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1.  Ixabepilone as Monotherapy or in Combination with Capecitabine for the Treatment of Advanced Breast Cancer 
Breast Cancer is the most prevalent cancer in the world with 4.4 million survivors up to 5 years following the diagnosis.1 In the US alone approximately forty thousand women die annually of metastatic breast cancer (MBC). Despite many effective systemic treatment options approximately 50% of women with MBC succumb to the disease within 24 months of the diagnosis.2 Ixabepilone is a novel, first in class member of the epothilone class of antineoplastic agents. Ixabepilone is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and Capecitabine. Ixabepilone is also indicated in combination with Capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Ixabepilone was extensively studied as a single agent in patients with MBC and was found to be effective and well tolerated with a predictable and manageable safety profile. Not surprisingly prior exposure to anthracyclines and taxanes affects significantly the potential for response to therapy with single agent Ixabepilone in metastatic setting. MBC patients with taxane resistant MBC have objective response rate (RR) of 12%, patients with prior low exposure to taxanes and/or resistance RR = 22%, Ixabepilone treatment after adjuvant anthracycline therapy exposure renders RR = 42% and in Taxane naïve patients RR = 57%. In two large phase III studies of Ixabepilone + Capecitabine versus Capecitabine alone, progression free survival (PFS) and overall response rates (RR) were higher in the combination treatment arms, but no survival advantage was seen overall. Treatment with Ixabepilone + Capecitabine in a phase II study resulted in an overall response rate (ORR) of 23% in ER/PR/HER2 negative, triple-negative breast cancer patients (TNBC) while ORR of 31% was seen in a preplanned pooled analysis of TNBC in the phase III trials of Ixabepilone + Capecitabine. Significantly prolonged median PFS was seen for TNBC treated with the combination of Ixabepilone + Capecitabine compared to Capecitabine alone 4.2 vs. 1.7 months respectively. Ixabepilone as single agent appears to show excellent antitumor activity in patients with TNBC MBC. Addition of Ixabepilone to Capecitabine results in approximately doubling in median PFS for TNBC versus Capecitabine alone. Single agent Ixabepilone is generally well tolerated, and its toxicity profile does not overlap with that of Capecitabine and therefore depending on prior exposure to chemotherapy both single agent Ixabepilone or in combination with Capecitabine can be used safely and effectively for treatment of advanced breast cancer.
PMCID: PMC3076013  PMID: 21494397
Ixabepilone; metastatic breast cancer; monotherapy; in combination with capecitabine; triple negative breast cancer
2.  Phase II Trial of Weekly Nanoparticle Albumin-Bound Paclitaxel With Carboplatin and Trastuzumab as First-line Therapy for Women With HER2-Overexpressing Metastatic Breast Cancer 
Clinical breast cancer  2010;10(4):10.3816/CBC.2010.n.036.
This multicenter phase II trial evaluated the efficacy and safety of weekly nanoparticle albumin-bound paclitaxel with carboplatin and weekly trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer (MBC).
Patients and Methods
We treated 32 patients who had measurable MBC that was HER2-positive defined by an immunohistochemical staining score of 3+ or gene amplification by fluorescence in situ hybridization, required for those with an IHC of 2+. Patients were treated with albumin-bound paclitaxel 100 mg/m2 and carboplatin at area under the curve (AUC) = 2 on days 1, 8, and 15 of a 28-day cycle. Trastuzumab was administered at 2 mg/kg weekly after a loading dose of 4 mg/kg. Because of hypersensitivity reactions occurring during carboplatin infusion numbers 6-8 in 4 of the first 13 patients with this premedication-free regimen, the protocol was amended for carboplatin and dosed at AUC = 6 day 1 each 28-day cycle, in lieu of introducing steroid prophylaxis. Patients were treated with 6 cycles and allowed to continue with all 3 drugs or trastuzumab alone if free of progression and unacceptable toxicity after 6 cycles.
The overall response rate (ORR) was 62.5% (95% CI, 45.7%-79.3%) with 3 confirmed complete responders (CRs; 9%) and 17 confirmed partial responses (PRs; 53%). An additional 6 patients (19%) had stable disease (SD) for greater than 16 weeks for a clinical benefit rate (ORR + SD > 16 weeks) of 81%. As of April 16, 2009, 20 patients (63%) had progressed with a median progression-free survival (PFS) of 16.6 months (95% CI, 7.5-26.5 months). Antitumor activity was similar for patients treated with weekly carboplatin and every-4-week carboplatin (ORR, 65% vs. 67%, respectively). Hematologic toxicities were the only grade 4 toxicities noted and were infrequent with grade 4 neutropenia in 3 patients (9%) and 1 febrile neutropenia. Grade 2/3 peripheral neuropathy was uncommon (13%/3%).
Weekly albumin-bound paclitaxel with carboplatin and trastuzumab is highly active in HER2-overexpressing MBC. In the absence of corticosteroid premedication, which we avoided with albumin-bound paclitaxel, carboplatin seems best dosed every 4 weeks rather than weekly because of carboplatin-associated hypersensitivity reactions. The regimen was very well tolerated with few grade 3 and 4 nonhematologic toxicities experienced, and severe hematologic toxicity and peripheral neuropathy were infrequent.
PMCID: PMC3883128  PMID: 20705560
Nab-paclitaxel; Neutropenia; Platinum agents; Progression-free survival
3.  A multicenter prospective phase II randomized trial of epirubicin/vinorelbine versus pegylated liposomal doxorubicin/vinorelbine as first-line treatment in advanced breast cancer. A GOIM study 
To evaluate activity and tolerability of two anthracycline-containing regimens as first-line treatment for anthracycline-naïve relapsed breast cancer patients.
Patients with relapsed breast cancer not previously treated with adjuvant anthracyclines were randomly assigned to epirubicin/vinorelbine (arm A: EPI/VNB, EPI 90 mg/m2 on day 1, VNB 25 mg/m2 on days 1,5 plus G-CSF subcutaneously on days 7-12, with cycles repeated every 21 days), or to pegylated liposomal doxorubicin/VNB (arm B: PLD/VNB, PLD 40 mg/m2 on day 1, VNB 30 mg/m2 on days 1, 15, with cycles repeated every 4 weeks). Primary objective was to evaluate the efficacy of the two regimens in terms of response rate, secondarily toxicity, progression free survival and overall survival.
One hundred and four patients have been enrolled (arm A 54, arm B 50): characteristics were well balanced between the 2 arms. Responses were as follows: arm A, 3 (5.6%) CR, 20 (37%) PR, (ORR 42.6%, 95%CI 29.3%-55.9%); arm B, 8 (16%) CR, 18 (36%) PR, (ORR 52%, 95%CI 38.2%-65.8%). Median progression free survival was 10.7 months in arm A (95% CI, 8.7-12.6), and 8.8 months in arm B (95% CI, 7.1-10.5). Median overall survival was 34.6 months in arm A (95%CI, 19.5-49.8) and 24.8 months in arm B (95%CI, 15.7-33.9). As toxicity concerns, both treatment regimens were well tolerated; myelosuppression was the dose-limiting toxicity, with G3-4 neutropenia occurring in 18.5% and 22% of the patients of arm A and B, respectively. No relevant differences in main toxic effects have been observed between the two arms, except for alopecia, more common in arm A, and cutaneous toxicity, observed only in arm B. No clinical congestive heart failures have been observed, one case of tachyarrhythmia was reported after the last EPI/VNB cycle, and two reversible ≥ 20% LVEF decreases have been observed in arm A.
Both anthracycline- containing regimens evaluated in the present study seem to be active and with a satisfactory tolerability in anthracycline-naïve relapsed breast cancer patients.
PMCID: PMC3082232  PMID: 21481280
4.  A Randomized Feasibility Study of Docetaxel Versus Vinorelbine in Advanced Breast Cancer 
The Oncologist  2012;17(11):1429-e47.
