Outcome without any adjuvant systemic treatment in stage I ER+/HER2- breast cancer patients included in the MINDACT trial.

BACKGROUND: Adjuvant systemic treatments (AST) reduce mortality, but have associated short- and long-term toxicities. Careful selection of patients likely to benefit from AST is needed. We evaluated outcome of low-risk breast cancer patients of the EORTC 10041/BIG 3-04 MINDACT trial who received no AST. PATIENTS AND METHODS: Patients with estrogen receptor-positive, HER2-negative, lymph node-negative tumors ≤2 cm who received no AST were matched 1 : 1 to patients with similar tumor characteristics treated with adjuvant endocrine therapy (ET), using propensity score matching and exact matching on age, genomic risk (70-gene signature) and grade. In a post hoc analysis, distant metastasis-free interval (DMFI) and overall survival (OS) were assessed by Kaplan-Meier analysis and hazard ratios (HR) by Cox regression. Cumulative incidences of locoregional recurrence (LRR) and contralateral breast cancer (CBC) were assessed with competing risk analyses. RESULTS: At 8 years, DMFI rates were 94.8% [95% confidence interval (CI) 92.7% to 96.9%] in 509 patients receiving no AST, and 97.3% (95% CI 95.8% to 98.8%) in 509 matched patients who received only ET [absolute difference: 2.5%, HR 0.56 (95% CI 0.30-1.03)]. No statistically significant difference was seen in 8-year OS rates, 95.4% (95% CI 93.5% to 97.4%) in patients receiving no AST and 95.6% (95% CI 93.8% to 97.5%) in patients receiving only ET [absolute difference: 0.2%, HR 0.86 (95% CI 0.53-1.41)]. Cumulative incidence rates of LRR and CBC were 4.7% (95% CI 3.0% to 7.0%) and 4.6% (95% CI 2.9% to 6.9%) in patients receiving no AST versus 1.4% (95% CI 0.6% to 2.9%) and 1.5% (95% CI 0.6% to 3.1%) in patients receiving only ET. CONCLUSIONS: In patients with stage I low-risk breast cancer, the effect of ET on DMFI was limited, but overall significantly fewer breast cancer events were observed in patients who received ET, after the relatively short follow-up of 8 years. These benefits and side-effects of ET should be discussed with all patients, even those at a very low risk of distant metastasis.

Cardiotoxicity during long-term trastuzumab use in patients with HER2-positive metastatic breast cancer: who needs cardiac monitoring?

PURPOSE: Patients with HER2-positive metastatic breast cancer (MBC) usually receive many years of trastuzumab treatment. It is unknown whether these patients require continuous left ventricular ejection fraction (LVEF) monitoring. We studied a real-world cohort to identify risk factors for cardiotoxicity to select patients in whom LVEF monitoring could be omitted. METHODS: We included patients with HER2-positive MBC who received > 1 cycle of trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Cardiotoxicity was defined as LVEF < 50% that declined > 10%-points and was categorized into non-severe cardiotoxicity (LVEF 40-50%) and severe cardiotoxicity (LVEF < 40%). Multivariable Cox and mixed model analyses were performed to identify risk factors associated with cardiotoxicity. Additionally, we explored the reversibility of cardiotoxicity in patients who continued trastuzumab. RESULTS: In total, 429 patients were included. Median follow-up for cardiotoxicity was 15 months (interquartile range 8-31 months). The yearly incidence of non-severe + severe cardiotoxicity in the first and second year was 11.7% and 9.1%, respectively, which decreased thereafter. The yearly incidence of severe cardiotoxicity was low (2.8%) and stable over time. In non-smoking patients with baseline LVEF > 60% and no cardiotoxicity during prior neoadjuvant/adjuvant treatment, the cumulative incidence of severe cardiotoxicity was 3.1% after 4 years of trastuzumab. Despite continuing trastuzumab, LVEF decline was reversible in 56% of patients with non-severe cardiotoxicity and in 33% with severe cardiotoxicity. CONCLUSIONS: Serial cardiac monitoring can be safely omitted in non-smoking patients with baseline LVEF > 60% and without cardiotoxicity during prior neoadjuvant/adjuvant treatment.

