Significantly longer time to deterioration of quality of life due to CANKADO PRO-React eHealth support in HR+ HER2- metastatic breast cancer patients receiving palbociclib and endocrine therapy: primary outcome analysis of the multicenter randomized AGO-B WSG PreCycle trial.

BACKGROUND: The multicenter, randomized, phase IV, intergroup AGO-B WSG PreCycle trial (NCT03220178) evaluated the impact of CANKADO-based electronic patient-reported outcome (ePRO) assessment on quality of life (QoL) in hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer (MBC) patients receiving palbociclib and an aromatase inhibitor or palbociclib + fulvestrant. CANKADO PRO-React, a European Union-registered medical device, is an interactive autonomous application reacting to patient self-reported observations. PATIENTS AND METHODS: Between 2017 and 2021, 499 patients (median age 59 years) from 71 centers were randomized (2 : 1, stratified by therapy line) between an active version of CANKADO PRO-React (CANKADO-active arm) and a version with limited functionality (CANKADO-inform arm). A total of 412 patients (271 CANKADO-active; 141 CANKADO-inform) were available for analysis of the primary endpoint, time to deterioration (TTD) of QoL [10-point drop on the Functional Assessment of Cancer Therapy-General (FACT-G) score], using an Aalen-Johansen estimator for cumulative incidence function of TTD DQoL (QoL deterioration) with 95% pointwise confidence intervals (CIs). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and DQoL. RESULTS: In all patients [intention-to-treat (ITT)-ePRO], cumulative incidence of DQoL was significantly more favorable (lower) in the CANKADO-active arm (hazard ratio 0.698, 95% CI 0.506-0.963). Among first-line patients (n = 295), the corresponding hazard ratio was 0.716 (0.484-1.060; P = 0.09), and in second-line patients (n = 117) it was 0.661 (0.374-1.168; P = 0.2). Absolute patient numbers declined in later visits; FACT-G completion rates were 80% and higher until about visit 30. Mean FACT-G scores showed a steady decline from baseline and an offset in favor of CANKADO-active. No significant differences in clinical outcome were observed between arms: median PFS (ITT population) was 21.4 (95% CI 19.4-23.7) (CANKADO-active) and 18.7 (15.1-23.5) months (CANKADO-inform); median OS was not reached (CANKADO-active) and 42.6 months (CANKADO-inform). CONCLUSIONS: PreCycle is the first multicenter randomized eHealth trial demonstrating a significant benefit for MBC patients receiving oral tumor therapy when using an interactive autonomous patient empowerment application.

Patients' perspectives towards malignant ascites: results of a prospective observational trial regarding expectations, characteristics and quality of life-a study of the North-Eastern-German Society of Gynecological Oncology.

PURPOSE: Malignant ascites (MA) is a frequent and common symptom in (gyneco-) oncological patients. The present trial evaluated and assessed patients' characteristics, clinical features and the possible influence of MA on QoL measurements. METHODS: A prospective observational trial was conducted from Oct 2013 until Nov 2016. Therefore an interdisciplinary questionnaire was developed. Overall 250 patients with histological confirmed MA were included with different cancer entities (gynecological, gastrointestinal). The correlation of MA caused symptoms and QoL measurements was assessed using Kendall's tau b. Multivariable logistic regression models were applied to analyze the risks of symptoms or severe limitation in daily activities. RESULTS: 125 questionnaires could be analyzed. The majority of patients with MA had diagnosis of ovarian cancer (68.8%) and were under current cancer treatment (57.6%), mostly chemotherapy. Over 50% reported abdominal tension as major symptom, around 56% of the patients had MA when cancer was firstly diagnosed. Regression analysis showed that patients with MA above 2l were significantly more likely to be harmed in everyday activities. However, the age, gender, type of malignancy and the current treatment (chemotherapy vs. no chemotherapy) had no significant influence. CONCLUSION: MA has a significantly impact on QoL measurements in cancer patients and might influence everyday activities including basic needs like eating, walking and body care. There is a high need for more information and education of patients with MA.

Health resource utilisation associated with skeletal-related events in patients with bone metastases secondary to solid tumours: regional comparisons in an observational study.

