Breast Cancer Res Treat (2012) 131:939–947 Individually tailored treatment with epirubicin and paclitaxelwith or without capecitabine as first-line chemotherapyin metastatic breast cancer: a randomized multicenter trial T. Hatschek • L. Carlsson • Z. Einbeigi • E. Lidbrink • B. Linderholm •B. Lindh • N. Loman • M. Malmberg • S. Rotstein • M. So¨derberg •M. Sundquist • T. M. Walz • M. Hellstro¨m • H. Svensson • G. A Y. Brandberg • J. Carstensen • M. Ferno¨ • J. Bergh Received: 11 August 2011 / Accepted: 7 November 2011 / Published online: 18 November 2011Ó Springer Science+Business Media, LLC. 2011 Anthracyclines and taxanes are active cytotoxic (FarmorubicinÒ) and paclitaxel (TaxolÒ) alone (ET) or in drugs in the treatment of early metastatic breast cancer. It is combination with capecitabine (XelodaÒ, TEX). Starting yet unclear whether addition of capecitabine to the com- doses for ET were epirubicin 75 mg/m2 plus paclitaxel bination of these drugs improves the treatment outcome.
175 mg/m2, and for TEX epirubicin 75 mg/m2, paclitaxel Patients with advanced breast cancer were randomized to 155 mg/m2, and capecitabine 825 mg/m2 BID for 14 days.
first-line chemotherapy with a combination of epirubicin Subsequently, doses were tailored related to side effects.
Primary endpoint was progression-free survival (PFS);secondary endpoints were overall survival (OS), time totreatment failure (TTF), objective response (OR), safetyand quality of life (QoL). 287 patients were randomized, This study was conducted on behalf of TEX study group.
143 to ET and 144 to TEX. Median PFS was 10.8 months Participating investigators of the TEX study group are given inAppendix.
T. Hatschek (&)  E. Lidbrink  S. Rotstein  G. A Y. Brandberg  J. Bergh Department of Oncology, Ska˚ne University Hospital, Malmo¨, Breast-Sarcoma Unit, Department of Oncology, Karolinska University Hospital, Karolinska Institutet, 17176 Stockholm,Sweden Department of Oncology, Kalmar General Hospital, Kalmar, Sweden Department of Oncology, Sundsvall General Hospital, Department of Oncology, Linko¨ping University Hospital, Sundsvall, Sweden Linko¨ping, Sweden Z. Einbeigi  B. Linderholm  H. Svensson Department of Oncology, Sahlgrenska University Hospital, Clinical Trial Unit, Department of Oncology, Karolinska Gothenburg, Sweden University Hospital, Stockholm, Sweden Department of Oncology, Umea˚ University Hospital, Umea˚, Department of Radiology, Uppsala University Hospital, Uppsala, Department of Oncology, Ska˚ne University Hospital Lund, Department of Health and Society, Linko¨ping University, Linko¨ping, Sweden Department of Oncology, Helsingborg General Hospital, Department of Oncology, Clinical Sciences, Lund University, Helsingborg, Sweden Breast Cancer Res Treat (2012) 131:939–947 for patients treated with ET, and 12.4 months for those taxane docetaxel and capecitabine and expression of TP in treated with TEX (HR 0.84, 95% CI 0.65–1.07, P = 0.16); tumor tissue Also, anthracyclines have been reported to median OS was 26.0 months for women in the ET versus enhance TP upregulation [].
