Evidence from trial or study results: systemic therapies

CHEMOTHERAPIES

Two systematic reviews addressed the effectiveness of systemic therapies in the management of central nervous system (CNS) metastases from various primary tumours, including breast cancer.^28,61

The systematic review by Mehta et al (2010) addressed the role of chemotherapy in the management of newly diagnosed brain metastases.²⁸ The use of chemotherapy for brain metastases was investigated in four questions, however, only the comparison of chemotherapy plus WBRT vs. WBRT alone was relevant as the other questions included studies of only lung cancer patients.

Five studies met the inclusion criteria for the question chemotherapy plus WBRT vs. WBRT alone: two phase III RCT’s, two phase II RCT’s and one retrospective cohort study.²⁸ In each RCT, patients were randomised to receive WBRT or WBRT plus carboplatin, chloroethylnitrosoureas or temozolomide.  

The systematic review by Ammirati et al (2010) addressed the treatment of patients who develop recurrent/progressive brain metastases after initial therapy.⁶¹ The review identified ten studies evaluating the role of chemotherapy in patients with recurrent/progressive metastatic brain disease. Of these, five are prospective single arm phase II studies, and five are case series. The chemotherapy agents assessed include cisplatin, temozolomide, vinorelbine, or fotemustine.

Six prospective studies were identified investigating different chemotherapies including temozolomide, sagopilone and patupilone.^62-67 All were phase I or phase II single arm studies, including small patient populations. These chemotherapies are not considered appropriate for use in breast cancer or funded through the Pharmaceutical Benefits Scheme; off-label use is not recommended. Four studies were in populations with CNS metastases from breast cancer only^63-66 and two studies were in populations with CNS metastases from various primary cancers including breast cancer.^62,67 Four studies investigated the use of temozolomide either alone or in combination with other chemotherapies; one study investigated sagopilone, and one study investigated patupilone.^62-67

Overall survival

The systematic review by Mehta 2010 did not pool the results of the five identified studies. In the four RCTs, there was no significant survival difference between the control or intervention arms.²⁸

The systematic review by Ammirati et al (2010) reported that median survival ranged from 3.5 months to 6.6 months in patients with recurrent or progressive brain metastases from various primary tumours.⁶¹

Among the prospective studies investigating temozolomide, sagopilone or patupilone, median survival ranged from 5.3 months to 6.9 months.^62-67

Progression free survival

The ten studies identified in the systematic review by Ammirati et al (2010) indicated that some patients with recurrent or progressive brain metastases will have an objective radiographic response and/or improvement in functional status following treatment with chemotherapy.⁶¹ Median time to recurrence after retreatment with various chemotherapy regimens ranged from 2 to 4 months. Of the three studies investigating chemotherapy regimens (temozolomide with cisplatin or vinorelbine), two studies reported a median time to recurrence ranging from 1.9 to 2.9 months.⁶¹ Christodoulou 2005 investigated temozolomide and cisplatin; of the 32 patients assessed, complete response was observed for one patient, partial response was observed in nine patients, and five patients had stable disease.⁶² The two studies investigating temozolomide and vinorelbine (Iwamoto 2008⁹⁷ and Omuro 2006⁹⁸) observed complete responses for one patient each. Patients experienced progressive disease at a rate of 76% (Iwamoto 2008⁹⁷) and 56% (Omuro 2006⁹⁸).⁶¹

HER2-DIRECTED THERAPIES: Trastuzumab

Six retrospective studies were identified in the Cancer Australia systematic review that evaluated the use of trastuzumab in patients with brain metastases from HER2-positive breast cancer.^30-34,99

Overall survival

Five studies reported on overall survival, see Table 2 below for results.^30-34 Patients with HER2-positive disease who received trastuzumab treatment, experienced longer median survival times compared to HER2-positive patients who did not receive trastuzumab and compared to HER2-negative patients.

Table 2: Overall median survival outcomes by HER2 status and trastuzumab treatment

Abbreviations: BM – brain metastases; HER2 - human epidermal growth factor receptor 2, NR – not reported, T – trastuzumab

Two studies (Park 2009; and Park, Park et al 2009) reported on overall survival for HER2-positive patients only,^33,99 (see Table 3 below for results). Both studies found significantly improved survival associated with trastuzumab treatment.

Table 3: Overall median survival outcomes among HER2-positive patients

Abbreviations: HER2 - human epidermal growth factor receptor 2.

Time to diagnosis of brain metastases

Three studies reported on the association between trastuzumab treatment and time to diagnosis of brain metastases.^30,33,99 Each study found that brain metastases were delayed in HER2-positive patients on trastuzumab compared to HER2-positive patients not taking trastuzumab or HER2-negative patients.