Skeletal-related events (SREs) including spinal cord compression, pathologic fracture, and radiation or surgery to bone, occur frequently due to bone metastases in advanced cancer. This analysis of a multicentre, observational study was designed to describe cross-regional differences in health resource utilisation (HRU) of SREs in Western Europe and the US. Patients with bone metastases due to breast, lung or prostate cancer, or multiple myeloma who had experienced a SRE within the past 97 days were enrolled. Investigators recorded HRU associated with SREs, including hospitalisation and length of stay (LOS), outpatient visits, procedures and bisphosphonate use. This subanalysis includes 668 patients with solid tumours (US, n = 190 with 354 SREs; EU, n = 478 with 893 SREs). The rate of SREs associated with hospitalisation(s) was higher in the EU vs. the US (30% vs. 15%, P < 0.001) and LOS was longer in the EU [mean (SD) days/SRE: 19.87 (17.31) vs. 10.61 (9.39)]. However, the US was associated with higher rate of SREs with outpatient visits than the EU (88% vs. 74%, P < 0.0001) and more procedures [mean (SD)/SRE: 11.26 (7.94) vs. 6.91 (6.48)]. Bisphosphonates were less often used in the EU (65% vs. 76% of US, P = 0.0033). In patients experiencing SREs due to bone metastases, HRU patterns reflect regional diversity with a substantial burden in both regions.

ABC3 Consensus Commented from the Perspective of the German Guidelines: Third International Consensus Conference for Advanced Breast Cancer (ABC3), Lisbon, 07. 11. 2015.

The Third International Consensus Conference for Advanced Breast Cancer ABC3 on the diagnosis and treatment of advanced breast cancer was held in Lisbon from 5 to 7 November 2015. This year the focus was the treatment of metastatic breast cancer (stage IV) - including the patient perspectives. Important topics were questions relating to quality of life, the care for long-term survivors as well as the management of disease-related symptoms and treatment-based side effects. The use of standardised tools to assess individual treatment success and the benefits of new substances were important points for discussion. The diagnosis and treatment of inoperable locally advanced breast cancer were discussed two years ago during the ABC2 consensus 1. A working group of German breast cancer experts commented on the results of the ABC panellists, paying particular attention to the German guidelines (AGO, S3, DGHO) on the diagnosis and treatment of breast cancer 2, 3, 4, 5 in Germany.

Neurocognitive function, brain-derived neurotrophic factor (BDNF) and IL-6 levels in cancer patients with depression.

BACKGROUND: Increased IL-6 and decreased brain-derived neurotrophic factor (BDNF) levels have been implicated in the pathophysiology of depression. The objective was to assess the influence of BDNF and IL-6 on cognitive function and depression in patients with cancer. METHODS: Serum BDNF and plasma IL-6 were measured in patients with metastatic cancer. Diagnosis of depression was established according to DSM-IV criteria. Cognitive function was assessed by the Verbal Learning and Memory Test (VLMT). RESULTS: A total of 59 patients were recruited in this study. Only IL-6 levels were significantly elevated in patients with clinical depression (35.7 vs. 6.9 pg/ml; p<0.001). There were no differences in hemoglobin levels (p=0.3) or BDNF levels (p=0.16). Patients with clinical depression showed significant impairment of short-term memory (STM) (24.4 vs. 37.5; p=0.01), but not of long-term memory (LTM) (3.9 vs. 2.8; p=0.3). STM was dependent on the level of BDNF and younger age (b=0.60; p=0.001; b= -0.63; p=0.003, respectively). IL-6 was not only strongly associated with depression, but was an independent predictor of BDNF level as well (b= -0.50; p=0.01). LTM was associated only with a good KPS (b=0.47; p=0.037). Hemoglobin levels and the prior number of chemotherapy lines were not predictive of memory performance. CONCLUSIONS: Low BDNF is associated with cognitive impairment, STM, in patients with cancer, however no influence on depression could be found. IL-6 is strongly associated with depression and an independent predictor of BDNF levels.

Breast Cancer Update 2014 - Focus on the Patient and the Tumour.