Impact of Second Opinions in Breast Cancer Diagnostics and Treatment: A Retrospective Analysis.

BACKGROUND: Breast cancer care is becoming increasingly complex, and patients with breast cancer are increasingly aware of the different treatment options, resulting in requests for second opinions (SOs). The current study investigates the impact of breast cancer SOs on final diagnosis and treatment in the Netherlands Cancer Institute (NCI) using a newly designed Breast Cancer Second Opinion (BCSO) classification system. METHODS: Patients who visited the NCI for an SO between October 2015 and September 2016 were included. Demographics, diagnostics, and treatment proposals were compared between first and SO. Discrepancy was categorized using our BCSO classification system, categorizing SOs into (1) noncomparable, (2) identical, and (3) minor or (4) major discrepancy. RESULTS: The majority of SOs (n = 591) were patient initiated (90.7%). A total of 121 patients underwent treatment prior to their SO, leaving 470 patients for assessment of discrepancies according to our BCSO classification system. More than 45% of these SOs resulted in at least one discrepancy, with comparable rates for physician- and patient-initiated SOs (42.5% vs. 45.6%, p = 0.708). Significantly more discrepancies were observed in patients with additional imaging (51.3% vs. 37.2%, p = 0.002) and biopsies (53.7% vs. 40.3%, p = 0.005). Almost 60% of all discrepancies were categorized as major (neoadjuvant systemic treatment instead of primary surgery, breast-conserving surgery instead of mastectomy, and proposing postmastectomy immediate breast reconstruction). CONCLUSIONS: Our findings show substantial differences in diagnostic and treatment options in breast cancer patients visiting the Netherlands Cancer Institute for an SO, thereby emphasizing more consensus for the indications of these treatment modalities.

The impact of health symptoms on health-related quality of life in early-stage breast cancer survivors.

PURPOSE: In breast cancer patients, treatment-related health symptoms can occur that may affect their health-related quality of life (HRQoL). This study aimed to determine the impact of health symptoms on HRQoL in breast cancer patients up to 5 years after diagnosis. METHODS: Females surgically treated for early-stage breast cancer diagnosed between 2012 and 2016 (n = 876) were selected from the Netherlands Cancer Registry and invited for a survey about current health symptoms ('Symptoms and Perceptions questionnaire', SaP) and HRQoL ('EORTC-QLQ-C30'). From the latter, functioning and global health were included. Mean scores were compared to norm population scores (T test). Multivariable linear regression analyses were performed to determine the association between health symptoms and global health and functioning. RESULTS: 404 patients (46%) responded. The median age was 62.2 ± 10.9 years. Respondents had significantly lower mean scores for role, cognitive, emotional, and social functioning than the general population. The most frequently reported health symptoms were musculoskeletal (including pain/complaints in lower/upper extremities/back/neck; 71%) and central nervous system symptoms (including concentration impairment, dizziness, neuralgia; 66%), and fatigue (63%). While most symptoms affected functioning, irrespective of time since diagnosis, especially fatigue, musculoskeletal, central nervous system, and gastrointestinal symptoms were significantly associated (p < 0.05) with lower functioning. CONCLUSIONS: The majority of health symptoms that occur after breast cancer treatment were associated with lower functioning of patients in daily life. This paper urges healthcare providers to support breast cancer patients in alleviating or coping with health symptoms, even years after end of treatment, to improve their functioning.

Radiological complete remission in HER2-positive metastatic breast cancer patients: what to do with trastuzumab?

