MSc Anne Oberguggenberger
email: anne.oberguggenberger@uki.at

MD Michael Hubalek
email: michael.hubalek@i-med.ac.at

MSc Monika Sztankay
email: monika.sztankay@student.uibk.ac.at

PhD Verena Meraner
email: verena.meraner@uki.at

MD Beate Beer
email: beate.beer@i-med.ac.at

PhD Herbert Oberacher
email: herber.oberacher@i-med.ac.at

PhD Johannes Giesinger
email: johannes.giesinger@i-med.ac.at

PhD Georg Kemmler
email: georg.kemmler@uki.at

MD Daniel Egle
email: daniel.egle@i-med.ac.at

MSc Eva-Maria Gamper
email: eva.gamper@uki.at

MD Barbara Sperner-Unterweger
email: barbara.sperner-unterweger@uki.at

PhD Bernhard Holzner
email: bernhard.holzner@uki.at

Is the toxicity of adjuvant aromatase inhibitor therapy underestimated? Complementary information from patient-reported outcomes (PROs)

Keywords: early breast cancer, aromatase inhibitors, postmenopausal, patient-reported outcomes, toxicity

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Patients and Methods: A cross-sectional study sample of 280 postmenopausal, early stage breast cancer patients was subjected to a comprehensive PRO assessment (FACT -B/ +ES) at their after-care appointment. Prevalence and severity of patient-reported physical side-effects and psychosocial burden related to adjuvant AI therapy were compared with prevalences derived from pivotal phase IV trials (ATAC 2005, BIG1-98 2005).

Results: Across all symptom categories, highest prevalence rates were found for joint pain (59.6%), hot flushes (52%), lost interest in sexual intercourse (51.4%) and lack of energy (40.3%). Overall, PROs resulted in significantly higher prevalence rates as compared to physician ratings for all symptoms published in pivotal clinical trials except vaginal bleeding and nausea. The treatment duration exerted no significant impact on symptom frequency (p>0.05).

Conclusion: Established prevalence rates of endocrine treatment-related toxicity seem to be underestimated. The incorporation of PRO data should be mandatory or at least highly recommended in clinical treatment planning in order to arrive at a more accurate assessment of a patient"s actual symptom burden enabling improved individualized management of sideeffects and mediating the preservation of treatment adherence.

Background

Adjuvant endocrine therapy has been proven to significantly reduce recurrence rates in breast cancer patients [START_REF]Collaborative Group (1998) Tamoxifen for early breast cancer: an overview of the randomised trials[END_REF][START_REF] Jonat | Effectiveness of switching from adjuvant tamoxifen to anastrazole in postmenopausal women with hormone-sensitive early-stage breast cancer[END_REF]. Substantial research has shown improved disease free survival and reduced incidence of contralateral breast cancer under endocrine treatment. To date, after 20 years of gold-standard tamoxifen treatment, aromatase inhibitors (AIs) have become the first choice option in the treatment of postmenopausal breast cancer [START_REF] Howell | Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years" adjuvant treatment for breast cancer[END_REF][START_REF]The Breast International Group 1-98 Collaborative Group (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer[END_REF][START_REF] Cuzick | Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial[END_REF].

While efficacy of treatment with AIs has been extensively evaluated, research has focused to a lesser extent on toxicity profiles. The terms toxicity or adverse drug reaction hereby refer to "...a response to a medicine which is noxious and unintended, and which occurs at doses normally used in man" [START_REF]Safety of Medicines. A guide to detecting and reporting adverse drug reactions[END_REF].Yet, phase III and IV studies indicate a distinct prevalence of musco-sceletal complaints, arthralgia, fractures, vaginal dryness, loss of libido, dyspareunia and diarrhea [START_REF]The Breast International Group 1-98 Collaborative Group (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer[END_REF][START_REF] The | Group (2002) Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial[END_REF][START_REF] Muss | Efficacy, Toxicity, and Quality of Life in Older Women With Early-Stage Breast Cancer Treated With Letrozole or Placebo After 5 Years of Tamoxifen: NCIC CTG Intergroup Trial MA.17[END_REF][START_REF] Coombes | A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer[END_REF]. These treatment-related adverse effects have a strong impact on patients' quality of life (QOL) and limit the therapy"s risk benefit ratio resulting in morbidity and treatment discontinuation [START_REF] Howell | Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years" adjuvant treatment for breast cancer[END_REF][START_REF] Fallowfield | Quality of life issues in relation to the aromatase inhibitor[END_REF][START_REF] Cella | Recognition and management of treatment-related side effects for breast cancer patients receiving adjuvant endocrine therapy[END_REF].