Author Summary: Abstract and Brief Discussion
Docetaxel and vinorelbine have demonstrated efficacy in the treatment of metastatic breast cancer (MBC). This prospective feasibility study compared the efficacy of these two treatments in MBC.
Patients with MBC progressing following anthracycline treatment were randomly assigned to either docetaxel (100mg/m2day 1 q3W) or vinorelbine (25mg/m2 day 1 q2W). Patients were eligible to cross over at progression. Objective response rates (ORR), time to progression (TTP) and overall survival (OS) were measured.
37 patients were randomised. 2 patients were excluded due to protocol violations. Of 35 remaining patients 17 received docetaxel and 18 received vinorelbine per protocol. ORR was 12.5% and 6.0% respectively for docetaxel and vinorelbine. The median time to progression was 10.4 weeks (range 6-14 weeks) in docetaxel arm and 7.6 weeks (range 4-11 weeks) in vinorelbine arm (p = .82). The clinical benefit rate (defined as complete response, partial response plus stable disease) was 44% in the docetaxel arm and 12% in the vinorelbine arm. Based on intent to treat the median OS in the docetaxel arm was 34 weeks (95% CI, 20.7-48) and 21.2 weeks (95% CI, 17-25.4) in vinorelbine arm (p = .388). 16 patients crossed over, 5 from docetaxel to vinorelbine and 11 from vinorelbine to docetaxel. At cross over the ORR was 0% and 18% on cross over to vinorelbine and docetaxel respectively with a median TTP of 17.3 weeks (95% CI, 16.3-18.1) and 18.7 weeks (95% CI, 13.9-23.4) for those receiving vinorebine and docetaxel at cross over respectively. Vinorelbine however was much better tolerated with fewer grade 3-4 toxicity events (n = 4) than docetaxel (n = 27).
While docetaxel resulted in a longer TTP and OS in this study it did not reach statistical significance. TTP duration for those patients who crossed over was similar, but overwhelmingly vinorelbine had fewer significant grade 3-4 toxicities than docetaxel. Only two previous randomized studies have compared the efficacy of single agent docetaxel and vinorelbine following prior anthracycline exposure, one in an unselected population [16], and the other, HERNATA, in HER2 positive disease with trastuzumab used in both arms [17]. The patients randomized in this study were relatively heavily pretreated with the majority having received 2-3 lines of prior treatment for their metastatic disease. The lower response rates with vinorelbine as compared to docetaxel in this study concur with results reported in other studies [16]. However, the numbers in both this study and the other unselected study [16] are small and need to be interpreted with caution. With regard to toxicity, in the present study, grade 3-4 hematological adverse events and infection were tenfold greater with docetaxel as compared with vinorelbine, consistent with results in HERNATA [17]. While others have reported a significantly higher number of overall grade 3-4 toxicities with vinorelbine [16], the fact that, as in HERNATA, discontinuations due to toxicities in that study [16] were significantly greater with docetaxel as compared to vinorelbine suggests either the toxicity data collected did not reflect the true toxicities on treatment or that docetaxel toxicities were in some way more severe or protracted leading to more numerous discontinuations [16]. Larger randomized studies are needed to determine (1) the efficacy of docetaxel versus vinorelbine in anthracycline pretreated disease and (2) the efficacy of vinorelbine after prior taxane exposure, and particularly how it may compares both with regard to efficacy and tolerability with other possible regimens that may utilized such as carboplatin-gemcitabine [20] or eribulin [21]. The longer as well as comparable TTP at cross over for both agents compared to that upfront suggests there may be enrichment at cross over of a group of patients who are not only fit for further treatment but are more likely to a derive continued benefit from additional treatment.
PMCID: PMC3500364  PMID: 23002126
5.  Cisplatin improves antitumor activity of weekly nab-paclitaxel in patients with metastatic breast cancer 
Although nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is approved to be given every 3 weeks, weekly use of this drug is becoming a new standard of care in patients with metastatic breast cancer (MBC). This prospective Phase II study was conducted to improve the efficacy of weekly nab-paclitaxel with cisplatin in MBC patients. Seventy-three women with recurrent or MBC were eligible for participation. Nab-paclitaxel was administered weekly at a dose of 125 mg/m2 on day 1, day 8, and day 15, followed by cisplatin 75 mg/m2 on day 1, repeated every 28 days with a maximum of 6 cycles. The primary objective was investigator-assessed overall response rate (ORR). A high ORR of 67.1% was obtained, with rates of 80.6% for the first-line patients and 80% for patients not pretreated with taxanes. Among those who had objective responses, a large percentage of patients (83.7%) showed quickly remarkable tumor shrinkage during the first two cycles. The median progression-free and overall survival times were 9.8 and 26.9 months, respectively. For the patients receiving first-, second-, and third-line therapy or beyond, median progression-free survival was 11.7, 7.7, and 7.6 months, respectively (P=0.005). Molecular subtype was not significantly associated with ORR or disease progression. Grade 4 neutropenia occurred in 46 patients (63.0%), with febrile neutropenia found in 9 patients (12.3%). Grade 3 peripheral neuropathy was an accumulated dose-limiting toxicity occurring in 19 patients (26.0%). Efficacy of weekly nab-paclitaxel can be improved by adding cisplatin. The doublet is highly effective, with quick response, manageable toxicity, and possible equivalence across molecular subtypes in MBC patients.
PMCID: PMC3964033  PMID: 24672237
metastatic breast cancer; nanoparticle albumin-bound paclitaxel; cisplatin; taxane-pretreated
6.  Randomised phase 3 open-label trial of first-line treatment with gemcitabine in association with docetaxel or paclitaxel in women with metastatic breast cancer: a comparison of different schedules and treatments 
BMC Cancer  2013;13:164.
This open-label study compared docetaxel/gemcitabine vs. paclitaxel/gemcitabine and a weekly (W) vs. 3-weekly (3 W) schedule in metastatic breast cancer (MBC).
Patients relapsed after adjuvant/neoadjuvant anthracycline-containing chemotherapy were randomized to: A) gemcitabine 1000 mg/m2 Day 1,8 + docetaxel 75 mg/m2 Day 1 q3W; B) gemcitabine 1250 mg/m2 Day 1,8 + paclitaxel 175 mg/m2 Day 1 q3W; C) gemcitabine 800 mg/m2 Day 1,8,15 + docetaxel 30 mg/m2 Day 1,8,15 q4W; D) gemcitabine 800 mg/m2 Day 1,15 + paclitaxel 80 mg/m2 Day 1,8,15 q4W. Primary endpoint was time-to-progression (TTP). Secondary endpoints were overall survival (OS) and overall response rate (ORR).
Interim analysis led to accrual interruption (241 patients enrolled of 360 planned). Median TTP (months) was 8.33 (95% CI: 6.19-10.16) with W and 7.51 (95% CI: 5.93-8.33) with 3 W (p=0.319). No differences were observed in median TTP between docetaxel and paclitaxel, with 85.6% and 87.0% of patients progressing, respectively. OS did not differ between regimens/schedules. ORR was comparable between regimens (HR: 0.882; 95% CI: 0.523-1.488; p=0.639), while it was significantly higher in W than in the 3 W (HR: 0.504; 95% CI: 0.299-0.850; p=0.010) schedule. Grade 3/4 toxicities occurred in 69.2% and 71.9% of patients on docetaxel and paclitaxel, and in 65.8% and 75.2% in W and 3 W.
Both treatment regimens showed similar TTP. W might be associated with a better tumour response compared with 3 W.