29.7 months in the TEX arm (HR 0.84, 95% CI 0.63–1.11, A phase II trial on the combination of capecitabine with P = 0.22). OR was achieved in 44.8% (ET) and 54.2% paclitaxel in patients pretreated with anthracycline showed (TEX), respectively (v2 3.66, P = 0.16). TTF was signifi- promising results in terms of objective response (OR) and cantly longer for patients treated with TEX, 6.0 months, time to progression High response rates were also versus 5.2 months following ET (HR 0.73, 95% CI reported from a phase II trial evaluating the combination of 0.58–0.93, P = 0.009). Severe hematological side effects epirubicin, capecitabine, and docetaxel Data from a related to epirubicin and paclitaxel were evenly distributed randomized phase III trial of docetaxel plus epirubicin with between the treatment arms, mucositis, diarrhea, and Hand- or without capecitabine presented at the ASCO meeting 2008 Foot syndrome were significantly more frequent in the by the same group showed significantly higher response rates TEX arm. Toxicity-adjusted treatment with ET and TEX for the three-drug combination, but no significant improve- showed similar efficacy in terms of PFS, OS, and OR. In ment of progression-free survival (PFS) [].
this trial with limited power, the addition of capecitabine to Despite debate on dose intensity and individual dose epirubicin and paclitaxel as first-line treatment did not adjustment –chemotherapy is generally dosed in translate into clinically relevant improvement of the relation to the body surface area (BSA). Dose reductions are performed in relation to the grade of toxicity, but it isnot common practice to increase doses above standard as a Advanced breast cancer  First-line treatment  consequence of no or few side effects. Studies on single Epirubicin  Paclitaxel  Capecitabine nucleotide polymorphisms (SNP) have shown that drugtolerance and efficacy are better explained by genetic hostcharacteristics than BSA ]. In the present trial, we chose to modify the drugs with increasing or decreasing dosesseparately in relation to the experienced side effects. This Anthracyclines and taxanes are commonly used cytotoxic concept was tested in a pilot trial by our group ].
drugs in adjuvant therapy and for treatment of early dis- The rationale of this trial was to investigate, if the seminated breast cancer. The combination of an anthracy- proposed conversion of capecitabine to 5-fluorouracil in cline with the taxane paclitaxel has been found more the presence of higher concentrations of TP induced by the efficient in terms of response and time to treatment failure taxane results in higher efficacy of the combination. With (TTF) than use of either of the drugs alone []. For pre- the intention to minimize the significance of merely the viously untreated patients or for those who have received addition of one further drug, a concept of individual few cycles of adjuvant treatment with either one or both adjustment to equitoxic doses was applied. The study was drugs, anthracycline–taxane combinations may be one planned as a composite translational research project. In reasonable option in the management of metastatic disease.
addition to the comparison between the two different Due to the frequent use of these compounds in the adjuvant treatment schedules, tumor tissue samples were obtained setting, there is need for additional drugs in the manage- from patients with metastatic sites accessible for aspiration ment of early metastatic disease. Capecitabine is one such biopsy. Also, tissue from the primary tumors and blood option. This compound is, after transformation to the pro- samples were collected. The results from correlations with drug 50DFUR, converted into fluorouracil (5-FU) in the the clinical data will be reported separately.
presence of the enzyme thymidine phosphorylase (TP). Theconcentration of fluorouracil is dependent on TP which isenriched in the liver and in tumor tissue Enhancement Patients and methods of the transformation of capecitabine into fluorouracil inthe presence of taxanes has been confirmed by laboratory The study was designed as an open-labeled randomized data. The taxanes, in particular paclitaxel, induce TP, multicenter phase III trial with three treatment arms, where possibly through induction of TNFa ]. As a result of one option entailed a combination of epirubicin (Farmo- the combination of a taxane with capecitabine, induction of rubicinÒ) and paclitaxel (TaxolÒ, ET), the second a three- TP in tumor tissue is expected to increase the local con- drug combination containing the same drugs but with the centration of fluorouracil, resulting in a synergistic rather addition of capecitabine (XelodaÒ, TEX). A third arm than additive effect of this combination. This is supported contained a combination of fluorouracil, epirubicin, and by clinical observations of a significant relationship cyclophosphamide (FEC), and was designed as standard between response to treatment with the combination of the treatment. However, since publications showed superiority Breast Cancer Res Treat (2012) 131:939–947 of treatment alternatives containing taxanes [the TEX Table 1 Individualized dose schedules trial group took the decision to discontinue randomization to FEC in May 2004. Therefore, the 17 patients who hadbeen allocated to this option were not included in the present analyses. Likewise, it was decided to terminate Epirubicin [day 1 (mg/m2 IV)] enrollment of patients with HER2 amplified tumors in June 2006 after publication of data demonstrating the impor- tance of early onset of treatment with trastuzumab [, These patients are, however, included in the analyses.