The therapy for patients with breast cancer has developed markedly in the past ten years. Our understanding of the molecular biology of tumours and the characteristics of the patients has shaped the recent advances. In this review we present the latest knowledge about the therapy for breast cancer. There are new tests and options not only in the field of anti-HER2 therapy but also in the management of triple negative and hormone receptor-positive patients. Comprehension of prognosis and therapeutic response to chemotherapies is little by little helping to define patient groups who will not respond to chemotherapy or who do not need treatment because their prognosis is extremely good. In the field of anti-HER2 therapy, work is continuing on the development of drugs suitable for and able to overcome trastuzumab resistance. For hormone receptor-positive cancers, we now have a better understanding of which therapy groups will benefit from which anti-endocrine drugs, and which will be able to overcome a possible resistance (treatment of the PI3K pathways, inhibition of the cell cycle). Molecular tests are still being evaluated with regard to the clinical situations in which they may have the greatest relevance for therapeutic decision-making; however, evidence is also increasing as to the fields in which good predictions for the prognosis can be obtained. On the whole, more work is needed to promote our understanding of the new developments in diagnostics and therapy and to involve both physicians and patients equally in the procedures.

Biomarkers in Patients with Metastatic Breast Cancer and the PRAEGNANT Study Network.

Progress has been made in the treatment of metastatic breast cancer in recent decades, but very few therapies use patient or tumor-specific characteristics to tailor individualized treatment. More than ten years after the publication of the reference human genome sequence, analysis methods have improved enormously, fostering the hope that biomarkers can be used to individualize therapies and offer precise treatment based on tumor and patient characteristics. Biomarkers at every level of the system (genetics, epigenetics, gene expression, micro-RNA, proteomics and others) can be used for this. This has led to changes in clinical study designs, with drug developments often only focusing on small or very small subgroups of patients and tumors. The screening and registration of patients and their molecular tumor data has therefore become very important for the successful completion of clinical studies. This new form of medicine presents particular challenges for patients and physicians. Even in this new age of genome-wide analysis, the focus should still be on the patients' quality of life. This review summarizes recent developments and describes how the PRAEGNANT study network manages the aforementioned medical challenges and changes to create a professional infrastructure for patients and physicians.

A survey of treatment approaches of malignant ascites in Germany and Austria.

BACKGROUND: Malignant ascites (MA) is a common manifestation of advanced cancer. Currently, there are no evidence-based guidelines for the management of MA. We conducted a survey with physicians throughout Germany and Austria, to get an overview of current approaches and opinions in the treatment of MA. METHODS: One hundred and twenty-eight medical oncologists (MO), gastroenterologists (GE), and gynecologists (GYN) completed an electronic questionnaire consisting of 33 questions. RESULTS: Ninety percent of the physicians were from Germany and 10% from Austria; 48% of those were MO, 30% were GYN, and 14% were GE. Most physicians treated an average of 34 patients (pts)/year with MA. Twenty-six percent of these pts suffered from ovarian, 20% from pancreatic, 17% from gastric, and 14% from colorectal cancer. The majority of the physicians associated MA with poor prognosis (92%) and significant reduction in quality of life (87%). One third felt that MA was a contraindication for full dosing of systemic chemotherapy. Paracentesis (PC) was performed in 70% of pts with symptom relieve and quality of life being the main reasons. Almost half of the pts required 3-5 PC, 50% even more than 5 PC during the course of their disease. Only 15% of pts needed multiple PC per week; the majority (79%) needed the procedure either once a week or every 14 days. In 61% of pts, 3-5 L of ascites fluid was drained. Only in 8%, 5 L and more were removed. Volume substitution with IV albumin was performed in 40% of pts. Most pts (55%) had to stay 1-3 h in a healthcare facility for the procedure. However, 21% had to stay ≥1 day. While almost all physicians (89%) performed a PC at some point in the treatment of MA, 75% felt that a systemic chemotherapy and 55% thought a concomitant diuretic therapy were a necessary adjunct. Seven percent of the pts received a targeted treatment with catumaxomab. CONCLUSIONS: Repeated PC is the main pillar of treatment of MA; its effect is only temporary and requires significant hospital resources. Further treatment strategies of MA have to be evaluated in prospective studies. Targeted therapies like catumaxomab and VEGF inhibitors should be integrated into these.

Influence of comorbidity, age and performance status on treatment efficacy and safety of cetuximab plus irinotecan in irinotecan-refractory elderly patients with metastatic colorectal cancer.