Still many AI adverse effects are underrecognized, underreported and thereafter, are undertreated in breast cancer patients undergoing AI therapy [START_REF] Fallowfield | Quality of life issues in relation to the aromatase inhibitor[END_REF]. Available data on toxicities are generally based on clinicians' impressions and proxy ratings [START_REF] Basch | The Missing Voice of Patients in Drug-Safety Reporting[END_REF]. Although health care providers are supposed to be at the best position to report on toxicity [START_REF]Safety of Medicines. A guide to detecting and reporting adverse drug reactions[END_REF], several studies on endocrine strategies in breast cancer treatment [START_REF] Coombes | A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer[END_REF][START_REF] Fellowes | Tolerability of hormone therapies for breast cancer: How informative are documented symptom profiles in medical notes for "well-tolerated" treatments?[END_REF][START_REF] Savage | He said/she said: how much agreement is there on symptoms between common toxicity criteria and quality of life?[END_REF][START_REF] Fallowfield | Why patient recorded outcomes should be mandatory in and outside clinical trials to guide management of patients with metastatic breast cancer[END_REF] have shown a poor concordance of expert ratings and patient-reported frequencies for treatment related non-life threatening symptoms. In the only study to date comparing patient-reported outcomes (PROs) in breast cancer patients receiving endocrine therapy with expert ratings [START_REF] Ruhstaller | Breast Cancer Patients on Endocrine Therapy Reveal More Symptoms when Self-Reporting than in Pivotal Trials: An Outcome Research Study[END_REF], numerous symptoms (e.g. hot flushes/ sweats, low energy, vaginal dryness) have been reported in a significantly higher percentage by patients than by physicians. There is a lack of prevalence data generated in prospective studies specifically aiming for the assessment of adverse effects in this treatment group. Admission trials alone, given their non-naturalistic setup, might not fully reflect the actual condition of patients. Additionally, reported toxicities are frequently incomplete and show great variability in both definition of adverse effects and toxicities as well as the criteria of reporting them if reported at all [START_REF] Gibson | Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women[END_REF].

The implementation of patient reported outcomes (PROs), a measurement based on a patient"s report about his or her own health condition coming directly from the patient without amendment or interpretation by a clinician or anyone else (e.g. self report questionnaires such as The Functional Assessment of cancer therapy -FACT G and supplements assessing quality of life) [START_REF]Use in Medical Product Development to Support Labeling Claims[END_REF], could provide a feasible supplement to common proxy rating-based toxicity evaluation. Enabling a more comprehensive assessment of side-effects, PROs may essentially contribute to medication evaluation and in conjunction, to individualized clinical decision making [START_REF] Basch | The Missing Voice of Patients in Drug-Safety Reporting[END_REF][START_REF] Giesinger | Towards the implementation of quality of life monitoring in daily clinical routine: methodological issues and clinical implication[END_REF].

Objectives

The objective of the present study is to determine prevalence and severity of patientreported physical side-effects and psychosocial burden (referred to as quality of life impairments) related to adjuvant AI therapy in postmenopausal breast cancer patients. In

Procedure

Eligible patients were identified by searching the medical records and were approached at their routine after-care appointments with their breast cancer specialist. Within after-care, breast cancer patients routinely attend the University Clinic of Gynecology and Obstetrics in three-month interval after-care appointments over a period of five years.

Patients within all treatment phases (from the start of endocrine treatment to the last day) were included at one of their 3-month-after care appointments and asked to complete this cross-sectional survey. While waiting for their follow-up medical examinations, patients were introduced to study details and asked to provide written informed consent. Afterwards, patients completed a comprehensive PRO assessment. Data collection was computerized using a software called "Computer based Health Evaluation System" (CHES) [20]. PRO data were entered by patients themselves via a Tablet-PC, a study assistant explaining the procedure and supervising the assessment.

Assessment instruments

To evaluate the impact of therapy on patients' QOL, we administered the "Functional assessment of Cancer therapy -Breast and Endocrine Subscale" (FACT-B/+ES).

Functional assessment of cancer therapy -Breast (Fact-B). The FACT-B is a well-validated

and widely used self-report questionnaire composed of 36 items assessing QOL in breast cancer patients. It is a multi-dimensional tool covering general QOL domains (FACT-G: physical, emotional, functional and social well-being) and a specific domain for additional concerns related to breast cancer [START_REF] Brady | Reliability and validity of the Functional Assessment of Cancer Therapy-Breast quality-of-life instrument[END_REF]. The questionnaire employs a five-point-Likert scale and refers to the time-frame of the last 7 days. Response scales range from 0 (not at all) to 4 (very much). Maximum scoring for global well-being ranges from 0-108, for emotional well-being 0-24 and for physical, functional and social well being 0-28. High scores indicate good QOL.

Functional assessment of cancer therapy -endocrine subscale (Fact-ES). The Fact-B is supplemented by the endocrine subscale (FACT-ES) measuring symptoms and side-effects related to endocrine therapy for breast cancer e.g. hot flushes, vaginal discharge or loss of libido [START_REF] Fallowfield | Assessment of quality of life in women undergoing hormonaltherapy for breast cancer: validation of an endocrine symptomsu bscale for the FACT-B[END_REF]. The FACT-ES comprises 19 items and applies to the FACT-B regarding format and response scale.