Paclitaxel [day 1 (mg/m2 IV)] The study was approved by the Independent Review Boards with jurisdiction for the participating centers and by the Swedish Medical Product Agency. All patients received oral and written information about the study and consented to participate.
Capecitabine [day 1–14 (mg/m2 PO)] Study subjects with morphologically confirmed loco- 1,000 9 2 (2,000) regional inoperable or disseminated breast carcinoma were 1,250 9 2 (2,500) enrolled unless they had received treatment with ananthracycline, a taxane or 5-FU within 1 year before study Patients were started on level ‘‘0''. Doses for each of the drugs was entry. Previous endocrine treatment for advanced disease in thereafter adjusted individually patients with hormone receptor positive breast cancer wasallowed. Patients with known brain metastases or other with stable response in whom accumulated epirubicin malignancies within the last 5 years were excluded.
doses approached levels of increased risk of cardiac tox-icity (C900 mg/m2), or who experienced intolerable Study treatment and assessments symptoms related to any of the cytotoxic drugs despitedose adjustment, treatment continued after removal of Patients were randomized to receive either epirubicin these drugs until progression or other medical reasons for 75 mg/m2 and paclitaxel 175 mg/m2 (ET) on day 1 or the terminating the treatment. Patients who progressed after combination of epirubicin 75 mg/m2, paclitaxel 155 mg/m2 first-line treatment with ET were offered capecitabine as on day 1 and capecitabine 825 mg/m2 BID on days 1–14 second-line treatment on progression. Toxicity was repor- (TEX). After the first course, treatment was individually ted after every course of treatment and was graded adjusted in relation to the grade of toxicity (Table Both according to NCI CTC version 2.0.
combinations were administered in a 3-week schedule. Allpatients received premedication with cetirizine, ranitidine, Statistical design corticosteroids, and antiemetics. Prophylactic use ofG-CSF was used if necessary. Response evaluations based Randomization was performed using a permuted block on RECIST version 1.0 were performed after every technique, stratified for the 10 participating centers. The third course. In patients with metastases confined to bone, two treatments were compared with regard to PFS as the WHO classification criteria for evaluation of bone metas- primary endpoint, defined as the interval from date of tases based on bone X-rays were applied [New lesions randomization to date of disease progression or death. TTF, detected either by CT scan or bone scan were considered as defined as the time from randomization until termination progressive disease regardless of response in previously on progression, death, toxicity or patients wish, overall observed metastases. Treatment was continued until pro- survival (OS), OR rate, safety and quality of life (QoL) gression, occurrence of unacceptable toxicity or other were secondary endpoints. Patients randomized to ET or medical reasons, or on patients' request for termination. In TEX were included in the analysis (intention to treat).
cases with stable disease or OR with no further improve- Treatment with the combination ET was regarded as ref- ment found at repeated evaluations, study treatment was, erence treatment in this study. With an expected 6 months on patients' request, replaced by either endocrine treatment median progression-free period for patients in this group, a in cases with hormone receptor positive tumors, or, in the prolongation by 2.5 months following the TEX regimen ET arm, switch to treatment with capecitabine alone using was regarded as a clinically relevant benefit. We assumed 1,250 mg/m2 9 2 days 1–14 as starting dose. In patients Breast Cancer Res Treat (2012) 131:939–947 exponentially distributed giving an expected hazard ratio of analyses were performed using the statistical package JMP TEX versus ET of 0.7059. Using standard formulas version 7.0.1.
we calculated a required number of 258 events plus addi-tional 10% for patients without ‘‘events'' at the time of themain analysis, totally 284 patients. In the dimensioning, a 3.5-year accrual period followed by a 12 months follow-upperiod was assumed.