PURPOSE: Patients with HER2-positive metastatic breast cancer (MBC) treated with trastuzumab may experience durable tumor response for many years. It is unknown if patients with durable radiological complete remission (rCR) can discontinue trastuzumab. We analyzed clinical characteristics associated with rCR and overall survival (OS) in a historic cohort of patients with HER2-positive MBC and studied the effect of stopping trastuzumab in case of rCR. METHODS: We included patients with HER2-positive MBC treated with first or second-line trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Data were collected from medical records. We used multivariable regression models to identify independent prognostic factors for rCR and OS. Time-to-progression after achieving rCR for patients who continued and stopped trastuzumab, and breast cancer-specific survival were also evaluated. RESULTS: We identified 717 patients with a median age of 53 years at MBC diagnosis. The median follow-up was 109 months (IQR 72-148). The strongest factor associated with OS was achievement of rCR, adjusted hazard ratio 0.27 (95% CI 0.18-0.40). RCR was observed in 72 patients (10%). The ten-year OS estimate for patients who achieved rCR was 52 versus 7% for patients who did not achieve rCR. Thirty patients with rCR discontinued trastuzumab, of whom 20 (67%) are alive in ongoing remission after 78 months of median follow-up since rCR. Of forty patients (58%) who continued trastuzumab since rCR, 13 (33%) are in ongoing remission after 68 months of median follow-up. Median time-to-progression in the latter group was 14 months. CONCLUSIONS: Achieving rCR is the strongest predictor for improved survival in patients with HER2-positive MBC. Trastuzumab may be discontinued in selected patients with ongoing rCR. Further research is required to identify patients who have achieved rCR and in whom trastuzumab may safely be discontinued.

Patient-reported health problems and healthcare use after treatment for early-stage breast cancer.

BACKGROUND: A clear picture of treatment-related health problems following breast cancer treatment is useful in anticipating the informational and other needs of patients during follow-up. This study aimed to identify treatment-related health problems in breast cancer patients up to five years after diagnosis. Secondly, the use of care associated with these health problems was identified. METHODS: 876 surgically-treated female patients diagnosed between 2012 and 2016 with early-stage breast cancer were asked to complete an online survey about their current health problems and use of care. Multivariate logistic regression analyses were applied to determine the effect of patient and treatment characteristics on health problems. RESULTS: 404 patients responded (46%). The median age was 62.0 years (SD:10.9). Apart from breast surgery, patients had been treated with radiotherapy (72%), chemotherapy (49%), anti-hormonal therapy (57%), and axillary dissection (21%). Ninety-three percent experienced one or more health problems. Over 50% of respondents experienced fatigue, psychological problems, and health problems regarding the breast, and/or musculoskeletal, central nervous, and reproductive system. Treatment with chemotherapy was significantly associated (p < 0.05) with an increased risk of health problems, respectively fatigue (OR:2.00), respiratory (OR:1.81), gastrointestinal (OR:1.87), central nervous (OR:3.40), and skin problems (OR:2.62). Use of healthcare for one or more health problems was reported by 64% of respondents. DISCUSSION: Almost all patients experienced health problems up to five years after breast cancer diagnosis, with a range of complaints that were consistently present over time. Factors associated with the development of health problems are useful for better informing patients beforehand and targeting follow-up care.

Treatment decision-making in elderly women with ovarian cancer: an age-based comparison.

OBJECTIVE: To investigate treatment choices and outcomes in women with ovarian cancer, comparing elderly (≥75 years) and younger patients (<75 years). METHODS: A single-center retrospective analysis of patients diagnosed with ovarian cancer between 2010 and 2015. The initial treatment plan and course of treatment were extracted from medical files. RESULTS: Of 128 included patients, 34% were aged ≥75 years. The initial treatment plan consisted of the combination of cytoreductive surgery and platinum-based doublet chemotherapy (ie, standard treatment) in only 10% of the elderly patients with an indication for this treatment. 5% of these patients completed this treatment without adaptations (compared with 85% and 48%, respectively, in younger patients). 38% of the elderly patients with an indication for cytoreductive surgery and chemotherapy received best supportive care only. Patient preference was an important reason to withhold standard treatment. Surgery- and chemotherapy-related complications and hospital admissions did not differ between groups. Median survival was lower in the elderly (p=0.002) and in patients receiving best supportive care (p<0.001). CONCLUSIONS: Elderly patients were less frequently treated in accordance with the treatment guideline. To select those older patients who may benefit from (adapted) treatment is challenging. Future studies should evaluate determinants associated with treatment completion to improve outcomes in this vulnerable population.