Trial registration ID NCT00236899
PMCID: PMC3621657  PMID: 23537313
Metastatic breast cancer; Weekly schedule; 3-weekly schedule
7.  nab-Paclitaxel for first-line treatment of patients with metastatic breast cancer and poor prognostic factors: a retrospective analysis 
Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has demonstrated clinical benefit in metastatic breast cancer (MBC) in a randomized phase III trial versus paclitaxel (CA012; N = 454) and in a randomized phase II trial versus docetaxel (CA024; N = 300). This retrospective analysis examines whether patients with poor prognostic factors demonstrate similar outcomes to the intent-to-treat (ITT) populations in these trials. This retrospective analysis evaluated the efficacy and safety of previously untreated patients with MBC with the following poor prognostic factors: visceral dominant metastases and short disease-free interval (DFI; ≤2 years). In CA012 (n = 186 first-line patients), nab-paclitaxel demonstrated a significantly higher overall response rate (ORR) versus paclitaxel in patients with visceral dominant metastases (42 vs. 23 %; P = 0.022), whereas the higher ORR for nab-paclitaxel in patients with a short DFI (43 vs. 33 %; P = NS) was not statistically significant. In CA024, a significantly higher ORR for nab-paclitaxel 150 mg/m2 versus docetaxel was observed in patients with visceral dominant metastases (76 vs. 37 %; P < 0.001). No significant differences in ORR were observed in patients with a short DFI. Although progression-free survival (PFS) and overall survival showed trends similar to ORR, statistical significance was only achieved for comparisons of PFS in patients with visceral dominant metastases in CA024 (13.1 months for nab-paclitaxel 150 mg/m2 vs. 7.8 months for docetaxel [P = 0.019] and 7.5 months for nab-paclitaxel 100 mg/m2 [P = 0.010]). Safety results were similar to previous reports of the ITT populations. nab-Paclitaxel demonstrated similar efficacy in patients with poor prognostic factors as in the ITT populations of these two trials. In each trial, ORR was significantly higher for nab-paclitaxel versus the comparator taxane among patients with visceral dominant metastases.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-013-2447-8) contains supplementary material, which is available to authorized users.
PMCID: PMC3631516  PMID: 23563958
nab-Paclitaxel; Visceral disease; Metastatic breast cancer; Taxanes
8.  Neoadjuvant Dose-Dense Gemcitabine plus Docetaxel and Vinorelbine plus Epirubicin for Operable Breast Cancer 
Drugs in R&d  2012;11(2):147-157.
Background: Neoadjuvant anti-tumor activity of an alternating taxane- and anthracycline-based dose-dense regimen in patients with operable, noninflammatory large breast cancer was investigated.
Objective: The objective is to study the rate of pathological complete response in patients with breast cancer receiving dose-dense chemotherapy sequentially with gemcitabine plus docetaxel and vinorelbine plus epirubicin.
Methods: Women (n = 74) with clinical stage II or III breast cancer were enrolled in this open-label, multicenter study to receive six 2-weekly courses of gemcitabine 1000 mg/m2 plus docetaxel 75 mg/m2 on days 1 and 15, and vinorelbine 25 mg/m2 plus epirubicin 100mg/m2 on days 29 and 43. Patients with an objective response on day 56 then received another cycle of gemcitabine/ docetaxel on day 57 and of vinorelbine/epirubicin on day 71. Conservative surgery was scheduled for all patients.
Results: Of the patients enrolled, 30% had triple-negative breast cancer (TNBC). The pathologic complete response (pCR) rate was 22% overall, but was higher in TNBC than patients without TNBC (40.9% vs 14.0%; p=0.028). Among patients with a pCR, patients with TNBC had similar recurrence-free survival (RFS) and overall survival (OS) to patients without TNBC. Among those without a pCR, RFS rates for patients with TNBC were significantly lower than for patients without TNBC (p=0.04). The most common severe hematologic toxicity was neutropenia.
Conclusions: Administering four drugs in a dose-dense alternating sequence gave a high pCR in patients with operable, invasive breast cancer. Patients with TNBC with a pCR had similar OS to patients without TNBC, whereas patients with TNBC without a pCR had poorer survival rate than their non- TNBC counterparts.
PMCID: PMC3585987  PMID: 21679005
9.  Neoadjuvant Dose-Dense Gemcitabine plus Docetaxel and Vinorelbine plus Epirubicin for Operable Breast Cancer 
Drugs in R&D  2012;11(2):147-157.
Background: Neoadjuvant anti-tumor activity of an alternating taxane- and anthracycline-based dose-dense regimen in patients with operable, noninflammatory large breast cancer was investigated.
Objective: The objective is to study the rate of pathological complete response in patients with breast cancer receiving dose-dense chemotherapy sequentially with gemcitabine plus docetaxel and vinorelbine plus epirubicin.
Methods: Women (n = 74) with clinical stage II or III breast cancer were enrolled in this open-label, multicenter study to receive six 2-weekly courses of gemcitabine 1000 mg/m2 plus docetaxel 75 mg/m2 on days 1 and 15, and vinorelbine 25 mg/m2 plus epirubicin 100mg/m2 on days 29 and 43. Patients with an objective response on day 56 then received another cycle of gemcitabine/ docetaxel on day 57 and of vinorelbine/epirubicin on day 71. Conservative surgery was scheduled for all patients.
Results: Of the patients enrolled, 30% had triple-negative breast cancer (TNBC). The pathologic complete response (pCR) rate was 22% overall, but was higher in TNBC than patients without TNBC (40.9% vs 14.0%; p=0.028). Among patients with a pCR, patients with TNBC had similar recurrence-free survival (RFS) and overall survival (OS) to patients without TNBC. Among those without a pCR, RFS rates for patients with TNBC were significantly lower than for patients without TNBC (p=0.04). The most common severe hematologic toxicity was neutropenia.
Conclusions: Administering four drugs in a dose-dense alternating sequence gave a high pCR in patients with operable, invasive breast cancer. Patients with TNBC with a pCR had similar OS to patients without TNBC, whereas patients with TNBC without a pCR had poorer survival rate than their non- TNBC counterparts.
PMCID: PMC3585987  PMID: 21679005
10.  Multicenter phase II study of Apatinib in non-triple-negative metastatic breast cancer 
BMC Cancer  2014;14(1):820.
Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2(VEGFR-2). This study was conducted to assess the efficacy and safety of apatinib in patients with non-triple-negative metastatic breast cancer who had received prior chemotherapy for their metastatic disease.
This multicenter, open-label, single arm study enrolled patients with non-triple-negative breast cancer, pretreated with anthracycline, taxanes and capecitabine, and who failed in the metastatic setting at least 1 and at most 4 prior chemotherapy regimens and at least one endocrine drug for hormone receptor-positive patients as well as at least one anti-Her2 drug for Her2-positive patients. The primary end point of this study was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. Apatinib was administered as 500 mg daily on days 1 through 28 of each 4-week cycle.
38 patients were enrolled with a median age of 49 years (range, 35 to 62 years) and received apatinib for a median of 4 cycles (range from 0 to 10 cycles). 18 (47.4%) patients experienced dose reduction during treatment. The median relative dose intensity (relative to assigned dose for each cycle) was 82% (range, 45.0% to 100.0%). Median follow-up time was 10.1 months. Median PFS of all 38 patients was 4.0 months (95% confidence interval (CI), 2.8 m – 5.2 m). 36 patients were eligible for efficacy analysis. ORR was 16.7% (6/36). DCR was 66.7% (24/36). Median OS was 10.3 months (95% CI, 9.1 m – 11.6 m). The most common grade 3/4 treatment-related AEs were hypertension (20.5%), hand-foot syndrome (10.3%), and proteinuria (5.1%). Of three possibly drug-related SAEs recorded in the study, 2 (3.4%) deaths occurred within 28 days of last treatment and were both considered to be the result of disease progression. The other one was grade 2 diarrhea needing hospitalization.
Apatinib exhibited objective efficacy in heavily pretreated, metastatic non-triple-negative breast cancer with manageable toxicity, and it might be better to be tested in breast cancer with high angiogenesis dependency.
Trial registration NCT01653561.
PMCID: PMC4237755  PMID: 25376790
Apatinib; Metastatic breast cancer; VEGF
11.  Mitomycin C, vinblastine and cisplatin (MVP): an active and well-tolerated salvage regimen for advanced breast cancer 
British Journal of Cancer  2005;92(3):475-479.