Patient population Comparisons of groups were performed using standard Chi-square procedures. For analyses of prognostic vari- From December 2002 until June 2007, 291 patients were ables, the log rank test for univariate and Cox proportional included. Four patients were randomized but never treated.
hazard models for multivariate analyses were applied. All Two of these were incorrectly randomized, before theinvolved participating center had been approved by the Table 2 Baseline characteristics of the primary tumors Swedish Medical Product Agency. A third patient wasdiagnosed with brain metastases, and the fourth with liver lesions detected by CT scan but, after randomization, TNM stage at diagnosis identified as benign by cytology. In both of these latter cases, the incorrect inclusion was detected within few days after randomization. Two hundred eighty-seven patients were eligible, 143 in the ET and 144 in the TEX arm.
Tumor characteristics at diagnosis of the primary tumor are shown in Table . The disease-free interval was 2 years or Histologic subtype less in 43 cases (30%) in the ET versus 40 (28%) in the TEX arm. The majority, 204 patients (71%), had received previous adjuvant therapy. Among these, 74 women (52%)in the ET arm and 68 (47%) in the TEX arm had received adjuvant chemotherapy, either alone or followed by endocrine treatment. The adjuvant chemotherapy regimens contained anthracyclines in 57 women in the ET arm and 45 in the TEX arm, fluorouracil in 70 (ET), and 61 cases (TEX), respectively. Use of a taxane was limited to doce- taxel in three (ET) and two women (TEX). In none of these cases had chemotherapy been given 12 months before Estrogen receptor enrollment in the present trial.
Previous local relapse without signs of dissemination was found in 42 cases (15%), 18 (13%) in the ET and 24 (17%) in the TEX arm. Five of these patients underwent Progesterone receptor surgery followed by a limited series of chemotherapy, one in the TEX arm and four in the ET arm. These patients had not received adjuvant chemotherapy before, and the che- motherapy following local recurrence had been terminated at least 12 months before randomization.
Eighty-six patients, 30%, with hormone receptor posi- tive tumors had received endocrine therapy as first-line treatment of disseminated disease prior to enrollment, 24% Adjuvant systemic treatment (ET), and 35% (TEX), respectively.
Median age at study entry was 57.0 years for patients Chemotherapy alone allocated to ET and 55.7 years for those receiving TEX.
Endocrine treatment alone Seventy-one (25%) had metastases confined to one site, Chemotherapy followed by endocrine with bone metastases accounting for 20 cases as the most frequent localization, followed by 19 each for lymph node and liver metastases. The vast majority, 75%, had multiple Adjuvant therapy is reported only for patients with limited disease sites involved. Distribution of all reported metastatic sites is shown in Table Breast Cancer Res Treat (2012) 131:939–947 Table 3 Distribution of metastatic sites Local recurrence or contralateral breast Twenty-five percent had metastases in a single metastatic site, 75%,had multiple sites involved The median PFS was 10.8 months for patients treated withET compared with 12.4 months for those who had received TEX (HR 0.84, 95% CI 0.65–1.07, P = 0.16, Fig. a).
Median OS was 26.0 months for women treated with ETversus 29.7 months for those treated with TEX (HR 0.84, 95% CI 0.63–1.11, P = 0.22, Fig. b).
TTF was significantly different between the two alter- natives (Fig. ). The median treatment period was 5.2 months for ET and 6.0 months for TEX (HR 0.73, 95% CI 0.58–0.93, P = 0.009) with treatment duration up to 19 months with ET and 42 months with TEX.