Current decisions on neoadjuvant chemotherapy for early breast cancer: Experts' experiences in the Netherlands.

PURPOSE: To evaluate the opinion of surgical and medical oncologists on neoadjuvant chemotherapy (NAC) for early breast cancer. METHODS: Surgical and medical oncologists (N = 292) participating in breast cancer care in the Netherlands were invited for a 20-question survey on the influence of patient, disease, and management related factors on their decisions towards NAC. RESULTS: A total of 138 surgical and medical oncologists from 64 out of 89 different Dutch hospitals completed the survey. NAC was recommended for locally advanced breast cancer (94%) and for downstaging to enable breast conserving surgery (BCS) (75%). Despite willingness to downstage, 64% of clinicians routinely recommended NAC when systemic therapy was indicated preoperatively. Reported reasons to refrain from NAC are comorbidities (68%), age >70 years (52%), and WHO-performance status ≥2 (93%). Opinions on NAC and surgical management were inconclusive; while 75% recommends NAC to enable BCS, some stated that BCS after NAC increases the risk of a non-radical resection (21%), surgical complications (9%) and recurrence of disease (5%). CONCLUSION: This article emphasizes the need for more consensus among specialists on the indications for NAC in early BC patients. Unambiguous and evidence-based treatment information could improve doctor-patient communication, supporting the patient in chemotherapy timing decision-making.

Randomized phase 2 study of gemcitabine and cisplatin with or without vitamin supplementation in patients with advanced esophagogastric cancer.

PURPOSE: Preclinical research and prior clinical observations demonstrated reduced toxicity and suggested enhanced efficacy of cisplatin due to folic acid and vitamin B12 suppletion. In this randomized phase 2 trial, we evaluated the addition of folic acid and vitamin B12 to first-line palliative cisplatin and gemcitabine in patients with advanced esophagogastric cancer (AEGC). METHODS: Patients with AEGC were randomized to gemcitabine 1250 mg/m2 (i.v. days 1, 8) and cisplatin 80 mg/m2 (i.v. day 1) q 3 weeks with or without folic acid (450 µg/day p.o.) and vitamin B12 (1000 µg i.m. q 9 weeks). The primary endpoint was response rate (RR). Secondary endpoints included overall survival (OS), time to progression (TTP), toxicity, and exploratory biomarker analyses. Cisplatin sensitivity and intracellular platinum levels were determined in adenocarcinoma cell lines cultured under high and low folate conditions in vitro. RESULTS: Adenocarcinoma cells cultured in medium with high folate levels were more sensitive to cisplatin and this was associated with increased intracellular platinum levels. In the randomized phase 2 clinical trial, which ran from October 2004 to September 2013, treatment was initiated in 78 of 82 randomized pts, 39 in each study arm. The RR was similar; 42.1% for supplemented patients vs. 32.4% for unsupplemented patients; p = 0.4. Median OS and TTP were 10.0 and 5.9 months for supplemented vs. 7.7 and 5.4 months for unsupplemented patients (OS, p = 0.9; TTP, p = 0.9). Plasma homocysteine was lower in the supplemented group [n = 20, 6.9 ± 1.6 (mean ± standard error of mean, SEM) µM; vs. 12.5 ± 4.0 µM; p < 0.001]. There was no significant difference in the Cmax of gemcitabine and cisplatin in the two treatment groups. CONCLUSION: Folic acid and vitamin B12 supplementation do not improve the RR, PFS, or OS of cisplatin and gemcitabine in patients with AEGC.

Patients' experiences with decisions on timing of chemotherapy for breast cancer.