This phase II study assessed the clinical efficacy and tolerability of a combination of mitomycin C, vinblastine and cisplatin in patients with metastatic breast cancer (MBC) previously treated with chemotherapy. A total of 87 patients with MBC, most of whom had been exposed to anthracyclines (92%) and/or taxanes (29%) in the adjuvant and/or metastatic setting, were treated with mitomycin C (8 mg m−2 day 1 cycles 1, 2, 4 and 6), vinblastine (6 mg m−2 day 1) and cisplatin (50 mg m−2 day 1) repeated each 21 days for a maximum of six cycles. The overall response rate (ORR) was 32% (95% CI: 22–42%) with 31% partial response (PR) and one complete response (CR). Stable disease (SD) rate was 21% (95% CI: 12–29%). There was no statistically significant difference in the ORR when MVP was given as the first-line treatment for MBC vs second or subsequent line (38 vs 30%, P=0.6), or between patients with an early (<6 months) vs late (>6 months) relapse post-anthracyclines (30 vs 52%, P=0.3). Toxicity profile was mild. This platinum-based chemotherapy is an effective, well-tolerated and low-cost regimen for patients with MBC, including those pretreated with anthracyclines.
PMCID: PMC2362079  PMID: 15685237
anthracycline; metastatic breast cancer; chemotherapy; cisplatin
12.  Phase II study of gemcitabine, doxorubicin and paclitaxel (GAT) as first-line chemotherapy for metastatic breast cancer: a translational research experience 
BMC Cancer  2006;6:76.
Patients with metastatic breast cancer are frequently treated with anthracyclines and taxanes, which are among the most active agents in this disease. Gemcitabine is an interesting candidate for a three-drug combination because of its different mechanism of action and non-overlapping toxicity with respect to the other two drugs. We aimed to evaluate the activity and toxicity of the GAT (gemcitabine, doxorubicin and paclitaxel) regimen, derived from experimental preclinical studies, as first-line chemotherapy in patients with stage IIIB-IV breast cancer.
Patients with locally advanced or metastatic breast cancer and at least one bidimensionally measurable lesion were included in the present study. Adequate bone marrow reserve, normal cardiac, hepatic and renal function, and an ECOG performance status of 0 to 2 were required. Only prior adjuvant non anthracycline-based chemotherapy was permitted. Treatment consisted of doxorubicin 50 mg/m2 on day 1, paclitaxel 160 mg/m2 on day 2 and gemcitabine 800 mg/m2 on day 6, repeated every 21–28 days.
Thirty-three consecutive breast cancer patients were enrolled onto the trial (7 stage IIIB and 26 stage IV). All patients were evaluable for toxicity and 29 were assessable for response. A total of 169 cycles were administered, with a median of 6 cycles per patient (range 1–8 cycles). Complete and partial responses were observed in 6.9% and 48.3% of patients, respectively, for an overall response rate of 55.2%. A response was reported in all metastatic sites, with a median duration of 16.4 months. Median time to progression and overall survival were 10.2 and 36.4 months, respectively. The most important toxicity was hematological, with grade III-IV neutropenia observed in 69% of patients, sometimes requiring the use of granulocyte colony-stimulating factor (27%). Non hematological toxicity was rare and mild. One patient died from sepsis during the first treatment cycle before the administration of gemcitabine.
The strong synergism among the three drugs found in the preclinical setting was confirmed in terms of both clinical activity and hematological toxicity. Our results seem to indicate that the GAT regimen is effective in anthracycline-naïve metastatic breast cancer and provides a feasible chemotherapeutic option in this clinical setting.
PMCID: PMC1434761  PMID: 16551351
13.  Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer 
British Journal of Cancer  2013;108(10):1985-1993.
Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours.
This was a phase I/II, open-label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluated the safety, efficacy, and pharmacokinetics of the combination at the MTD in patients with HER2-positive breast cancer.
Eight patients were included in the dose-escalation study; no dose-limiting toxicities were observed, and an MTD of oral neratinib 240 mg once daily plus intravenous paclitaxel 80 mg m−2 on days 1, 8, and 15 of each 28-day cycle was determined. A total of 102 patients with HER2-positive breast cancer were enrolled in part 2. The overall median treatment duration was 47.9 weeks (range: 0.1–147.3 weeks). Common treatment-emergent adverse events (all grades/grade ⩾3) included diarrhoea (92%/29% none grade 4), peripheral sensory neuropathy (51%/3%), neutropenia (50%/20%), alopecia (46%/0%), leukopenia (41%/18%), anaemia (37%/8%), and nausea (34%/1%). Three (3%) patients discontinued treatment due to an adverse event (mouth ulceration, left ventricular ejection fraction reduction, and acute renal failure). Among the 99 evaluable patients in part 2 of the study, the overall response rate (ORR) was 73% (95% confidence interval (CI): 62.9–81.2%), including 7 (7%) patients who achieved a complete response; an additional 9 (9%) patients achieved stable disease for at least 24 weeks. ORR was 71% among patients with 0/1 prior chemotherapy regimen for metastatic disease and no prior lapatinib, and 77% among those with 2/3 prior chemotherapy regimens for metastatic disease with prior lapatinib permitted. Kaplan–Meier median progression-free survival was 57.0 weeks (95% CI: 47.7–81.6 weeks). Pharmacokinetic analyses indicated no interaction between neratinib and paclitaxel.
The combination of neratinib and paclitaxel was associated with higher toxicity than that of neratinib as a single agent, but was manageable with antidiarrhoeal agents and dose reductions in general. The combination therapy also demonstrated a high rate of response in patients with HER2-positive breast cancer. A phase III trial is ongoing to assess the benefit and risk of this combination in the first-line setting.
PMCID: PMC3670493  PMID: 23632474
breast cancer; HER2; neratinib; paclitaxel; tyrosine kinase inhibitor
14.  Gemcitabine and Vinorelbine Combination Chemotherapy in Anthracycline- and Taxane-pretreated Advanced Breast Cancer 
Anthracycline and taxanes are effective agents in advanced breast cancer and prolong survival times. Some patients achieve prolongation of life with capecitabine, gemcitabine, or vinorelbine, even after failure of both anthracycline and taxanes. We analyzed the efficacy and toxicity of gemcitabine and vinorelbine combination chemotherapy in anthracycline- and taxane-pretreated advanced breast cancer.
Materials and Methods
The medical records of anthracycline- and taxane-pretreated metastatic breast cancer patients who received gemcitabine and vinorelbine combination chemotherapy at the Seoul National University Hospital were reviewed. Gemcitabine (1,000 mg/m2) and vinorelbine (25 mg/m2) were administered intravenously on days 1 and 8 every 3 weeks.
Between 2000 and 2006, 57 patients were eligible (median age, 45 years), and the median number of previous chemotherapy regimens was 3 (range, 1~5). The overall response rate was 30% (95% CI, 18.1~41.9), and the disease control rate was 46% (PR, 30%; SD, 16%). The median duration of follow-up was 33.4 months, the median time-to-progression (TTP) was 3.9 months, and the median overall survival was 10.8 months. None of thepatients with patients with anthracycline and taxane primary resistance showed a response and the median TTP for these patients was significantly shorter than that of other patients (1.9 vs. 4.4 months; p=0.018). Although the efficacy was unsatisfactory in patients with both anthracycline and taxane primary resistance, gemcitabine and vinorelbine combination chemotherapy showed comparable efficacy in anthracycline- and/or taxane-sensitive patients and the patients with secondary resistance, even after failure of second-line therapy. Grade 3/4 hematologic toxicities included neutropenia (18.1%) and febrile neutropenia (0.3%), and non-hematologic toxicities were tolerable.
Gemcitabine and vinorelbine combination chemotherapy in anthracycline- and taxane-pretreated advanced breast cancer was effective and tolerable.