Median PFS for the subgroup of patients with triple- negative tumors was 6.1 months with ET, and 12.1 months with TEX. Based on only 66 patients in this subgroup, thedifference between the two treatments was not significant.
Independently from the treatment arm, chemonaı¨ve patients with primarily metastatic disease had a signifi- Fig. 1 a progression-free survival (HR 0.84, 95% CI 0.65–1.07, cantly longer time to progression compared with those who P = 0.16) and b overall survival (HR 0.84, 95% CI 0.63–1.11, had received adjuvant chemotherapy (HR 0.77 HR, 95% CI P = 0.22) in months since randomization. ET: dotted line, TEX: 0.60–0.99, P = 0.039). Only 10 patients with primary histologic grade 1 tumors were enrolled. These tumorswere associated with a shorter progression-free survival, 7.9 months, compared with grade 2 (14.0 months) andgrade 3 tumors (10.0 months, P = 0.01). Although these factors had prognostic impact on the post-recurrence sur-vival, none of them favored any of the two treatment alternatives on a significant level. Previous endocrine treatment had no impact on the efficacy of the chemo- therapy regimens used in the trial.
Of the eligible 287 patients, 269 (94%) were evaluable (CR ? PR) was achieved in 53% of the patients. The proportion of OR was higher in women allocated to treat- ment with TEX, but the difference was not statisticallysignificant (v2 3.66, P = 0.16). It should be mentioned thateight of the eleven patients presenting with complete Fig. 2 Time to treatment failure (TTF) for first-line treatment shows a significant difference in favor of the TEX combination (HR 0.73, 95% 0.58–0.93, P = 0.009). ET: dotted line, TEX: black line Breast Cancer Res Treat (2012) 131:939–947 Table 4 Response according to RECIST 1.0 and WHO (bone) based Table 5 Reasons for termination of treatment on 269 evaluable patients (v2 3.66, df = 2, P = 0.16) Progressive disease Objective response Complete response Patients' request Clinical benefit (stable disease C6 cycles or confirmed objective Progressive disease Switch to capecitabine until progression* Unable to determine Endocrine treatment Local treatment with radiotherapy/surgery No treatment until progression Treatment was discontinued in 31% of cases due to Other reasons, not specified progressive disease and in 19% due to toxicity (Table In Ongoing treatment accordance with the protocol, patients with stable disease or OR were, after repeated evaluations without indicationof further improvement, offered maintenance treatmentwith capecitabine (following ET), endocrine treatment in as second-line treatment after previous therapy with ET case of hormone receptor positive tumors, local treatment developed CHF during treatment with this drug. In both of limited disease, or watchful waiting until progression.
arms, acute drug reactions were reported as serious events The majority, 104 patients (36%), chose to switch to one of in three cases. Serious diarrhea (grade 3) was reported in these treatment options.
seven cases associated with ET and 14 in cases with TEXtreatment.
Four treatment-related deaths (1.4%) occurred: two patients, one in each arm, succumbed due to septic shock Febrile neutropenia was equally frequent in both treatment following neutropenia; the other two due to circulatory arms (Table ). Symptoms related to paclitaxel, such as shock (ET) and severe cardiac heart failure (TEX).
sensory neuropathy, myalgia/arthralgia, and fatigue were Eight percent of the patients requested change of treat- more common among patients treated with ET. Vascular ment because they experienced side effects as intolerable.
events including deep vein thrombosis (DVT) and pul-monary embolism were more frequently reported due to TEX, assessed as life-threatening in nine of ten cases.