Pivotal trials and studies included for comparison

Trials and studies included for comparison were selected based on comparability regarding patient group and endocrine agent. Two trials [START_REF] Howell | Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years" adjuvant treatment for breast cancer[END_REF][START_REF]The Breast International Group 1-98 Collaborative Group (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer[END_REF] and a subprotocol of the ATAC trial [START_REF] Cella | Quality of life of postmenopausal women in the ATAC (""Arimidex"", tamoxifen, alone or in combination) trial after completion of 5 years" adjuvant treatment for early breast cancer[END_REF] were identified as eligible. [START_REF] Howell | Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years" adjuvant treatment for breast cancer[END_REF]. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, a double-blind randomized trial, compared 5 years of primary adjuvant treatment with anastrozole alone, tamoxifen alone or the combination of both in 9366 postmenopausal women with localized early breast cancer. Primary objectives were to evaluate the efficacy and tolerability of anastrazole compared with tamoxifen. Prevalence data of side-effects included in our study are derived from analysis of data after a median follow-up of 68 months [START_REF] Howell | Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years" adjuvant treatment for breast cancer[END_REF].

ATAC (2005)

In a subprotocol of the ATAC trial [START_REF] Cella | Quality of life of postmenopausal women in the ATAC (""Arimidex"", tamoxifen, alone or in combination) trial after completion of 5 years" adjuvant treatment for early breast cancer[END_REF], prospectively investigated the impact of anastrozole and tamoxifen on health-related QOL of a sub-sample of women enrolled into the trial (n = 1105). QOL data was assessed by means of FACT-B/+ES in patients receiving anastrazole (n = 335) or tamoxifen (n = 347) at baseline, 3 and 6 months, and every 6 months thereafter, up to and including confirmation of disease recurrence, cessation of trial therapy or withdrawal from the subprotocol.

BIG 1-98 (2005) [START_REF]The Breast International Group 1-98 Collaborative Group (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer[END_REF]. The Breast International Group (BIG) 1-98 study is a randomized, phase 3, double-blind trial comparing five years of treatment with four different adjuvant endocrine therapy regimens (i.e. letrozole, letrozole followed by tamoxifen, tamoxifen, and tamoxifen followed by letrozole) in postmenopausal women with hormone-receptor-positive breast cancer.

Prevalence and frequencies of side-effects found in our study were compared with data from the BIG 1-98 patient group included in the safety analysis (n = 3,975 for letrozole monotherapy). Adverse events were recorded by the checking of specific boxes on the case report forms, grades were determined according to the Common Toxicity Criteria of the National Cancer Institute (version 2.0) or according to criteria defined by a senior oncologist in the protocol otherwise.

Statistical analysis

Sample characteristics are given as percentages, ranges, means and standard deviations.

The prevalence of QOL impairment is presented as percentages and 95% confidence intervals.

We calculated the frequency of each symptom by summarizing percentages of the categories 'somewhat', 'quite a bit' and 'very much' on single item level of the FACT-G/+ES. Confidence intervals were calculated using the modified Wald method [START_REF] Vollset | Confidence intervals for a binomial proportion[END_REF]. Similar to Cella et al. [START_REF] Cella | Quality of life of postmenopausal women in the ATAC (""Arimidex"", tamoxifen, alone or in combination) trial after completion of 5 years" adjuvant treatment for early breast cancer[END_REF], items of the endocrine subscale were grouped as a) vasomotor symptoms, b) gynecologic symptoms, c) gastrointestinal symptoms, d) pain and e) psychological symptoms (see Table 3).

The chi-square test was used to compare symptom frequencies found in this study with those derived from the literature. The impact of age was as well analyzed using the chi-square test.

For the purpose of comparison, we defined age groups according to the MA.17 trial (<60y, 60-69y, >70) [START_REF] Muss | Efficacy, Toxicity, and Quality of Life in Older Women With Early-Stage Breast Cancer Treated With Letrozole or Placebo After 5 Years of Tamoxifen: NCIC CTG Intergroup Trial MA.17[END_REF]. To investigate the impact of treatment duration on side-effects, treatment duration was grouped into three categories: patients within the 1. and 2. year of treatment, 3-4 year and >4 years. These three groups were compared with regard to symptom frequencies by use of the Chi2 test. Moreover, group differences between substances (anastrazole vs. letrozole) with regard to toxicity rates were investigated using the Chi2 test.

Statistical analyses were performed using the software SPSS (version 15.0).

Results

Patient characteristics

Between June 2009 and May 2010 a total of 280 breast cancer patients were identified as eligible for inclusion in this analysis.

Patients varied in age between 46 to 85 years, with a mean age of 65.3 years. Mean treatment duration was 27.8 months on average. Almost half of the participants (49.4%) has been receiving endocrine therapy for less than two years. Anastrazole was the agent most frequently prescribed (83.1%), followed by letrozole. Only 1.1% of patients were taking exemestane.