INTRODUCTION: Despite potential advantages, application of chemotherapy in the neo-adjuvant (NAC) instead of adjuvant (AC) setting for breast cancer (BC) patients varies among hospitals. The aim of this study was to gain insight in patients' experiences with decisions on the timing of chemotherapy for stage II and III BC. MATERIALS AND METHODS: A 35-item online questionnaire was distributed among female patients (age>18) treated with either NAC or AC for clinical stage II/III invasive BC in 2013-2014 in the Netherlands. Outcome measures were the experienced exchange of information on the possible choice between both options and patients' involvement in the final decision on chemotherapy timing. Chemotherapy treatment experience was measured with the Cancer Therapy Satisfaction Questionnaire (CTSQ). RESULTS: Of 805 invited patients, 49% responded (179 NAC, 215 AC). NAC-treated patients were younger and more often treated in teaching/academic hospitals and high-volume hospitals. Information on the possibility of NAC was given to a minority of AC-treated patients (AC, stage II:14%, stage III: 31%). Information on pros and cons of both NAC and AC was rated sufficient in about three fourth of respondents. Respondents not always felt having a choice in the timing of chemotherapy (stage II: 54% NAC vs 36% AC; stage III: 26% NAC, 54% AC). CONCLUSION: The need to make a treatment decision on NAC was found to be made explicit in only a small number of adjuvant treated patients, in particular in BC stage II. Less than half of the respondents felt they had a real choice.

Variation in use of neoadjuvant chemotherapy in patients with stage III breast cancer: Results of the Dutch national breast cancer audit.

OBJECTIVES: Neoadjuvant chemotherapy (NAC) is important in the optimal treatment of patients with locally advanced (stage III) breast cancer (BC). The objective of this study was to examine the clinical practice of NAC for stage III BC patients in all Dutch hospitals participating in BC care. MATERIALS AND METHODS: All patients aged 18-70 years who received surgery for stage III BC from January 2011 to September 2015 were selected from the national multidisciplinary NABON Breast Cancer Audit. Multivariable logistic regression was used to assess independent predictors of NAC use, focussing on hospital factors. RESULTS: A total of 1230 out of 1556 patients with stage III BC (79%) received NAC prior to surgery. The use of NAC did not change over time. We observed a large variation of NAC use between hospitals (0-100%). Age <50 years, breast MRI, large tumour size, advanced nodal disease, negative hormone receptor status and hospital participation in neoadjuvant clinical studies were significant independent predictors of NAC use (all P < 0.001). NAC use in stage III BC was not influenced by hospital type and hospital surgical volume. After adjustment for all independent predictors, variation in NAC use between hospitals remained (0% to 97%). CONCLUSION: NAC was used in 79% of patients with stage III BC, which represent a high quality of care in the NL. Patient, tumour, clinical management and hospital factors could not explain considerable variation in its use between hospitals. Hospital participation in neoadjuvant studies did show to improve the use of NAC in daily practice.

Impact of gene-expression profiling in patients with early breast cancer when applied outside the guideline directed indication area.

PURPOSE: In Dutch guidelines, gene expression profiles (GEP) are indicated in estrogen receptor positive early breast cancer patients in whom benefit of chemotherapy (CT) is uncertain based on traditional prognostic factors alone. Aim of the present study is to assess the use and impact of GEP on administration of adjuvant CT in breast cancer patients who have according to national guidelines a clear indication to either use or withhold adjuvant chemotherapy (clinical high or low risk). METHODS: Clinical low- and high-risk patients, according to Dutch breast cancer guidelines, diagnosed between 2011 and 2014 were selected from the Netherlands Cancer Registry. Influence of GEP use and GEP test result on CT administration was assessed with logistic regression. RESULTS: Overall, 26,425 patients were identified; 4.8% of patients with clinical low risk (444/9354), 7.5% of the patients with a clinical high risk (1281/17,071) received a GEP. GEP use was associated with significantly increased odds of CT administration in clinical low-risk patients (OR = 2.12 95% CI: 1.44-3.11). In clinical high-risk patients, GEP use was associated with a decreased frequency of CT administration (OR = 0.55, 95% CI: 0.48-0.63). Adherence to the GEP result was higher in clinical high-risk patients with a discordant GEP result as compared to clinical low-risk patients with a discordant GEP result: 71.7% vs. 52.2%, respectively. CONCLUSION: GEP is frequently used outside the indicated area and significantly influenced the administration of adjuvant CT, although adherence to the test result was limited.