These differences between the treatment arms were not Patients received at median seven cycles in both treatment statistically significant. In contrast, mucositis, diarrhea, and arms. Mean dose intensity related to the starting dose of Hand-Foot syndrome grades 1–3 were significantly more epirubicin was 95.6% (71.7 mg/m2/3 weeks), of paclitaxel often reported by patients who received capecitabine 92.9% (162.6 mg/m2/3 weeks) in the ET combination versus 88.8% of epirubicin (66.6 mg/m2/3 weeks) and In total, 135 Serious Adverse Events with probable or 92.5% of paclitaxel (143.4 mg/m2/3 weeks) of starting certain relationship to the study treatment were reported.
doses in the TEX combination. The mean dose intensity of Nineteen events of febrile neutropenia were reported for capecitabine was lower than anticipated in the TEX arm, each of the treatment arms, in three cases life-threatening 67.6% (557.8 mg 9 2/m2/3 weeks).
(grade 4). On the recommendation to add G-CSF prophy-lactic, the frequency of reported cases of febrile neutro- Second-line treatment penia decreased. Symptoms related to congestive heartfailure (CHF) prompted treatment discontinuation in 13 Seventy of the 143 patients (49%) randomized to the ET cases, three of these with severe symptoms. All but one of arm received capecitabine as second-line monotherapy, these cases had received cumulative doses of epirubicin either due to side effects of ET with persistent OR exceeding 800 mg/m2, but there was no relationship to (15 patients) or on progression (55 patients). Partial response accumulated doses of capecitabine or to radiotherapy of the following capecitabine was found in eight patients (12%), left thoracic wall. Due to the observed cardiotoxicity, stable disease in 32 patients (49%). Twenty-five cases (38%) the trial group decided to lower the threshold for maxi- progressed without response. In five cases, response could mum cumulative doses of epirubicin per individual to not be evaluated. Median time to progression was 800 mg/m2. Two of the patients who received capecitabine 6.0 months; median TTF was 4.4 months. Reasons for Breast Cancer Res Treat (2012) 131:939–947 Table 6 Proportion of patients with toxicity of all grades and severe (grade 3/4) toxicity according to CTC v. 2.0 Febrile neutropenia Sensory neuropathy Hand-foot syndrome Deep vein thrombosis Pulmonary embolism Mucositis, diarrhea, and hand-foot syndrome grades 1–3 were more frequently reported by patients treated with TEX (P 0.0001) treatment disruption were disease progression in 45 cases prolongation of PFS ]. In this study, the observed PFS (64.3%), and toxicity in 17 cases (24.3%). Three patients exceeded the anticipated time period, which altered the power with confirmed partial response requested switch to endo- of the study to reveal a minor difference between the study crine therapy. One woman died 1.6 months after start of therapy due to breast cancer, and in four cases, the reason for Effective cytotoxic treatment is restricted by the accu- disruption was not reported.
mulation of persistent side effects during long-term treat-ment. The use of anthracyclines, in the present trialepirubicin, involves a risk of cardiac toxicity unless dis- continued at defined maximum cumulative doses. Paclit-axel causes cumulative neurotoxicity and fatigue as major Addition of a drug to combination chemotherapy improves side effects in a large group of patients. Therefore, the use response rates, particularly if an anthracycline is involved, but of these drugs is limited despite lasting benefit. In the TEX has only limited impact on the outcome []. Use of taxanes arm, treatment continued with capecitabine alone after improves the efficacy of treatment significantly A trial termination of epirubicin and/or paclitaxel. The long-term comparing standard treatment with fluorouracil, doxorubicin, use probably explains the low-dose intensity compared and cyclophosphamide (FAC) with a combination of doxo- with the other drugs. Capecitabine is easier administered rubicin and paclitaxel (AT) showed significant benefit in favor for a longer period of time since it allows for dose of the regimen containing paclitaxel, 220 mg/m2 ]. This adjustments on a day-to-day basis. The prolonged use of contrasts with findings from another trial with AT using lower this drug reflects efficacy during a long time period in spite doses of paclitaxel, 175 mg/m2, which failed to show supe- of reduced dosage of the drug.