PMCID: PMC2697482  PMID: 19688053
Gemcitabine; Vinorelbine; Breast neoplasms; Anthracycline; Taxane
15.  Phase 2 study of eribulin mesylate as first-line therapy for locally recurrent or metastatic human epidermal growth factor receptor 2-negative breast cancer 
Eribulin mesylate, a novel non-taxane microtubule dynamics inhibitor, is approved for treatment of metastatic breast cancer (MBC) in patients who have previously received at least 2 chemotherapeutic regimens for MBC that should have included an anthracycline and a taxane in the adjuvant or metastatic setting. This phase 2 study evaluated efficacy and safety of eribulin as first-line therapy for human epidermal growth factor receptor 2-negative (HER2-negative) MBC. Patients with measurable HER2-negative locally recurrent breast cancer or MBC with ≥12 months since prior neoadjuvant or adjuvant (neo/adjuvant) chemotherapy received eribulin mesylate 1.4 mg/m2 IV on days 1 and 8 of each 3-week cycle. Endpoints included objective response rate (ORR) per RECIST v1.1 (primary), safety, progression-free survival (PFS), clinical benefit rate (ORR + stable disease ≥6 months; CBR), and duration of response (DOR). Fifty-six patients were enrolled and received eribulin; 38 (68 %) had prior neo/adjuvant therapy, including 33 who had anthracycline and/or taxane-containing chemotherapy; 41 (73 %) had estrogen receptor-positive disease, and 12 (21 %) had estrogen receptor-negative, progesterone receptor-negative, and HER2-negative (triple-negative) disease. Patients received a median of 7 cycles (range 1–43); 6 (11 %) received treatment for ≥12 months. ORR was 29 % (95 % CI 17.3–42.2), CBR was 52 %, and median DOR was 5.8 months. Median PFS was 6.8 months. Thirty-six patients (64 %) had grade 3/4 treatment-related adverse events; most common were neutropenia (50 %), leukopenia (21 %), and peripheral neuropathy (21 %). These results demonstrate that eribulin has substantial antitumor activity as first-line treatment for HER2-negative MBC with acceptable safety.
PMCID: PMC4085472  PMID: 24699910
Metastatic breast cancer; HER2-negative breast cancer; Triple-negative breast cancer; Eribulin; Progression-free survival
16.  Weekly paclitaxel plus trastuzumab in metastatic breast cancer pretreated with anthracyclines-a phase II multipractice study 
BMC Cancer  2012;12:165.
The 3-weekly combination of trastuzumab and paclitaxel has been approved for the treatment of advanced breast cancer based on a large pivotal study. However, mono and combination chemotherapy trials suggest that weekly paclitaxel has a better therapeutic index, especially in the palliative setting. The present trial examined the efficacy and safety of weekly paclitaxel over a limited duration combined with continued trastuzumab in HER2+ patients.
Patients with histologically confirmed metastatic breast cancer overexpressing HER2 were eligible if pretreated with anthracycline in either the adjuvant or palliative setting. Treatment consisted of weekly trastuzumab (2 mg/kg/week for up to one year after a loading dose of 4 mg/kg in week 1) and paclitaxel (90 mg/m², administered in weeks 1–6 and 8–13).
Twenty-seven German centers enrolled 121 patients. The median number of metastatic sites was two (range 1–5); 38% of patients had received chemotherapy for advanced disease. After a median 42 weeks of trastuzumab treatment, limited by disease progression in roughly half the patients, a best objective response rate (complete response + partial response) of 76% was achieved, including complete remissions in 29%. 74% of patients lived without tumor progression at six months. Median progression-free and overall survival were 9.4 (95% confidence interval [CI]: 8.1–11.3) and 22 months (95% CI: 17–46). After alopecia, Common Toxicity Criteria grade ≥2 toxicity was predominantly hematological (leukopenia [31%] and anemia [41%]); however, thrombocytopenia occurred in only 5%. Neurotoxicity was remarkably low. Two cardiac events (grades 2 and 3) were presumed treatment-related.
Weekly paclitaxel plus trastuzumab allows an increased dose density and offers an attractive and effective alternative to the conventional schedule. Limiting the duration of cytotoxic therapy to 3 months seems to be an option to reduce neurotoxicity without impairing long-term outcome.
PMCID: PMC3443018  PMID: 22559145
17.  Triple negative breast cancer in Moroccan women: clinicopathological and therapeutic study at the National Institute of Oncology 
BMC Women's Health  2012;12:35.
Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. This is an aggressive malignancy with a poor prognosis despite the high rates of response to chemotherapy. The aim of this study is to determine the clinicopathological, therapeutic features and outcomes associated with this type of breast cancer.
This is a retrospective study of confirmed triple negative breast cancer females collected at the National institute of oncology of Rabat in Morocco, between January 2007 and December 2008. Epidemiological, clinical, histological, therapeutic and evolutive data were analyzed. OS and DFS rates were estimated by Kaplan-Meier analysis.
A total of one 152 patients with breast cancer, were identified as having triple-negative breast cancer (16,5%). The median age at diagnosis was 46 years. 130 patients (86%) had infiltrating ductal carcinoma and thirteen had medullar carcinoma (9%). 84 cases (55%) were grade III Scarff-Bloom-Richardson (SBR). 48 % had positive lymph nodes, and 5 % had distant metastases at diagnosis. According TNM staging, 12 patients (8%) had stage I, 90 patients (60%) had stage II and the 43(28%) had stage III. 145 patients received surgery. 41 (28%) had conservative surgery and 104 (72%) received radical mastectomy with axillary lymph nodes dissection. 14 patients with advanced tumors or inflammatory breast cancer have received neoadjuvant chemotherapy and four patients (28%) had complete pathologic response. From 131 patients how received adjuvant chemotherapy, 99 patients (75,5%) had Anthracycline based chemotherapy) and 27 patients (20,6%) had sequential Anthracycline and docetaxel,. Seven patients with metastatic disease received anthracycline-based regimen in the first line metastatic chemotherapy. The median follow-up time was 46 months (range 6,1 -60 months). Overall survival at 5 years for all patients was 76,5%.
These results suggest that most TNBC characteristics in Moroccan patients are in accordance with literature data, especially concerning young age at diagnosis high grade tumors, advanced stage at diagnosis, and short time to relapse. Although the high response rate to chemotherapy, the overall prognosis of this subset of tumors remains poor.
PMCID: PMC3492031  PMID: 23039971
18.  Evaluation of vinorelbine-based chemotherapy as the second or further-line treatment in patients with metastatic breast cancer 
Contemporary Oncology  2013;17(1):78-82.
Aim of the study
The study examined the response rate, response duration and toxicity of vinorelbine and fluorouracil or vinorelbine alone in pretreated metastatic breast cancer.
Material and methods
Between June 2001 and September 2009, a group of 103 patients with locally advanced or metastatic breast cancer, who had progressed after anthracycline/taxane chemotherapy, was treated with a vinorelbine-based regimen. The treatment consisted of vinorelbine 25 mg/m2 and 5-fluorouracil (5-FU) 500 mg/m2 administered intravenously on days 1 and 8 of each cycle (53 patients) or vinorelbine alone at a dose of 30 mg/m2 on day 1 and 8 of the cycle, every 3 weeks (50 patients). Patients received chemotherapy as a second or further line of therapy. Treatment was continued until disease progression or unacceptable toxicity. The median age of patients treated with vinorelbine with 5FU was 54 years (range 38–76), and 55.5 years (range 38–73) in the group receiving vinorelbine monotherapy. A total of 417 cycles of chemotherapy were administered – 177 cycles of vinorelbine with 5-FU and 137 cycles of vinorelbine monotherapy. Patients were treated for a median of 4 cycles (range: 1 to 11 cycles). The evaluation of treatment effect was possible in 93 patients (10 patients received only one treatment cycle).