Results of scalp cooling during anthracycline containing chemotherapy depend on scalp skin temperature.

OBJECTIVES: The success of scalp cooling in preventing or reducing chemotherapy induced alopecia (CIA) is highly variable between patients undergoing similar chemotherapy regimens. A decrease of the scalp skin temperature seems to be an important factor, but data on the optimum temperature reached by scalp cooling to prevent CIA are lacking. This study investigated the relation between scalp skin temperature and its efficacy to prevent CIA. MATERIALS AND METHODS: In this explorative study, scalp skin temperature was measured during scalp cooling in 62 breast cancer patients undergoing up to six cycles of anthracycline containing chemotherapy. Scalp skin temperature was measured by using two thermocouples at both temporal sides of the head. The primary end-point was the need for a wig or other head covering. RESULTS: Maximal cooling was reached after 45 min and was continued for 90 min after chemotherapy infusion. The scalp skin temperature after 45 min cooling varied from 10 °C to 31 °C, resulting in a mean scalp skin temperature of 19 °C (SEM: 0,4). Intrapersonal scalp skin temperatures during cooling were consistent for each chemotherapy cycle (ANOVA: P = 0,855). Thirteen out of 62 patients (21%) did not require a wig or other head covering. They appeared to have a significantly lower mean scalp skin temperature (18 °C; SEM: 0,7) compared to patients with alopecia (20 °C; SEM: 0,5) (P = 0,01). CONCLUSION: The efficacy of scalp cooling during chemotherapy is temperature dependent. A precise cut-off point could not be detected, but the best results seem to be obtained when the scalp temperature decreases below 18 °C. TRIALREGISTER. NL NTR NUMBER: 3082.

Changes over time in the impact of gene-expression profiles on the administration of adjuvant chemotherapy in estrogen receptor positive early stage breast cancer patients: A nationwide study.

Ten years ago gene-expression profiles were introduced to aid adjuvant chemotherapy decision making in breast cancer. Since then subsequent national guidelines gradually expanded the indication area for adjuvant chemotherapy. In this nation-wide study the evolution of the proportion of patients with estrogen-receptor positive (ER+) tumors receiving adjuvant chemotherapy in relation to gene-expression profile use in patient groups that became newly eligible for chemotherapy according to national guideline changes over time is assessed. Data on all surgically treated early breast cancer patients diagnosed between 2004-2006 and 2012-2014 were obtained from the Netherlands Cancer Registry. ER+/Her2- patients with tumor-characteristics making them eligible for gene-expression testing in both cohorts and a discordant chemotherapy recommendation over time (2004 guideline not recommending and 2012 guideline recommending chemotherapy) were identified. We identified 3,864 patients eligible for gene-expression profile use during both periods. Gene-expression profiles were deployed in 5% and 35% of the patients in the respective periods. In both periods the majority of patients was assigned to a low genomic risk-profile (67% and 69%, respectively) and high adherence rates to the test result were observed (86% and 91%, respectively). Without deploying a gene-expression profile 8% and 52% (p <0.001) of the respective cohorts received chemotherapy while 21% and 28% of these patients received chemotherapy when a gene-expression profile was used (p 0.191). In conclusion, in ER+/Her2- early stage breast cancer patients gene-expression profile use was associated with a consistent proportion of patients receiving chemotherapy despite an adjusted guideline-based recommendation to administer chemotherapy.

Using a gene expression signature when controversy exists regarding the indication for adjuvant systemic treatment reduces the proportion of patients receiving adjuvant chemotherapy: a nationwide study.