The most frequent histopathologic cancer type in this study sample was invasive ductal carcinoma and grade II carcinomas. For further details see Table 1 and2. Across all symptom categories, highest prevalence rates for adverse events with AI treatment were found for joint pain (59.6%), hot flushes (52%), lost interest in sexual intercourse (51.4%) and lack of energy (40.3%). Vaginal dryness (31.9%) and breast sensitivity/ tenderness (26.4%) were the most prevalent gynecological symptoms. Gastrointestinal symptoms were reported less often with one-third of the patients having stated to suffer from weight gain (33%) presenting as the highest score in this group. Psychological symptoms appeared most frequently as lack of energy (40.3%) and mood swings (36.2%). Table 3 shows details on symptoms and comparative studies.

Frequency of symptoms and comparison with pivotal trials

Frequency of symptoms was not significantly associated with the type of substance prescribed (results not shown). Patients receiving exemestane (1.1%) were excluded for this analysis due to the small sample size.

Comparison with pivotal trials [START_REF] Howell | Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years" adjuvant treatment for breast cancer[END_REF][START_REF]The Breast International Group 1-98 Collaborative Group (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer[END_REF]. Overall, PROs resulted in higher prevalence rates as compared to physician ratings for all symptoms published in pivotal clinical trials except for vaginal bleeding (3.3% in BIG 1-98; 5.4% in ATAC; 0.4% in PRO-BeTh) and nausea (12.7% in ATAC; 5.3% in PRO-BeTh). We found significantly higher prevalence rates of hot flushes, night sweats, joint pain, lack of energy and mood swings based on the PRO assessment than derived from pivotal trials.

A comparison of the frequencies of adverse events showed agreement on highest prevalence for joint pain (20.3% in BIG 1-98; 35.6% in ATAC) as well as hot flushes (33.5% in BIG 1-98; 37.7% in ATAC). Lack of energy (18.6%) almost equaled mood swings (19.3%) in frequency in the ATAC trial, while lost interest in sexuality was assessed in neither clinical trial. Despite the congruence regarding the most frequent symptoms, their prevalence rates still rank below the scores recorded in our study.

Comparison with ATAC subprotocol [START_REF] Cella | Quality of life of postmenopausal women in the ATAC (""Arimidex"", tamoxifen, alone or in combination) trial after completion of 5 years" adjuvant treatment for early breast cancer[END_REF]. Lower prevalences for 17 out of 19 symptoms were found in the ATAC subprotocol (n=335) by Cella et al. [START_REF] Cella | Quality of life of postmenopausal women in the ATAC (""Arimidex"", tamoxifen, alone or in combination) trial after completion of 5 years" adjuvant treatment for early breast cancer[END_REF], of which 15 differed significantly. Lack of energy was more than twice as frequent in PRO-BeTh study patients (40.3% vs. 15.9%), followed by hot flushes (52% vs. 26.6%) and lost interest in sexual intercourse (51.4% vs. 34%). Analyses revealed a markedly increased prevalence of all psychological symptoms. Sleeping difficulties (16.4% in PRO BeTh vs. 19% in ATAC) and pain or discomfort with sexual intercourse (16% in PRO-BeTh vs. 17.3% in ATAC) were the only two symptoms showing a pattern contrary to the overall trend. No reference data could be found for joint pain and some other symptoms.

Impact of age and treatment duration

Comparison of three age groups (<60y, 60-69y, 70y) with respect to symptom burden revealed a significantly higher frequency of vasomotor symptoms, vaginal discharge, vaginal dryness, breast sensitivity, mood swings and being irritable in the youngest group (table 4). Moreover, we investigated the association of treatment duration with levels of side-effects comparing patients in the first and second year of endocrine treatment, in the third to fourth year and with more than four years of therapy. Regarding all side-effects, observed differences in symptom prevalences ranged from 0-18.3% (median 4.2) and did not reach statistical significance (p>0.05).

Discussion

Adjuvant endocrine therapy with aromatase inhibitors is considered to exert moderate toxicity and good tolerability. Yet, results on toxicity profiles are derived from proxy ratings in clinical trial settings which might not adequately reflect the toxicity burden experienced by patients.