BACKGROUND: We investigated the influence of comorbidity, Eastern Cooperative Oncology Group (ECOG) performance status and age on the efficacy and safety profile of cetuximab and irinotecan in elderly irinotecan-pretreated patients with mCRC. METHODS: 497 patients with mCRC were entered in the database of this non-interventional study (NIS). Comorbid conditions were recorded. RESULTS: A total of 247 and 250 patients aged <65 and >65 years, respectively, with a median age of 66 y were documented; 78% of the patients showed a reduced ECOG status. Grade III/IV toxicities occurred in 18% of patients without any difference between age groups although older patients had more comorbidities with a higher Charlson Comorbidity Index (CCI) (p = 0.002). Skin rash was strongly related to response (p = 0.006). Age, line of therapy, ECOG, gender and CCI had no influence on response. The objective response rates were similar: 38.1% for age <65 years versus 36.4% for age >65 years (p = 0.57). Progression-free survival (PFS) did not differ between patients 18-65 years (6.0 months) and patients >65 years (6.2 months; p = 0.99). Only PS had a negative impact on PFS (hazard ratio (HR): 0,499; 95% confidence interval (CI) 0.34-0.72; p=0.002), whereas the presence of skin toxicity (grade>1) influenced PFS and response rate (RR) positively (HR: 2.04; 95% CI, 1.6-2.6; p<0.001). CONCLUSIONS: Only PS and age had a negative influence on PFS irrespective of CCI or age. There were no significant differences in response rate and safety profile for elderly patients when treated with cetuximab and irinotecan. Comorbidities and age had no influence on efficacy or toxicity.

Health resource utilization associated with skeletal-related events in patients with bone metastases: Results from a multinational retrospective - prospective observational study - a cohort from 4 European countries.

BACKGROUND: Skeletal-related events (SREs; pathologic fracture, radiation or surgery to bone, spinal cord compression) frequently occur in patients with advanced cancer with bone metastases/lesions. Limited data on the associated patient and economic burden are available to aid in resource planning and evaluating treatment options. METHODS: Patients with bone metastases/lesions secondary to breast, lung or prostate cancer or multiple myeloma; with at least one SRE within 97 days prior to enrollment; life expectancy of at least 6 months; and Eastern Cooperative Oncology Group performance status 0, 1 or 2 were recruited. Information on health resource utilization (HRU; including number/duration of hospitalizations, outpatient visits, procedures), attributed by investigators to be associated with a SRE, was collected retrospectively for up to 97 days prior to enrollment and prospectively for up to 18-21 months. RESULTS: A total of 631 patients contributing 1282 SREs, were enrolled across Germany, Italy, Spain and the United Kingdom. Approximately a third of all SREs required an inpatient stay. Mean duration of inpatient stay for patients with SREs requiring one ranged from 8.4 to 41.1 days across all countries and SRE types. CONCLUSION: All types of SREs are associated with substantial HRU burden. Preventing SREs by using the best therapeutic options available may help to reduce the burden to patients and healthcare systems.

Cost of skeletal-related events in European patients with solid tumours and bone metastases: data from a prospective multinational observational study.

OBJECTIVES: Patients with bone metastases often experience skeletal-related events (SREs: radiation or surgery to bone, pathologic fracture, and spinal cord compression). This study examined health resource utilization and costs associated with SREs. METHODS: Data presented are from the European cohort (Germany, Italy, Spain, and the UK) of patients with solid tumours enrolled in a multi-national, prospective, observational study in patients with solid tumours or multiple myeloma. Patients with Eastern Cooperative Oncology Group score 0-2 and life expectancy ≥6 months, who experienced an SRE up to 97 days before enrolment, were eligible. Health resource utilization associated with SREs (including number/length of inpatient stays, numbers of procedures and outpatient visits) were collected through chart review for up to 97 days before enrolment and prospectively during follow-up. Country-specific cost calculations were performed. RESULTS: In total, 478 eligible patients contributed 893 SREs to this analysis. Radiation to bone occurred most frequently (66% of total). Spinal cord compression (7%) and surgery to bone (10%) were the least common events, but most likely to require inpatient stays. The most costly SREs were also spinal cord compression (mean per SRE across countries, €4884-€12,082) and surgery to bone (€3348-€9407). Inpatient stays were the main cost drivers. LIMITATIONS: Health resource utilization used to calculate the costs associated with SREs may have been under-estimated as a result of exclusion of patients with low performance status or life expectancy; unavailable information and exclusion of resource consumption associated with pain. Thus, the estimate of associated costs is likely to be conservative. CONCLUSIONS: SREs result in considerable health resource utilization, imposing a substantial financial burden driven by inpatient stays. Treatments that prevent/delay SREs may help ease this burden, thereby providing cost savings across European healthcare systems.

