrier¹⁴ and may help prevent local recurrence in patients who do not wish to undergo WBRT.¹⁶ However, chemotherapy wafers are not protective against CNS recurrences outside of the area of placement.¹⁶

Ms. R's renal insufficiency worsened in January 2004 with creatinine elevation to 2.1 mg/dL attributable to nonsteroidal anti-inflammatory drug use and zoledronic acid. The bisphosphonate was discontinued and her renal function returned to baseline, but it has waxed and waned since then with the addition of any nephrotoxic agent. Ms. R has been monitored routinely with positron emission tomography with noncontrast CT for anatomic localization, and she has been without evidence of disease.

Ms. R returned to therapy with vinorelbine plus trastuzumab 1 month later, and continued on this treatment until November 2006 when her oncologist convinced her to take a chemotherapy holiday. At that point, she switched to anastrozole/trastuzumab. She is still well, without evidence of intracranial or extracranial progression and with minor residual anomic aphasia as her only breast cancer-related symptom. However, she developed multiple myeloma in September 2009, which has been difficult to manage.

Conclusion

Although endocrine therapy is recommended for most women with hormone-sensitive metastatic breast cancer based on its safety and tolerability profile, chemotherapy is favored if the patient has become refractory to hormone therapy or has bulky visceral disease, severe symptoms, or rapid progression.¹ Taxanes are the most commonly used first-line chemotherapy for patients with prior exposure to anthracyclines, and weekly dosing of paclitaxel has demonstrated better outcomes than administration every 3 weeks. A single CNS metastasis should be considered for local treatment with surgery or SRS, possibly followed by WBRT.

It is noteworthy that this case patient has survived a decade (and counting) with metastatic breast cancer, even in the absence of WBRT for her CNS metastases. CNS involvement and multiple sites of metastases are poor prognostic factors in metastatic breast cancer.¹ However, in the setting of HER2-targeted therapy, survival after brain metastasis is significantly longer in HER2-positive disease than HER2-negative disease. In one study, those treated in the pre-trastuzumab era lived only 4 months after diagnosis of brain metastases, whereas those treated after development of HER2-targeted therapy lived 15 months.²⁶ In another study of patients with CNS metastases, median survival was 6.3 months in HER2-negative patients, 6.1 months in HER2-positive patients who had not been treated with trastuzumab, and 11.6 months in HER2-positive patients treated with trastuzumab.²⁷ Currently, with a combination of HER2-targeted therapy and advances in local therapy (surgery, SRS, and WBRT), patients with CNS disease are more likely to die from progression of systemic disease rather than from the CNS metastases.¹⁶ This potential for long-term survival supports aggressive management of both intra- and extracranial disease in this subtype.

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