The overall response rate (ORR) was 17% (7), including 2 (4%) complete responses (CR) and 5 (10.5%) partial responses (PR). Stable disease (SD) was observed in 50% of patients receiving vinorelbine with 5-FU (24 patients). In a group receiving vinorelbine alone the ORR was 20% (9), including 9 PR (20%) and 16 SD (35.5%). The median time to progression (TTP) for the entire group was 18 weeks (95% CI), 22 weeks among patients treated with vinorelbine with 5-FU and 16 weeks for a second group. The most common hematologic adverse events were neutropenia (20% of cycles) and thrombocytopenia (4%), with grade 3/4 incidence of 8% and 1.5% [according to National Cancer Institute Common Toxicity Criteria (NCI CTC)]. Nausea and vomiting were the most frequent non-hematologic forms of toxicity, occurring in 13% of cycles. The doses of cytotoxics were reduced in 26 (25%) cases. There were no treatment-related deaths.
Vinorelbine alone or in combination with 5-FU is an effective and safe treatment for pretreated advanced/ metastatic breast cancer patients. The combination of vinorelbine with 5-FU appears to be a more efficacious regimen than vinorelbine alone.
PMCID: PMC3685356  PMID: 23788967
breast cancer; winorelbine; chemotherapy; metastasis
19.  Anthracycline and concurrent radiotherapy as adjuvant treatment of operable breast cancer: a retrospective cohort study in a single institution 
BMC Research Notes  2010;3:247.
Concurrent chemoradiotherapy (CCRT) after breast surgery was investigated by few authors and remains controversial, because of concerns of toxicity with taxanes/anthracyclines and radiation. This treatment is not standard and is more commonly used for locally advanced breast cancer. The aim of our study was to evaluate the efficacy and safety of the concomitant use of anthracycline with radiotherapy (RT).
Four hundred women having operable breast cancer, treated by adjuvant chemotherapy (CT) and RT in concomitant way between January 2001 and December 2003, were included in this retrospective cohort study. The study compares 2 adjuvant treatments using CCRT, the first with anthracycline (group A) and the second with CMF (group B). The CT treatment was repeated every 21 days for 6 courses and the total delivered dose of RT was 50 Gy, divided as 2 Gy daily fractions. Locoregional recurrence free (LRFS), event free (EFS), and overall survivals (OS) were estimated by the Kaplan-Meier method. The log-rank test was used to compare survival events. Multivariate Cox-regression was used to evaluate the relationship between patient characteristics, treatment and survival.
In the 2 groups (A+B) (n = 400; 249 in group A and 151 in group B), the median follow-up period was 74.5 months. At 5 years, the isolated LRFS was significantly higher in group A compared to group B (98.7% vs 95.3%; hazard ratio [HR] = 0.258; 95% CI, 0.067 to 0.997; log-rank P = .034). In addition, the use of anthracycline regimens was associated with a higher rate of 5 years EFS (80.4% vs 75.1%; HR = 0.665; 95% CI, 0.455 to 1.016; log-rank P = .057). The 5 years OS was 83.2% and 79.2% in the anthracycline and CMF groups, respectively (HR = 0.708; 95% CI, 0.455 to 1.128; log-rank P = .143). Multivariate analysis confirmed the positive effect of anthracycline regimens on LRFS (HR = 0.347; 95% CI, 0.114 to 1.053; log-rank P = .062), EFS (HR = 0.539; 95% CI, 0.344 to 0.846; P = 0.012), and OS (HR = 0.63; 95% CI, 0.401 to 0.991; P = .046). LRFS, EFS and OS were significantly higher in the anthracycline group where the patients (n = 288) received more than 1 cycle of concurrent CT (P = .038, P = .026 and P = .038, respectively). LRFS and EFS were significantly higher in the anthracycline group within the BCT subgroup (P = .049 and P = .04, respectively). There were more hematologic, and more grade 2/3/4 skin toxicity in the anthracycline group.
After mastectomy or BCT, the adjuvant treatment based on anthracycline and concurrent RT reduced breast cancer relapse rate, and significantly improved LRFS, EFS and OS in the patients receiving more than 1 cycle of concurrent CT. There were more hematologic and non hematologic toxicities in the anthracycline group.
PMCID: PMC2958885  PMID: 20920323
20.  Bendamustine Is Effective Therapy in Patients With Rituximab-Refractory, Indolent B-cell Non-Hodgkin Lymphoma 
Cancer  2010;116(1):106-114.
Bendamustine hydrochloride is a novel alkylating agent. In this multicenter study, the authors evaluated the efficacy and toxicity of single-agent bendamustine in patients with rituximab-refractory, indolent B-cell lymphoma.
Eligible patients (N = 100, ages 31-84 years) received bendamustine at a dose of 120 mg/m2 by intravenous infusion on Days 1 and 2 every 21 days for 6 to 8 cycles. Histologies included follicular (62%), small lymphocytic (21%), and marginal zone (16%) lymphomas. Patients had received a median of 2 previous regimens (range, 0-6 previous regimens), and 36%were refractory to their most recent chemotherapy regimen. Primary endpoints included overall response rate (ORR) and duration of response (DOR). Secondary endpoints were safety and progression-free survival (PFS).
An ORR of 75% (a 14% complete response rate, a 3% unconfirmed complete response rate, and a 58% partial response rate) was observed. The median DOR was 9.2 months, and median PFS was 9.3 months. Six deaths were considered to be possibly treatment related. Grade 3 or 4 (determined using National Cancer Institute Common Toxicity Criteria [version 3.0.19]. reversible hematologic toxicities included neutropenia (61%), thrombocytopenia (25%), and anemia (10%). The most frequent nonhematologic adverse events (any grade) included nausea (77%), infection (69%), fatigue (64%), diarrhea (42%), vomiting (40%), pyrexia (36%), constipation (31%), and anorexia (24%).
Single-agent bendamustine produced a high rate of objective responses with acceptable toxicity in patients with recurrent, rituximab-refractory indolent B-cell lymphoma.
PMCID: PMC2916680  PMID: 19890959
bendamustine; non-Hodgkin lymphoma; B-cell lymphoma; rituximab-refractory; clinical trial
21.  Sunitinib in combination with trastuzumab for the treatment of advanced breast cancer: activity and safety results from a phase II study 
BMC Cancer  2014;14:166.
This phase II study evaluated the efficacy and safety/tolerability of sunitinib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC).
Eligible patients received sunitinib 37.5 mg/day and trastuzumab administered either weekly (loading, 4 mg/kg; then weekly 2 mg/kg) or 3-weekly (loading, 8 mg/kg; then 3-weekly 6 mg/kg). Prior trastuzumab and/or lapatinib treatment were permitted. The primary endpoint was objective response rate (ORR).
Sixty patients were enrolled and evaluable for safety; 57 were evaluable for efficacy. The majority of patients (58%) had received no prior chemotherapy in the metastatic setting. The ORR was 37%; the clinical benefit rate (CBR; percent objective response plus stable disease ≥ 24 weeks) was 56%. Among patients who were treatment-naïve or had received only adjuvant therapy, the ORR was 44% and the CBR was 59%. Overall, median overall survival had not been reached and the 1-year survival rate was 91%. The majority of adverse events (AEs) were mild to moderate in severity. Forty percent of patients experienced AEs related to measured left ventricular ejection fraction (LVEF) declines, which occurred more frequently in patients who had received prior anthracycline treatment. Ten percent of patients exhibited symptoms related to LVEF declines. One patient died on study from cardiogenic shock. Antitumor response and several safety parameters appeared to correlate with sunitinib exposure.
Sunitinib plus trastuzumab demonstrated antitumor activity in patients with HER2-positive ABC, particularly those who were treatment-naïve or had only received prior adjuvant treatment. Sunitinib plus trastuzumab had acceptable safety and tolerability in patients with HER2-positive ABC who had not received prior anthracycline therapy.
Trial registration
PMCID: PMC3995914  PMID: 24606768
Sunitinib; Trastuzumab; Advanced breast cancer
22.  Phase III, Double-Blind, Randomized Study Comparing Lapatinib Plus Paclitaxel With Placebo Plus Paclitaxel As First-Line Treatment for Metastatic Breast Cancer 
Journal of Clinical Oncology  2008;26(34):5544-5552.