Park 2009 reported patients receiving trastuzumab had a median time to diagnosis of brain metastases of 19 months, compared to 8 months for patients who did not receive trastuzumab, or had trastuzumab treatment after brain metastases were diagnosed (p=<0.001).³³  Similar results were identified in the Park, Park et al 2009 study: 15 months for patients with prior trastuzumab treatment compared to 10 months among patients never receiving trastuzumab (p=0.035).⁹⁹

The Dawood 2008 analysis found the median time to diagnosis of brain metastases among the whole cohort was 11.3 months.³² Among HER2-negative patients, time to diagnosis was 8.9 months; 2.1 months for HER2-positive patients who did not receive trastuzumab, and 13.1 months for HER2-positive patients who did receive trastuzumab for first line treatment of first site of metastases.  

Time to progression

Park 2009 investigated median time to progression of intracranial tumours, finding that progression was prolonged in patients treated with trastuzumab after diagnosis of brain metastases (7.8 months) compared to patients who never received trastuzumab (3.9 months) or who had trastuzumab after diagnosis of brain metastases (2.9 months) (p=0.006).³³

Incidence of CNS metastases as first relapse site

The HERA trial (Pestalozzi et al 2013) investigated use of trastuzumab compared to observation in patients with HER2-positive early breast cancer.²⁹ The incidence of CNS relapse as the first disease-free survival event did not differ between patients (p=0.55), however one year of trastuzumab was significantly associated with reduced incidence of non-CNS relapse (p=<0.0001).

HER2-DIRECTED THERAPIES: Lapatinib in previously untreated CNS metastases

The Cancer Australia systematic review⁷ identified one study (LANDSCAPE), a single arm phase II study³⁶, which investigated the use of lapatinib in combination with capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer. Exclusion criteria included single brain metastases amenable to surgical resection, previous WBRT or SRS, current radiation therapy or current systemic treatment for breast cancer. 

Overall survival

Overall survival at six months was 90.9%. Median overall survival was 17 months.³⁶

Response to treatment

An objective CNS response (all partial responses) was observed in 29 (65.9%) patients. A CNS volumetric reduction of 80% or greater was observed in nine patients (20%), and overall, 37 patients (84%) had some reduction in tumour volume. Forty-two of 44 patients were available for assessment of best CNS response according to Response Evaluation Criteria In Solid Tumors (RECIST); two patients (5%) had a complete response, 22 patients (52%) had a partial response; thus 24 patients (57%) had an objective CNS response.³⁶

Among the 30 patients who had prior trastuzumab treatment, 20 (67%) experienced an objective CNS response. Of the 14 patients who had not had prior trastuzumab, nine (64%) had an objective CNS response.³⁶

Progression

Among 41 patients with available data, the site of first progression was CNS alone for 32 patients (78%); extra-CNS alone in two patients (5%) and, for five patients (12%) progression was observed in both the CNS and extra-cranially. Median time to progression was 5.5 months, and median time to radiotherapy was 8.3 months.³⁶

Adverse events

Twenty-two of 45 patients experienced at least one grade 3 or grade 4 adverse event, and 14 (31%) experienced at least one serious adverse event.³⁶ The most commonly reported adverse events were diarrhoea and hand-foot syndrome. Sixteen patients required a reduction to their dose of lapatinib; 11 of which were during the first two cycles of treatment. Twenty-six patients required a dose reduction for capecitabine, most frequently in the second, third or fourth cycles.

Treatment discontinuation due to adverse events occurred in four patients (9%).³⁶

HER2-DIRECTED THERAPIES: Lapatinib in previously treated CNS metastases

Eight studies were identified in the Cancer Australia systematic review⁷ that examined the use of lapatinib for the treatment of CNS metastases in HER2-positive metastatic breast cancer patients previously treated.

Lin et al conducted two prospective phase II trials of lapatinib in patients with brain metastases from HER2 positive breast cancer, previously treated with trastuzumab and radiotherapy.^35,70 In Lin 2009 a subset of patients who progressed on lapatinib went on to receive lapatinib and capecitabine.³⁵ A subsequent randomised phase II trial comparing lapatinib in combination with capecitabine or topotecan was undertaken.⁶⁹ While these are small studies, they are some of the few high level evidence studies.