riority of AT compared with doxorubicin and cyclophospha- Use of predefined doses of cytotoxic drugs adjusted to BSA mide (AC) []. Capecitabine is a highly efficient drug in is common practice in the treatment of solid tumors. Combi- metastatic breast cancer, even in patients previously treated nation chemotherapy regimens using more intense dose with chemotherapy regimens including taxanes Pre- schedules have better prospects to prolong survival compared suming a biological synergy between epirubicin and paclit- with low-dose regimens []. Several studies comparing axel and the prodrug capecitabine, an addition of this drug regimens involving anthracyclines and/or taxanes in meta- would be expected to improve the efficacy of the treatment.
static breast cancer have shown significantly improved out- Previously presented phase II data, either with a similar three- come for the group of patients allocated to the drug or drug drug combination using docetaxel [], or paclitaxel with combination with more toxicity . Conclusions drawn capecitabine in patients pretreated with an anthracycline from these trials might have been altered if the competing drug showed promising results, but a randomized phase III trial regimens had been tailored in relation to hematological tox- comparing a combination of docetaxel and epirubicin alone or icity. This question is relevant for breast cancer trials together with capecitabine failed to show a significant involving both anthracyclines and taxanes, since both drug Breast Cancer Res Treat (2012) 131:939–947 groups cause comparable rates of neutropenia. In the present protocol, the starting dose for paclitaxel was lower in thethree-drug combination in order to create equivalent levels of Toxicity-adjusted tailored treatment with both ET and TEX toxicity. Thereafter, separate dose adjustments for each of the showed similar efficacy in terms of PFS, OS, and OR.
drugs in relation to observed side effects were encouraged.
However, the addition of capecitabine to epirubicin and The purpose was to reduce the impact of dose intensity as a paclitaxel as first-line treatment in metastatic breast cancer major factor for differences in efficacy concealing the pure did not translate into clinically relevant improvement of the effect of the combination of paclitaxel as inducer of TP and outcome in the present trial.
conversion of capecitabine into active 5-fluorouracil in thetumor tissue. This approach allows for dose intensities adap- Members of the Independent Review Commit- tee Prof. Lars Holmberg, Division of Cancer Studies, King's College, ted to individual drug tolerance as an alternative to BSA.
London, UK, Assoc. Prof. Torgil Mo¨ller, Dept of Cancer Epidemi- Individually tailored treatment schedules have been tested in a ology, Lund University, Sweden, and Prof. Erik Wist, Oslo University few randomized trials on solid tumors based either on the Hospital, Oslo, Norway, for constructive discussions during the study.
degree of bone-marrow reaction ] or on pharmacokinetic Unrestricted grants from Bristol-Myers Squibb Sweden concentrations of the cytotoxic drug based on data from pre- AB, Pfizer Sweden AB and Roche Sweden AB, the Research Funds at vious treatment cycles []. In these trials, individualized dose Radiumhemmet, the Swedish Cancer Society, the Swedish Breast adjustment resulted in an improvement of the outcome com- Cancer Association (BRO) and ALF/FOU research funds at the pared with standard dosing based on BSA. An individualized Karolinska Institutet and Stockholm County Council.
dose adjustment on a cycle-to-cycle basis for fluorouracil- Conflict of interest T. Hatschek: Consulting/advisory role: Pfizer; related drugs is supported by measurements of the activity of Funding: Roche, Sanofi-aventis. L. Carlsson: None. Z. Einbeigi: dihydropyrimidine dehydrogenase (DPD) in peripheral None. E. Lidbrink: None. B. Linderholm: None. B. Lindh: None.
mononuclear cells related to the metabolism of fluorouracil N. Loman: None. M. Malmberg: None. S. Rotstein: None.
which may vary in relation to nutritional and other environ- M. So¨derberg: Consultant/advisory role: BMS, Roche. M. Sundquist:None. T. M. Walz: None. M. Hellstro¨m: None. K. Hammarlund: mental conditions Data from a small trial also indicates None. H. Svensson: None. G. A ˚ stro¨m: None. Y. Brandberg: None.