Lapatinib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR/ErbB1) and human epidermal growth factor receptor 2 (HER-2/ErbB2), is effective against HER-2–positive locally advanced or metastatic breast cancer (MBC). This phase III trial evaluated the efficacy of lapatinib in HER-2–negative and HER-2–uncharacterized MBC.
Patients and Methods
Women with MBC were randomly assigned to first-line therapy with paclitaxel 175 mg/m2 every 3 weeks plus lapatinib 1,500 mg/d or placebo. A preplanned retrospective evaluation of HER-2 status was performed using fluorescence in situ hybridization and immunohistochemistry. The primary end point was time to progression (TTP); secondary end points were objective response rate (ORR), clinical benefit rate (CBR), event-free survival (EFS), and overall survival (OS).
In the intent-to-treat population (n = 579), there were no significant differences in TTP, EFS, or OS between treatment arms, although differences in ORR and CBR were noted. In 86 HER-2–positive patients (15%), treatment with paclitaxel-lapatinib resulted in statistically significant improvements in TTP, EFS, ORR, and CBR compared with paclitaxel-placebo. No differences between treatment groups were observed for any end point in HER-2–negative patients. The most common adverse events were alopecia, rash, and diarrhea. The incidence of diarrhea and rash was significantly higher in the paclitaxel-lapatinib arm. The rate of cardiac events was low, and no difference was observed between treatment arms.
Patients with HER-2–negative or HER-2–untested MBC did not benefit from the addition of lapatinib to paclitaxel. However, first-line therapy with paclitaxel-lapatinib significantly improved clinical outcomes in HER-2–positive patients. Prospective evaluation of the efficacy and safety of this combination is ongoing in early and metastatic HER-2–positive breast cancer patients.
PMCID: PMC2651098  PMID: 18955454
23.  Phase II Study of Vinorelbine Plus Trastuzumab in HER2 Overexpressing Metastatic Breast Cancer Pretreated with Anthracyclines and Taxanes 
Journal of Breast Cancer  2011;14(2):140-146.
The role of first-line trastuzumab-based therapy has been firmly established in patients with human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer. In this trial, we evaluated the efficacy and safety of a vinorelbine and trastuzumab combination chemotherapy in patients who were pretreated with anthracyclines and taxanes.
Thirty-three patients with HER2 overexpressing metastatic breast cancer, all of whom had previously been treated with anthracyclines and taxanes, were included in this study. The patients were treated with 25 mg/m2 of vinorelbine (over a 15-minute infusion) on days 1 and 8 every 3 weeks. Additionally, trastuzumab was administered at an initial dose of 4 mg/kg over 90 minutes, and was subsequently administered at weekly doses of 2 mg/kg (over 30 minutes).
The median age of the patients was 53 years (range, 39-72 years). The overall response rate was 30.3% (10 patients; 95% confidence interval [CI], 23-57%). The median time to progression was 6.8 months (95% CI, 5.3-8.2 months). The median overall survival was 12.4 months (95% CI, 10.3-14.6 months). In the 194 cycles of treatment, the incidence rates of grade ≥3 neutropenia and anemia were 7.2% and 1.0%, respectively. Neutropenic fever was detected in three cycles (1.5%). The non-hematological toxicities were not severe: grade 1 or 2 nausea or vomiting was detected in 15.2%, and grade 2 neuropathy was noted in 6.1% of patients. None of the patients experienced any serious cardiac toxicity, and no treatment-related deaths occurred.
These results show that a combination chemotherapy consisting of vinorelbine and trastuzumab is useful in patients with HER2-overexpressing metastatic breast cancer who were pretreated with anthracyclines and taxanes, with a favorable toxicity profile.
PMCID: PMC3148545  PMID: 21847410
Breast neoplasms; Metastasis; Trastuzumab; Vinorelbine
24.  Gemcitabine Single or Combination Chemotherapy in Post Anthracycline and Taxane Salvage Treatment of Metastatic Breast Cancer: Retrospective Analysis of 124 Patients 
To evaluate the efficacy of gemcitabine-based chemotherapy, particularly in patients with anthracycline- and taxane-pretreated 2nd-line or greater metastatic breast cancer, and to compare gemcitabine monotherapy (G) with two gemcitabine-based doublets, gemcitabine/vinorelbine (GV) and gemcitabine/capecitabine (GX).
Materials and Methods
Of 124 consecutive patients who progressed after anthracycline- and taxane-containing chemotherapy, 58 received G alone, 38 received GV, and 28 received GX; their outcomes were analyzed retrospectively.
The median number of prior metastatic chemotherapy regimens was 2 (range 0~4). Visceral metastases were observed in 65 patients (51.4%). The overall response rate was 19.3% (21 partial responses). After a median follow-up period of 21.4 months, the overall survival was 7.6 months (95% CI: 5.5~9.6 months) and the median time to progression was 3.1 months (95% CI: 2.0~4.2 months). Compared with monotherapy (G), com - bination therapy with vinorelbine or capecitabine (GV/GX) was associated with a significantly higher response rate (8.2% vs. 28.3%, p=0.008) and a significantly longer median time to progression (2.8 vs. 3.5 months; p=0.028), but overall survival did not differ between the groups (7.4 vs. 8.2 months, respectively; p=0.54). Most of the adverse treatment-related events were mild to moderate in intensity. The most common adverse event was hematologic toxicity. Multivariate analysis showed that poor performance status and a short disease-free interval were independent prognostic factors for impaired overall survival.
The combination of gemcitabine with vinorelbine or capecitabine was an active and well-tolerated treatment option for taxane- and anthracycline-pretreated 2nd-line or greater metastatic breast cancer patients, and gemcitabine-based doublets were more beneficial than gemcitabine monotherapy in alleviating symptoms for these patients.
PMCID: PMC2741648  PMID: 19771244
Gemcitabine; Chemotherapy; Combination; Breast neoplasms
25.  Epidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer 
Executive Summary
In February 2010, the Medical Advisory Secretariat (MAS) began work on evidence-based reviews of the literature surrounding three pharmacogenomic tests. This project came about when Cancer Care Ontario (CCO) asked MAS to provide evidence-based analyses on the effectiveness and cost-effectiveness of three oncology pharmacogenomic tests currently in use in Ontario.
Evidence-based analyses have been prepared for each of these technologies. These have been completed in conjunction with internal and external stakeholders, including a Provincial Expert Panel on Pharmacogenetics (PEPP). Within the PEPP, subgroup committees were developed for each disease area. For each technology, an economic analysis was also completed by the Toronto Health Economics and Technology Assessment Collaborative (THETA) and is summarized within the reports.
The following reports can be publicly accessed at the MAS website at: or at
Gene Expression Profiling for Guiding Adjuvant Chemotherapy Decisions in Women with Early Breast Cancer: An Evidence-Based Analysis
Epidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer: an Evidence-Based Analysis
K-RAS testing in Treatment Decisions for Advanced Colorectal Cancer: an Evidence-Based Analysis
The Medical Advisory Secretariat undertook a systematic review of the evidence on the clinical effectiveness and cost-effectiveness of epidermal growth factor receptor (EGFR) mutation testing compared with no EGFR mutation testing to predict response to tyrosine kinase inhibitors (TKIs), gefitinib (Iressa®) or erlotinib (Tarceva®) in patients with advanced non-small cell lung cancer (NSCLC).