Influence of age, performance status, cancer activity, and IL-6 on anxiety and depression in patients with metastatic breast cancer.

Depression and anxiety are the core disorders causing emotional distress in patients (pts) with metastatic breast cancer. The aim of our study was to screen metastatic breast cancer outpatients for anxiety and depression, and to investigate the influence of age, Karnofsky Performance Status (KPS), cancer activity, and inflammation as represented by IL-6 levels on these two mood disorders. Pts treated with chemotherapy for metastatic breast cancer (n = 70) were assessed using the Hospital Anxiety and Depression Scale (HADS) for symptoms (scores 0-21) and caseness (score ≥11) of clinical depression and anxiety. Blood samples for IL-6 concentrations were collected at 10:00 a.m. A total of 22 (31.4 %) pts were diagnosed with caseness of clinical depression and 23 (32.9 %) pts with clinical anxiety, while 12 pts were diagnosed positive for both mood disorders. Depression and anxiety were positively but moderately correlated (Spearman's r (2) = 0.24, p < 0.001). IL-6 was significantly correlated with symptoms of depression (r (2) = 0.42, p < 0.001) and to a lesser extent to symptoms of anxiety (r (2) = 0.16, p = 0.001). In addition, IL-6 was positively associated with tumor progression (p < 0.001). Multiple linear regression analysis showed that tumor progression (standardized b = 0.226, p = 0.047), symptoms of anxiety (b = 0.292, p = 0.016), and IL-6 (b = 0.314, p = 0.007) were independently associated with clinical depression, whereas anxiety was linked to tumor progression (b = 0.238, p = 0.030), symptoms of depression (b = 0.407, p < 0.001) and age (b = -0.381, p < 0.001), but not to IL-6 (b = 0.168, p = 0.134). Even though a positive correlation between depression and anxiety exists, clinical parameters like age, cancer activity, KPS, and IL-6 do influence depression and anxiety differently. Unlike clinical depression, anxiety is not associated with increased IL-6 levels, however, shows a reciprocal correlation with age.

Cetuximab-based therapy in elderly comorbid patients with metastatic colorectal cancer.

BACKGROUND: Clinical trials under-represent patients (pts) >65 years. Non-interventional studies (NISs) help to evaluate therapies in daily practice. This NIS evaluates efficacy and safety of cetuximab in combination with chemotherapy in metastatic colorectal cancer (mCRC) pts aged >65 years vs ≤ 65 years. METHODS: A total of 657 pts were recruited into the NIS and analysed applying descriptive statistics and χ(2) or Fisher's exact test. RESULTS: A total of 309 and 305 pts aged ≤ 65 and >65 years, respectively, were documented; 80% showing a reduced ECOG status of 1-2 and 95% having received at least one palliative treatment. Cetuximab was combined with irinotecan according to approval status. Grade III/IV toxicities occurred in 20% of pts without any difference between age groups although the older pts had significantly more pre-existing comorbidities (P=0.001). A total of 64.2% of the pts developed skin rash, which was strongly related to response (P<0.0002) without any difference between age groups (P=0.34). The objective response rates were 37.9% for ages 18-65 years vs 35.4% for >65 years. Progression-free survival (PFS) did not differ between pts 18-65 years old (6.5 months) in comparison with pts >65 years (7.0 months). In a multivariate analysis only ECOG status had a negative impact on PFS (HR: 0,675; 95% Cl, 0.53-0.87; P=0.0019). CONCLUSION: This NIS reports one of the largest mCRC collectives >65 years and reduced performance status. Cetuximab has a similar efficacy and safety profile for pts aged ≤ 65 and >65 years.

Advances in Breast Cancer - Looking Back over the Year.