Hence, in some contrast to current opinion based large phase III and IV adjuvant studies on AI treatment symptom burden, this large scale PRO study here revealed a higher level of psychosocial burden and physical side-effects in breast cancer patients undergoing endocrine therapy with older patients apparently suffering from significantly less symptoms. Despite the agreement on symptoms with highest prevalence rates (i.e. joint pain, vasomotor symptoms, loss of interest in sexual intercourse) pivotal trials report significantly lower rates [START_REF] Howell | Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years" adjuvant treatment for breast cancer[END_REF][START_REF]The Breast International Group 1-98 Collaborative Group (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer[END_REF]. Our results, thereby, confirm the presumption that PROs reveal a higher level of symptom burden than conventional pivotal clinical trials [START_REF] Cella | Recognition and management of treatment-related side effects for breast cancer patients receiving adjuvant endocrine therapy[END_REF][START_REF] Basch | The Missing Voice of Patients in Drug-Safety Reporting[END_REF][START_REF] Fallowfield | Treatment-decision making in breast cancer: the patient-doctor relationship[END_REF][START_REF] Marquis | Patient-Reported Outcomes and Health-Related Quality of Life in Effectiveness Studies: Pros and Cons[END_REF].

Ruhstaller and colleagues [START_REF] Ruhstaller | Breast Cancer Patients on Endocrine Therapy Reveal More Symptoms when Self-Reporting than in Pivotal Trials: An Outcome Research Study[END_REF] reported comparable results in their PRO based study. Though differing sample characteristics (i.e. treatment with tamoxifen) precluded direct comparison with our study results, their findings support the notion that the use of PROs leads to reporting of increased symptom frequency. Similar findings were obtained by Fellowes et al. [START_REF] Fellowes | Tolerability of hormone therapies for breast cancer: How informative are documented symptom profiles in medical notes for "well-tolerated" treatments?[END_REF], who found significant differences between physician-recorded side-effects of endocrine agents with interview-based PROs. Also Basch [START_REF] Basch | The Missing Voice of Patients in Drug-Safety Reporting[END_REF] claimed that established methods for treatment evaluation in clinical trials such as proxy ratings lack sensitivity; e.g. physicians tend to downgrade their patient's actual symptom burden resulting in deficient toxicity profiles.

Moreover, some patients might not report disturbing side-effects to their full extent in routine clinical examinations because of their fear of being perceived as overly needy or their subjective perceptions of the physicians not interested in the matter. In fact, side-effects found most problematic by patients often differ from those that most concern clinicians [START_REF] Fallowfield | Treatment-decision making in breast cancer: the patient-doctor relationship[END_REF].

One may, however, hypothesize that presented differences in symptom frequencies between PRO assessments and pivotal trials are not to be solely explained by the use of self-report instruments but also by the impact of the methodologically different features of implemented study designs (as such non-trial designs). This might explain the difference between the reported symptom frequencies in the naturalistic after-care setting of our study and the significantly lower rates registered by Cella et al. [START_REF] Cella | Quality of life of postmenopausal women in the ATAC (""Arimidex"", tamoxifen, alone or in combination) trial after completion of 5 years" adjuvant treatment for early breast cancer[END_REF] who investigated patient-reported sideeffects of adjuvant anastrazole therapy in a subprotocol of the ATAC trial. Although randomized controlled clinical trials (RCTs) provide higher internal validity [START_REF] Cole | Generalizing Evidence From Randomized Clinical Trials to Target Populations: The ACTG 320 Trial[END_REF], the generalizability of results from RCTs is limited due to a lack of representativity of the study population and clinical setting [START_REF] Greenhouse | Generalizing from clinical trial data: A case study. The risk of suicidality among pediatric antidepressant users[END_REF]. Findings concerning impact of age on levels of side-effects experienced were consistent with current literature [START_REF] Muss | Efficacy, Toxicity, and Quality of Life in Older Women With Early-Stage Breast Cancer Treated With Letrozole or Placebo After 5 Years of Tamoxifen: NCIC CTG Intergroup Trial MA.17[END_REF][START_REF] Freedman | Pre-menopausal breast cancer and aromatase inhibitors: treating a new generation of women[END_REF]. Given recent knowledge about the manifestation of adverse effects in association with treatment duration [START_REF] Fallowfield | Quality of Life of postmenopausal women in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Adjuvant Breast Cancer Trial[END_REF][START_REF] Desta | CYP2D6 Genotype, Antidepressant Use, and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment[END_REF], the lack of impact of the latter on side-effect frequency was, however, unexpected. Our differing results may be explained by the crosssectional design of our study solely allowing comparisons between different duration groups at one assessment time point. A longitudinal study design provides another approach to capture the issue of time dependent symptom prevalence. Baseline-data, shorter time intervals and a higher frequency of assessments, particularly in the first two years, might provide further insight into this issue.

Interpretation of results presented in this manuscript is limited by the fact that an indirect comparison of symptom frequencies with prevalence rates reported in the literature cannot replace a direct comparison of PROs and expert ratings in the same patient population.

Additionally, lack of baseline data due to the cross-sectional design prevents us from concluding the observed relationship as a causal one. Nevertheless, this approach illustrates the relevance of the issue in question and demonstrates the need for further research on this matter. Moreover, given the importance of clinical trials in the development of clinical guidelines, it seems necessary to be aware of their limitations regarding reporting of treatment toxicity. Correspondingly, the FDA [START_REF]Use in Medical Product Development to Support Labeling Claims[END_REF] has recommended the use of PROs as primary endpoints in trials [START_REF] Cleeland | Assessing the Symptoms of Cancer Using Patient-Reported Outcomes (ASCPRO): Searching for Standards[END_REF] and underscores their relevance to secure labeling claims [START_REF] Doward | Patient reported outcomes: looking beyond the label claim[END_REF].