that both TP and DPD have impact on the therapeutic efficacy J. Carstensen: None. M. Ferno¨: None. J. Bergh: Consultant/advisory of capecitabine [].
role: Amgen, Astrazeneca, GlaxoSmithKline, Pfizer, Sanofi-aventis; In spite of preclinical data suggesting synergism Funding: Amgen, Merck, Sanofi-aventis.
between taxanes and capecitabine and previously publishedpromising phase II data on the addition of capecitabine topaclitaxel or docetaxel, the present trial could not signifi-cantly confirm improvement of the outcome associated with the combination of these drugs, despite a favorablehazard ratio for the TEX combination in terms of PFS and Participating investigators of the TEX study group OS. Both treatment alternatives exceeded the progression-free period anticipated for use of taxane combinations. A Coordinating Investigator: Thomas Hatschek, Translational recently published QoL analysis comparing the two treat- research: Ma˚rten Ferno¨, QoL: Yvonne Brandberg, Statis- ments in this trial favored the TEX treatment []. In trials tics: John Carstensen, Laboratory: Suzanne Egyhazy, with equivocal results, QoL might be a useful instrument to Marianne Frostvik Stolt, Lambert Skogh, Clinical Trial decide on the choice of treatment alternative.
Office: Mats Hellstro¨m, Maarit Maliniemi, Helene Svens- Which patients will respond to treatment with anthra- son, Radiology: Gunnar A ˚ stro¨m, Departments of Oncology cycline–taxane–capecitabine combinations? In an era of at 1. Karolinska University Hospital, Stockholm: Jonas rapid development of the understanding of biological pro- Bergh, Judith Bjo¨hle, Elisabet Lidbrink, Sam Rotstein, cesses, access to tumor tissue is a prerequisite to study the Birgitta Wallberg, 2. Sahlgrenska University Hospital, mechanisms behind treatment response and resistance. As Gothenburg: Zakaria Einbeigi, Per Carlsson, Barbro Lin- part of the present trial, fine-needle aspirates from metas- derholm, 3. Linko¨ping University Hospital: Thomas M tases and blood samples were collected shortly before start Walz, 4. Ska˚ne University Hospital Malmo¨: Martin of treatment. These samples are currently analyzed with the So¨derberg, 5. Ska˚ne University Hospital Lund: Niklas intention to relate tumor biological characteristics to Loman, Per Malmstro¨m, 6. Helsingborg General Hospital: treatment response in metastatic disease. We hope that this Martin Malmberg, 7. Sundsvall General Hospital: Lena investigation will reveal new predictive markers for the Carlsson, 8. Umea˚ University Hospital: Birgitta Lindh, 9.
treatment of patients with advanced breast cancer. These Kalmar General Hospital: Marie Sundqvist, 10. Karlstad results will be presented separately.
General Hospital: Lena Malmberg.
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Source: http://weinsteinimaging.net/userfiles/breast%20cancer%20treatment%203.pdf

Der galenische trick

Verschiedene Wirkstoffe geschickt in einer Tablette kombiniert Der galenische Trick Lang anhaltender Bluthochdruck kann dramatische Folgen haben: Herzinfarkt oder Schlaganfal drohen. Um vor-zubeugen, nehmen viele Menschen Medikamente – meist gleich mehrere Präparate. Wissenschaftler von Bayer HealthCare bringen nun Ordnung in die Pil en-Vielfalt: Sie haben zwei bewährte Wirkstoffe in einer Tablette vereint. Eine Meisterleistung der Galenik, denn die beiden Substanzen müssen ganz unterschiedlich im Körper freigesetzt werden.


Load-securing device Product competence from EUROPART n Lashing straps n Accessories for lashing straps n Safety nets n Non-slip mats n Blocking elements n Lashing chains n Lashing points n Tarpaulins/fastening chains Sling bands/round slings