PURPOSE: The Dutch national guideline advises use of gene-expression signatures, such as the 70-gene signature (70-GS), in case of ambivalence regarding the benefit of adjuvant chemotherapy (CT). In this nationwide study, the impact of 70-GS use on the administration of CT in early breast cancer patients with a dubious indication for CT is assessed. METHODS: Patients within a national guideline directed indication area for 70-GS use who were surgically treated between November 2011 and April 2013 were selected from the Netherlands Cancer Registry database. The effect of 70-GS use on the administration of CT was evaluated in guideline- and age-delineated subgroups addressing potential effect of bias by linear mixed-effect modeling and instrumental variable (IV) analyses. RESULTS: A total of 2,043 patients within the indicated area for 70-GS use were included, of whom 298 received a 70-GS. Without use of the 70-GS, 45% of patients received CT. The 70-GS use was associated with a 9.5% decrease in CT administration (95% confidence interval (CI): -15.7 to -3.3%) in linear mixed-effect model analyses and IV analyses showed similar results (-9.9%; 95% CI: -19.3 to -0.4). CONCLUSION: In patients in whom the Dutch national guidelines suggest the use of a gene-expression profile, 70-GS use is associated with a 10% decrease in the administration of adjuvant CT.Genet Med 18 7, 720-726.Genetics in Medicine (2016); 18 7, 720-726. doi:10.1038/gim.2015.152.

CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increases endoxifen serum concentrations without increasing side effects.

Breast cancer patients with absent or reduced CYP2D6 activity and consequently low endoxifen levels may benefit less from tamoxifen treatment. CYP2D6 poor and intermediate metabolizers may need a personalized increased tamoxifen dose to achieve effective endoxifen serum concentrations, without increasing toxicity. From a prospective study population of early breast cancer patients using tamoxifen (CYPTAM: NTR1509), 12 CYP2D6 poor and 12 intermediate metabolizers were selected and included in a one-step tamoxifen dose escalation study during 2 months. The escalated dose was calculated by multiplying the individual's endoxifen level at baseline relative to the average endoxifen concentration observed in CYP2D6 extensive metabolizers by 20 mg (120 mg maximum). Endoxifen levels and tamoxifen toxicity were determined at baseline and after 2 months, just before patients returned to the standard dose of 20 mg. Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased endoxifen concentrations (p < 0.001; p = 0.002, respectively) without increasing side effects. In intermediate metabolizers, dose escalation increased endoxifen to levels comparable with those observed in extensive metabolizers. In poor metabolizers, the mean endoxifen level increased from 24 to 81 % of the mean concentration in extensive metabolizers. In all patients, the endoxifen threshold of 5.97 ng/ml (=16.0 nM) reported by Madlensky et al. was reached following dose escalation. CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increased endoxifen concentrations without increasing short-term side effects. Whether such tamoxifen dose escalation is effective and safe in view of long-term toxic effects is uncertain and needs to be explored.

Geriatric oncology in the Netherlands: a survey of medical oncology specialists and oncology nursing specialists.

To identify ways to improve cancer care for older patients, we set out to examine how older patients in the Netherlands are currently being evaluated prior to oncological treatment and to explore the potential obstacles in the incorporation of a geriatric evaluation, using a web-based survey sent to Dutch medical oncology specialists and oncology nursing specialists. The response rate was 34% (183 out of 544). Two-thirds of respondents reported that a geriatric evaluation was being used, although primarily on an ad hoc basis only. Most respondents expressed a desire for a routine evaluation or more intensive collaboration with the geriatrician and 86% of respondents who were not using a geriatric evaluation expressed their interest to do so. The most important obstacles were a lack of time or personnel and insufficient availability of a geriatrician to perform the assessment. Thus, over 30% of oncology professionals in the Netherlands express an interest in geriatric oncology. Important obstacles to a routine implementation of a geriatric evaluation are a lack of time, or insufficient availability of geriatricians; this could be overcome with policies that acknowledge that quality cancer care for older patients requires the investment of time and personnel.