To obtain a more accurate picture of the true extent of toxicity caused by adjuvant endocrine therapy, direct comparison of all available treatment strategies within a longitudinal study design should be considered, which, however, requires larger sample size to ensure statistical comparability. Furthermore, the impact of other variables (e.g. co-morbidities, marital status, genetic variables, depression or menopausal state) on side-effects should be explored in more detail aiming for reevaluation of toxicity profiles in both post-and premenopausal women by use of patient-based instruments.

Regarding clinical practice, our findings emphasize the necessity of increased application of self-report instruments given that outcomes voiced by patients provide essential information on treatment impact (e.g. pain intensity, pain relief) that are difficult to obtain from other sources [START_REF] Marquis | Patient-Reported Outcomes and Health-Related Quality of Life in Effectiveness Studies: Pros and Cons[END_REF]. Screening for self-reported data could minimize potential negative consequences of patient attitudes toward their physician and/or symptom experience and could help identify patients suffering from side-effects otherwise missed. This is even more important in the light of 33% of breast cancer patients undergoing adjuvant endocrine therapy outside a clinical trial setting are assumed to not to adhere to treatment recommendations over the 5-year treatment period due to symptom burden [START_REF] Fallowfield | Quality of life issues in relation to the aromatase inhibitor[END_REF]. This patient non-adherence not only compromises treatment efficacy but diminishes patient quality of life [START_REF] Partridge | Non-adherence to endocrine therapy for breast cancer[END_REF][START_REF] Partridge | Adherence to Therapy With Oral Antineoplastic Agents[END_REF][START_REF] Osterberg | Adherence to Medication[END_REF] and could be mediated by improved side-effect management based on PROs. This entails considering potential barriers to their implementation [START_REF] Basch | The Missing Voice of Patients in Drug-Safety Reporting[END_REF][START_REF] Snyder | Relevant content for a patient-reported outcomes questionnaire for use in oncology clinical practice: Putting doctors and patients on the same page[END_REF].

In conclusion, according to our findings, established prevalence rates of endocrine treatmentrelated toxicity seem to be underestimated. Hence, monitoring a patient's subjective perception of his or her side-effects complementing clinician ratings, may provide a more comprehensive picture of the patient experience. The incorporation of PRO data should be mandatory or at least highly recommended in clinical treatment planning in order to arrive at a more accurate assessment of a patient"s actual symptom burden enabling improved individualized management of side-effects and mediating preservation of treatment adherence.

Tables

  detail, we aim to address the following research questions: To what degree do breast cancer patients experience QOL impairments related to AI therapy? How concordant is the prevalence in our study compared with prevalences derived from the pivotal phase IV trials? Does age or treatment duration have an impact on the degree of QOL impairment? This study is part of the comprehensive research project PRO-BETh (Patient-Reported Outcomes in Breast Cancer Patients Undergoing Endocrine Therapy) conducted by the Department of Psychiatry and Psychotherapy in cooperation with the Department of Gynecology and Obstetrics and the Department of Legal Medicine, Innsbruck Medical University, Austria. The PRO-BETh study aims for a multi-method assessment of adherence and QOL among breast cancer patients at all stages of adjuvant endocrine therapy. Ethical approval for this project was obtained from the Ethics Committee of Innsbruck Medical University. Patients and methods Sample PRO-BETh was conducted at the out-patient unit of the Department of Gynecology and Obstetrics at Innsbruck Medical University. Data were derived from the cross-sectional study sample which includes breast cancer patients with the following characteristics: a diagnosis of breast cancer stage I -III upfront adjuvant endocrine therapy with AIs for at least one month after primary surgery for breast cancer (no prior tamoxifen) postmenopausal state maximum age of 85 years written informed consent no recurrent or metastatic disease no overt cognitive impairment no previous treatment with anti-hormonal medication.

  Quality of Life and frequency of symptoms. Patients scored high regarding FACT-B global well-being (mean 87.3, SD 13.7), physical well-being (mean 23.9, SD 4.2), emotional wellbeing (mean 19.4, SD 3.7, functional well-being (mean 21.4, SD 5.0) and social well-being (mean 22.0, SD 5.8). The frequency of endocrine symptoms experienced by this patient population amounted to a mean of 15.8, SD 9.2.