Three additional studies examined the combination of lapatinib and capecitabine, (including a conference abstract report¹⁰⁰), however none included a control arm of capecitabine alone.^68,100,101

Two further phase I studies (conference abstract reports) reported outcomes for use of lapatinib with temozolomide and lapatinib with WBRT.^102,103

Overall survival

Two studies investigating the use of lapatinib reported on overall survival.^35,68 Metro 2011 found that patients treated with lapatinib and capecitabine (n=30) had a median overall survival of 27.9 months, significantly longer than patients treated only with trastuzumab-based therapies (n=23, 16.7 months; p=0.01).⁶⁸ Among the patients (n=6) who received lapatinib and capecitabine as the first systemic option after development of brain metastases, median overall survival was not reached. Among the 24 patients who received lapatinib and capecitabine after at least one trastuzumab-based therapy following development of brain metastases, overall survival was 27.1 months.⁶⁸

Lin 2009 reported on outcomes for 242 patients treated with lapatinib, following prior trastuzumab treatment and local therapies. Median overall survival was 6.4 months.³⁵

Response rate

Five studies investigating lapatinib use reported on response rates.^35,68-70,101 Lin 2008 assessed 39 patients receiving lapatinib after prior treatment with trastuzumab and other systemic and local therapies.⁷⁰ One patient achieved a partial CNS response, and four patients achieved partial responses in non-CNS sites. Three patients achieved at least 30% volumetric reductions in CNS lesions, and an additional seven patients achieved reductions of 10% to 30%. A trend towards a longer time to progression was found for patients with at least 30% volumetric reduction compared to other patients.⁷⁰

Lin 2009 investigated the use of lapatinib among 242 patients, with 50 patients opting to enter a subsequent phase of treatment with lapatinib and capecitabine.³⁵ Among the 242 patients treated with lapatinib, an objective CNS response rate of 6% was observed. No complete responses were seen; 15 partial responses occurred. Assessment of volumetric changes to CNS lesions were available for 200 patients. Nineteen patients (8%) experienced a volumetric reduction of >50%, and a total of 50 patients (21%) experienced a >20% reduction to their CNS lesions. A lower risk of disease progression compared to the rest of the study population was observed among patients who had at least a >20% volumetric reduction to their CNS lesions. Of the fifty patients who opted to enter the lapatinib and capecitabine extension phase, ten (20%) experienced an objective CNS response; all were classified as partial responses.³⁵

Lin 2011 compared lapatinib and capecitabine with lapatinib and topotecan.⁶⁹ Of the 13 patients treated with lapatinib and capecitabine, five patients experienced a partial response. No objective responses were observed among the nine patients treated with lapatinib and topotecan.

Time to progression

Sutherland 2010 investigated lapatinib and capecitabine and reported on time to progression.¹⁰¹ Median time to progression for the 34 patients with CNS metastases was 22 weeks. Among those previously treated with capecitabine, median time to progression was 17 weeks, compared to 30 weeks for patients who are capecitabine-naïve (p=0.06).

Progression free survival

Two studies reported on progression free survival.^35,68 On review of 237 patients treated with lapatinib in Lin 2009, the median progression free survival was 2.4 months.³⁵ Among the 50 patients opting to have a lapatinib and capecitabine extension phase of treatment, the median progression free survival was 3.65 months.

Metro 2011 assessed 30 patients for progression free survival from the start of lapatinib and capecitabine.⁶⁸ The median progression free survival was 5.1 months, with a median brain-progression free survival of 5.6 months.

Adverse events

Three studies reported on adverse events associated with lapatinib.^35,69,70 The most commonly reported adverse events include diarrhoea, rash, nausea and vomiting. The most commonly reported adverse events associated with lapatinib and capecitabine were palmar-plantar erythrodysesthesia, diarrhoea and nausea.

Among patients treated with lapatinib and topotecan, commonly reported adverse events include diarrhoea, nausea, fatigue and thrombocytopenia. The Lin 2011 study closed accrual of patients to the lapatinib and topotecan arm due to tolerability issues, in combination with a lack of early efficacy.⁶⁹

TRIPLE NEGATIVE PATIENTS

One retrospective analysis of patients with metastatic triple-negative breast cancer was identified.¹⁰⁴ Lin and Claus et al 2008 retrospectively reviewed 116 patients with triple-negative breast cancer. Sixteen patients (14%) were diagnosed with CNS metastases at the initial metastatic diagnosis, 53 (46%) had a CNS metastasis at some point.¹⁰⁴

Overall survival

Among the 53 patients with CNS metastases, the median survival from time of diagnosis of any metastasis was 11.6 months, and 4.9 months from time of diagnosis of first CNS metastasis. ¹⁰⁴

Response rate

Of the 53 assessed patients, 3 were judged to have stable or responsive systemic disease. ¹⁰⁴