Clinical Need: Target Population and Condition
With an estimated 7,800 new cases and 7,000 deaths last year, lung cancer is the leading cause of cancer deaths in Ontario. Those with unresectable or advanced disease are commonly treated with concurrent chemoradiation or platinum-based combination chemotherapy. Although response rates to cytotoxic chemotherapy for advanced NSCLC are approximately 30 to 40%, all patients eventually develop resistance and have a median survival of only 8 to 10 months. Treatment for refractory or relapsed disease includes single-agent treatment with docetaxel, pemetrexed or EGFR-targeting TKIs (gefitinib, erlotinib). TKIs disrupt EGFR signaling by competing with adenosine triphosphate (ATP) for the binding sites at the tyrosine kinase (TK) domain, thus inhibiting the phosphorylation and activation of EGFRs and the downstream signaling network. Gefitinib and erlotinib have been shown to be either non-inferior or superior to chemotherapy in the first- or second-line setting (gefitinib), or superior to placebo in the second- or third-line setting (erlotinib).
Certain patient characteristics (adenocarcinoma, non-smoking history, Asian ethnicity, female gender) predict for better survival benefit and response to therapy with TKIs. In addition, the current body of evidence shows that somatic mutations in the EGFR gene are the most robust biomarkers for EGFR-targeting therapy selection. Drugs used in this therapy, however, can be costly, up to C$ 2000 to C$ 3000 per month, and they have only approximately a 10% chance of benefiting unselected patients. For these reasons, the predictive value of EGFR mutation testing for TKIs in patients with advanced NSCLC needs to be determined.
The Technology: EGFR mutation testing
The EGFR gene sequencing by polymerase chain reaction (PCR) assays is the most widely used method for EGFR mutation testing. PCR assays can be performed at pathology laboratories across Ontario. According to experts in the province, sequencing is not currently done in Ontario due to lack of adequate measurement sensitivity. A variety of new methods have been introduced to increase the measurement sensitivity of the mutation assay. Some technologies such as single-stranded conformational polymorphism, denaturing high-performance liquid chromatography, and high-resolution melting analysis have the advantage of facilitating rapid mutation screening of large numbers of samples with high measurement sensitivity but require direct sequencing to confirm the identity of the detected mutations. Other techniques have been developed for the simple, but highly sensitive detection of specific EGFR mutations, such as the amplification refractory mutations system (ARMS) and the peptide nucleic acid-locked PCR clamping. Others selectively digest wild-type DNA templates with restriction endonucleases to enrich mutant alleles by PCR. Experts in the province of Ontario have commented that currently PCR fragment analysis for deletion and point mutation conducts in Ontario, with measurement sensitivity of 1% to 5%.
Research Questions
In patients with locally-advanced or metastatic NSCLC, what is the clinical effectiveness of EGFR mutation testing for prediction of response to treatment with TKIs (gefitinib, erlotinib) in terms of progression-free survival (PFS), objective response rates (ORR), overall survival (OS), and quality of life (QoL)?
What is the impact of EGFR mutation testing on overall clinical decision-making for patients with advanced or metastatic NSCLC?
What is the cost-effectiveness of EGFR mutation testing in selecting patients with advanced NSCLC for treatment with gefitinib or erlotinib in the first-line setting?
What is the budget impact of EGFR mutation testing in selecting patients with advanced NSCLC for treatment with gefitinib or erlotinib in the second- or third-line setting?
A literature search was performed on March 9, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, Wiley Cochrane, CINAHL, Centre for Reviews and Dissemination/International Agency for Health Technology Assessment for studies published from January 1, 2004 until February 28, 2010 using the following terms:
Non-Small-Cell Lung Carcinoma
Epidermal Growth Factor Receptor
An automatic literature update program also extracted all papers published from February 2010 until August 2010. Abstracts were reviewed by a single reviewer and for those studies meeting the eligibility criteria full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, and then a group of epidemiologists, until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
The inclusion criteria were as follows:
Population: patients with locally advanced or metastatic NSCLC (stage IIIB or IV)
Procedure: EGFR mutation testing before treatment with gefitinib or erlotinib
Language: publication in English
Published health technology assessments, guidelines, and peer-reviewed literature (abstracts, full text, conference abstract)
Outcomes: progression-free survival (PFS), Objective response rate (ORR), overall survival (OS), quality of life (QoL).
The exclusion criteria were as follows:
Studies lacking outcomes specific to those of interest
Studies focused on erlotinib maintenance therapy
Studies focused on gefitinib or erlotinib use in combination with cytotoxic agents or any other drug
Grey literature, where relevant, was also reviewed.
Outcomes of Interest
ORR determined by means of the Response Evaluation Criteria in Solid Tumours (RECIST)
Quality of Evidence
The quality of the Phase II trials and observational studies was based on the method of subject recruitment and sampling, possibility of selection bias, and generalizability to the source population. The overall quality of evidence was assessed as high, moderate, low or very low according to the GRADE Working Group criteria.
Summary of Findings
Since the last published health technology assessment by Blue Cross Blue Shield Association in 2007 there have been a number of phase III trials which provide evidence of predictive value of EGFR mutation testing in patients who were treated with gefitinib compared to chemotherapy in the first- or second-line setting. The Iressa Pan Asian Study (IPASS) trial showed the superiority of gefitinib in terms of PFS in patients with EGFR mutations versus patients with wild-type EGFR (Hazard ratio [HR], 0.48, 95%CI; 0.36-0.64 versus HR, 2.85; 95%CI, 2.05-3.98). Moreover, there was a statistically significant increased ORR in patients who received gefitinib and had EGFR mutations compared to patients with wild-type EGFR (71% versus 1%). The First-SIGNAL trial in patients with similar clinical characteristics as IPASS as well as the NEJ002 and WJTOG3405 trials that included only patients with EGFR mutations, provide confirmation that gefitinib is superior to chemotherapy in terms of improved PFS or higher ORR in patients with EGFR mutations. The INTEREST trial further indicated that patients with EGFR mutations had prolonged PFS and higher ORR when treated with gefitinib compared with docetaxel.
In contrast, there is still a paucity of strong evidence regarding the predictive value of EGFR mutation testing for response to erlotinib in the second- or third-line setting. The BR.21 trial randomized 731 patients with NSCLC who were refractory or intolerant to prior first- or second-line chemotherapy to receive erlotinib or placebo. While the HR of 0.61 (95%CI, 0.51-0.74) favored erlotinib in the overall population, this was not a significant in the subsequent retrospective subgroup analysis. A retrospective evaluation of 116 of the BR.21 tumor samples demonstrated that patients with EGFR mutations had significantly higher ORRs when treated with erlotinib compared with placebo (27% versus 7%; P=0.03). However, erlotinib did not confer a significant survival benefit compared with placebo in patients with EGFR mutations (HR, 0.55; 95%CI, 0.25-1.19) versus wild-type (HR, 0.74; 95%CI, 0.52-1.05). The interaction between EGFR mutation status and erlotinib use was not significant (P=0.47). The lack of significance could be attributable to a type II error since there was a low sample size that was available for subgroup analysis.
A series of phase II studies have examined the clinical effectiveness of erlotinib in patients known to have EGFR mutations. Evidence from these studies has consistently shown that erlotinib yields a very high ORR (typically 70% vs. 4%) and a prolonged PFS (9 months vs. 2 months) in patients with EGFR mutations compared with patients with wild-type EGFR. Although having a prolonged PFS and higher respond in EGFR mutated patients might be due to a better prognostic profile regardless of the treatment received. In the absence of a comparative treatment or placebo control group, it is difficult to determine if the observed differences in survival benefit in patients with EGFR mutation is attributed to prognostic or predictive value of EGFR mutation status.
Based on moderate quality of evidence, patients with locally advanced or metastatic NSCLC with adenocarcinoma histology being treated with gefitinib in the first-line setting are highly likely to benefit from gefitinib if they have EGFR mutations compared to those with wild-type EGFR. This advantage is reflected in improved PFS, ORR and QoL in patients with EGFR mutation who are being treated with gefitinib relative to patients treated with chemotherapy.
Based on low quality of evidence, in patients with locally advanced or metastatic NSCLC who are being treated with erlotinib, the identification of EGFR mutation status selects those who are most likely to benefit from erlotinib relative to patients treated with placebo in the second or third-line setting.
PMCID: PMC3377519  PMID: 23074402

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