  Fraser et al. (2011) [29] have highlighted in their community based population study the problems of applying clinical trial data to a generalized, non-trial population and revealed a distinct difference to the PACS 01 trial results regarding toxicity of a chemotherapeutic regime. Moreover, patients change their medication intake behavior outside clinical trial settings resulting in divergent outcomes [10]. An implemented study design might reduce the selection bias evident in clinical trials. In this study, a minimal refusal rate of overall 7-10% enabled us to assess a broad cross section of breast cancer cohorts minimizing the risk for a selection bias and, thus, enhancing generalizability of results. Moreover, direct comparisons for toxicity rates with the ATAC PRO-subprotocol are to be interpreted with caution due to the different substances administered. The sample population in our study received any type of AIs compared to anastrozole as the only substance prescribed in the ATAC subprotocol. We did not find significant group differences between the types of substances prescribed concerning side-effect frequency. This is in accordance with the literature proving the non-steroidal aromatase inhibitors to cause very similar symptom burden.

Table 1

 1

	Sociodemographic data (N=280)
			Frequency
			(%)
	Age	Mean (SD)	65.3 y (8.2 y)
		Range	46-85y
	Marital status	Single	25 (10.1%)
		Partnership, marriage	153 (61.7%)
		Divorced, separated	31 (12.5%)
		Widowed	39 (15.7%)
	Education	Less than compulsory	4 (1.7%)
		school
		Compulsory school	81 (33.8%)
		Apprenticeship/ professional school A-level University degree Other	114 (47.5%) 28 (11.7%) 11 (4.6%) 2 (0.8%)
	Employment status	Full time	18 (7.3%)
		Part time	13 (5.3%)
		Unemployed	5 (1.8%)
		Homemaker	34 (13.9%)
		Retired	169 (69.0%)
		Other	6 (2.4%)
	Table 2 Clinical data (N=280)
			Frequency
			(%)
	Diagnosis	DCIS	14 (5.1%)
		Invasive ductal Invasive lobular	217 (79.2%) 32 (11.7%)
		Other	11 (4.1%)
	Grading	Grade I	41 (14.6%)
		Grade II Grade III unknown	199 (71.1%) 13 (4.6%) 27 (9.6%)
	Tumor size	≤ 2 cm (incl. ypT0)	193 (68.9%)
		2-5 cm	57 (20.4%)
		>5 cm	9 (3.2%)
		unknown	21 (7.5%)
	Nodal status	negative (incl. NX)	178 (63.6%)
		positive	86 (30.7%)
		unknown	16 (5.7%)
	Duration of adjuvant	Mean (SD)	27.8 (19.6) mo.
	endocrine therapy	Range	0.5-101 mo.
	(months)
	Endocrine agent	Anastrazole	232 (83.1%)
		Letrozole	44 (15.8%)
		Exemestane	4 (1.1%)
	Primary surgical	Mastectomy	93 (33.8%)
	treatment	Reconstruction	50 (18.2%)
	Chemotherapy		55 (19.9%)
	Radiotherapy		191 (69.0%)
	Antidepressants		53 (18.9%)
	Complementary medicine		54 (19.3%)

Table 4

 4 Impact of age on symptom burden

	FACT-ES (N=280)
	Additional concerns*age	<60y	60-69y	>70y	Group differences
	Vasomotor symptoms				Chi 2	p
	Hot flushes	74,6%	49,6%	36,1%	20.458	<0.001
	Cold sweats	34,4%	16,2%	14,1%	10.489	0.005
	Night sweats	52,5%	29,3%	23,0%	14.598	0.001
	Sleeping difficulties	17,5%	18,2%	13,5%	0.758	0.684
	Gynaecologic symptoms
	Vaginal discharge	13,1%	4,2%	1,4%	9.682	0.008
	Vaginal itching/ irritation	12,9%	5,9%	5,3%	3.598	0.165
	Bleeding or spotting	0,0%	0,0%	1,3%	2.409	0.300
	Vaginal dryness	45,2%	31,9%	20,5%	9.351	0.009
	Breast sensitivity/ tenderness	37,7%	26,5%	16,4%	7.759	0.021
	Pain or discomfort with intercourse	23,1%	17,2%	6,3%	5.411	0.067
	Lost interest in sex	49,2%	51,4%	53,4%	0.217	0.987
	Gastrointestinal symptoms
	Having vomited	4,9%	0,8%	2,8%	2.953	0.228
	Diarrhoea	8,2%	8,2%	10,0%	0.207	0.902
	Nausea	5,0%	6,1%	6,8%	0.199	0.905
	Gained weight	41,3%	34,7%	23,0%	5.48	0.065
	Feeling bloated	16,4%	18,3%	9,6%	2.737	0.254
	Pain
	Headaches	25,8%	20,2%	11,1%	4.889	0.087
	Joint pain	61,3%	59,0%	59,5%	0.091	0.956
	Psychological symptoms
	Mood swings	54,1%	32,0%	28,4%	11.369	0.003
	Being irritable	44,3%	27,3%	18,7%	11.007	0.003
	Lack of energy	49,2%	36,9%	38,2%	2.814	0.245
	Dizziness	25,8%	14,2%	24,7%	4.848	0.089

Acknowledgements

We would like to thank Prof.Dr. Fleischhacker from the University Clinic of Biological Psychiatry, Innsbruck Medical University for insightful comments. Monika Sztankay MSc and Anne Oberguggenberger MSc were financially supported by the Innsbruck Leopold-Franzens-University Innsbruck, Austria.