Risk estimations and treatment decisions in early stage breast cancer: agreement among oncologists and the impact of the 70-gene signature.

BACKGROUND: Clinical decision-making in patients with early stage breast cancer requires adequate risk estimation by medical oncologists. This survey evaluates the agreement among oncologists on risk estimations and adjuvant systemic treatment (AST) decisions and the impact of adding the 70-gene signature to known clinico-pathological factors. METHODS: Twelve medical oncologists assessed 37 breast cancer cases (cT1-3N0M0) and estimated their risk of recurrence (high or low) and gave a recommendation for AST. Cases were presented in two written questionnaires sent 4 weeks apart. Only the second questionnaire included the 70-gene signature result. RESULTS: The level of agreement among oncologists in risk estimation (κ=0.57) and AST recommendation (κ=0.57) was 'moderate' in the first questionnaire. Adding the 70-gene signature result significantly increased the agreement in risk estimation to 'substantial' (κ=0.61), while agreement in AST recommendations remained 'moderate' (κ=0.56). Overall, the proportion of high risk was reduced with 7.4% (range: 6.9-22.9%; p<0.001) and the proportion of chemotherapy that was recommended was reduced with 12.2% (range: 5.4-29.5%; p<0.001). CONCLUSION: Oncologists' risk estimations and AST recommendations vary greatly. Even though the number of participating oncologists is low, our results underline the need for a better standardisation tool in clinical decision-making, in which integration of the 70-gene signature may be helpful in certain subgroups to provide patients with individualised, but standardised treatment.

A randomized phase III study comparing pegylated liposomal doxorubicin with capecitabine as first-line chemotherapy in elderly patients with metastatic breast cancer: results of the OMEGA study of the Dutch Breast Cancer Research Group BOOG.

BACKGROUND: Prospective data on chemotherapy for elderly patients with metastatic breast cancer (MBC) remain scarce. We compared the efficacy and safety of first-line chemotherapy with pegylated liposomal doxorubicin (PLD) versus capecitabine in MBC patients aged ≥65 years in a multicentre, phase III trial. PATIENTS AND METHODS: Patients were randomized to six cycles of PLD (45 mg/m(2) every 4 weeks) or eight cycles of capecitabine (1000 mg/m(2) twice daily, day 1-14 every 3 weeks). RESULTS: The study enrolled 78 of the planned 154 patients and was closed prematurely due to slow accrual and supply problems of PLD. Many included patients were aged ≥75 years (54%) and vulnerable (≥1 geriatric condition: 71%). The median dose intensity was 85% for PLD and 84% for capecitabine, respectively. In both arms, the majority of patients completed at least 12 weeks of treatment (PLD 73%; capecitabine 74%). After a median follow-up of 39 months, 77 patients had progressed and 62 patients had died of MBC. Median progression-free survival was 5.6 versus 7.7 months (P = 0.11) for PLD and capecitabine, respectively. Median overall survival was 13.8 months for PLD and 16.8 months for capecitabine (P = 0.59). Both treatments were feasible, grade 3 toxicities consisting of fatigue (both arms: 13%), hand-foot syndrome (PLD: 10%; capecitabine: 16%), stomatitis (PLD: 10%; capecitabine: 3%), exanthema (PLD: 5%) and diarrhoea (PLD: 3%; capecitabine: 5%). Only 1 of 10 patients aged ≥80 years completed chemotherapy, while 3 and 6 patients discontinued treatment due to toxicity or progressive disease, respectively. CONCLUSION: Both PLD and capecitabine demonstrated comparable efficacy and acceptable tolerance as first-line single-agent chemotherapy in elderly patients with MBC, even in vulnerable patients or patients aged ≥75 years. However, patients aged ≥80 years were unlikely to complete chemotherapy successfully. CLINICAL TRIAL NUMBERS: EudraCT 2006-002046-10; ISRCTN 11114726; CKTO 2006-09; BOOG 2006-02.