Luigi Cavanna

Massimo Ambroggi

Elisa Stroppa

Camilla Nunzio

Laura Dallanegra

Michela Monfredo

Return to work after treatment for breast cancer

LETTER TO THE EDITOR

Return to work after treatment for breast cancer

Luigi Cavanna, Massimo Ambroggi, Elisa Stroppa, Camilla Di Nunzio, Laura Dallanegra, Michela Monfredo In their interesting article "Trends in return to work of breast cancer survivors", published online inJanuary 2011 issue of "Breast Cancer Research and Treatment", Roelen et al [START_REF] Roelen | Trends in return to work of breast cancer survivors[END_REF] demonstrated that partial return to work (RTW) one year after the diagnosis of breast cancer was more or less stable around 70% in the period from 2002 to 2008, whereas full RTW showed a decreasing trend in women of all ages. We recently reported preliminary results of a prospective study aimed to explore the influence of breast cancer and related treatments about the decision to stop or to return to work [START_REF] Nunzio | La perdita e la ripresa dell'attività lavorativa dopo la diagnosi e cure per tumore. Studio preliminare[END_REF][START_REF] Dallanegra | Working during cancer treatment. Is it possible? Preliminary study[END_REF]. In our study the treating physician or psychoncologist recruited patients before the start of initial treatment, in the period from August 2007 to January 2008. We report here final results: 76 of 112 consecutive patients with early breast cancer admitted to our outpatient medical oncology accepted to participate this study and to complete the interviews; all patients were interviewed at diagnosis and after 1, 3, 6, 9, 18 and 24 months. Clinical and psychological data including diagnosis, stage, age, anxiety, depression, treatment planned, job at diagnosis were recorded for each patient. After 1 month from diagnosis 45% of patients stopped work and after 3 to 9 months 55,3% of patients stopped work. In our group of patients, 77,9% of them had full RTW after a median delay of 10,3 months, that is inferior when compared with the delay reported by Roelen et al [START_REF] Roelen | Trends in return to work of breast cancer survivors[END_REF]. Anxiety and depression seem affect employment by decreasing work hours, and increasing absence. According to other Authors [START_REF] Peugniez | Return to work after treatment for breast cancer: single-centre experience in a cohort of 273 patients[END_REF][START_REF] Boer | Cancer survivors and unemployment: a meta-analysis and meta-regression[END_REF]: age > 55 years, chemotherapy, physical and psychological status were the major factors affecting the return to work, while type of surgery, sentinel lymphnode biopsy or axillary dissection, radiation therapy and hormonal therapy did not negatively influence the return to work, as previously reported [START_REF] Peugniez | Return to work after treatment for breast cancer: single-centre experience in a cohort of 273 patients[END_REF]. People treated for cancer have reported a variety of problems at work [START_REF] Peugniez | Return to work after treatment for breast cancer: single-centre experience in a cohort of 273 patients[END_REF][START_REF] Boer | Cancer survivors and unemployment: a meta-analysis and meta-regression[END_REF][START_REF] Hassett | Factors influencing changes in employment among women with newly diagnosed breast cancer[END_REF]. Also the importance of social support from the workplace in relation to sickness absence in general is well documented [START_REF] Karasek | Healthy work[END_REF] and more recently Johnsson et al [START_REF] Johnsson | Factors influencing return to work: a narrative study of women treated for breast cancer[END_REF], in their study, clearly demonstrated the importance of social support from the employer and coworkers for the return to work. Work is important for individual's identity and provides also a social connection, however the experience of continuing or returning to work following cancer and related treatment is a largely unknown area of cancer research , so we believe that the report of Roelen et al [START_REF] Roelen | Trends in return to work of breast cancer survivors[END_REF] is important to involve clinicians and other professionals to enhance participation of cancer survivors in the work life.

Luigi Cavanna, Massimo Ambroggi, Elisa Stroppa, Camilla Di Nunzio, Laura Dallanegra, Michela Monfredo Oncology and Hematology Department, Oncology Unit, "Guglielmo da Saliceto" Hospital, Piacenza, Italy Correspondence to: Luigi Cavanna, Department of Oncology and Hematology, Oncology Unit, "Guglielmo da Saliceto" Hospital, Via Taverna 49, 29100 Piacenza, Italy, Tel +39 0523 302697; fax +39 0523 302141; e-mail address: l.cavanna@ausl.pc.it

Acknowledgments

The Authos are fully responsible for all the content and editorial decisions and have not received any financial support or other form of remuneration related to the development of this article.