Treatment options as well as the characteristics for therapeutic decisions in patients with primary and advanced breast cancer are increasing in number and variety. New targeted therapies in combination with established chemotherapy schemes are broadening the spectrum, yet not every new, promising combination achieves a better result. New data from the field of pharmacogenomics point to prognostic and predictive factors that take not only the properties of the tumour but also the genetic disposition of the patient into consideration. Current therapeutic decision-making is thus based on a combination of classical clinical and modern molecular biomarkers. Health-economic concerns are also being taken into consideration more frequently, meaning political decisions may also become a factor. This review presents the trends over the past year.

Breast Cancer 2012 - New Aspects.

Treatment options as well as the characteristics for therapeutic decisions in patients with primary and advanced breast cancer are increasing in number and variety. New targeted therapies in combination with established chemotherapy schemes are broadening the spectrum, however potentially promising combinations do not always achieve a better result. New data from the field of pharmacogenomics point to prognostic and predictive factors that take not only the properties of the tumour but also inherited genetic properties of the patient into consideration. Current therapeutic decision-making is thus based on a combination of classical clinical and modern molecular biomarkers. Also health-economic aspects are more frequently being taken into consideration so that health-economic considerations may also play a part. This review is based on information from the recent annual congresses. The latest of these are the 34th San Antonio Breast Cancer Symposium 2011 and the ASCO Annual Meeting 2012. Among their highlights are the clinically significant results from the CLEOPATRA, BOLERO-2, EMILIA and SWOG S0226 trials on the therapy for metastatic breast cancer as well as further state-of-the-art data on the adjuvant use of bisphosphonates within the framework of the ABCSG-12, ZO-FAST, NSABP-B34 and GAIN trials.

First safety and response results of a randomized phase III study with liposomal platin in the treatment of advanced squamous cell carcinoma of the head and neck (SCCHN).

BACKGROUND: Cisplatin is one of the most active chemotherapeutic agents used in the treatment of advanced squamous cell carcinoma of the head and neck (SCCHN). However, its clinical efficacy is limited by its renal and hematotoxicity profile. In a randomized, multicenter phase III trial, we replaced conventional cisplatin by a liposomal formulation of cisplatin (lipoplatin) and compared the safety and efficacy profiles of patients in the two treatment arms. PATIENTS AND METHODS: Main inclusion criteria were: histologically confirmed SCCHN, age between 18-75 years with sufficient renal function. Main endpoints for this interims analysis were hemato- and nephrotoxicity. First response data were collected. RESULTS: Forty-six patients were evaluable for outcome and toxicity. Grade III and IV hematotoxicity were more frequent in the cisplatin arm (31.7% vs. 12%), with grade IV leucopenia occurring in 22.2%. However, 16% of the patients in that treatment arm experienced grade III anemia compared to only 9.5% treated with the cisplatin regimen. A total 4% of the patients in the lipoplatin arm developed grade IV neuropathy, whereas in the cisplatin arm, 19% developed grade III neuropathy and none developed grade IV. The renal toxicity profile of both drugs also showed marked differences. In the cisplatin arm, 23.8% of patients suffered grade III toxicity. In contrast, no grade III or IV renal toxicity occurred in patients treated with lipoplatin. The efficacy results showed 38.8% objective partial remission in the cisplatin arm vs. 19% in the lipoplatin arm. However 64% of the patients achieved stable disease while being treated with lipoplatin/5-fluorouracil (5-FU), vs. 50% in the cisplatin/5-FU arm. CONCLUSION: Liposomal cisplatin seems to reduce both the renal and hematological toxicity to a clinically relevant extent as compared to conventional cisplatin. The clinical benefit rate is similar for both regimens.

Significant changes in circulating plasma levels of IGF1 and IGFBP3 after conventional or dose-intensified adjuvant treatment of breast cancer patients with one to three positive lymph nodes.

The insulin-like growth factor 1 (IGF1) and its binding protein IGFBP3 (insulin-like growth factor binding protein 3) play a pivotal role during the growth and development of tissues. The purpose of this study was to evaluate the influence of anthracycline- and taxane-containing adjuvant chemotherapy in breast cancer patients on the circulating plasma levels of IGF1 and its main binding protein, IGFBP3. This investigation was part of a prospective randomized phase III study in which breast cancer patients were treated with either conventional or dose-intensified adjuvant chemotherapy. The factors were quantified in the plasma of 151 patients with a commercially available sandwich enzyme immunoassay. Before therapy, both parameters were within the normal range in most patients (n=145 and n=144). After therapy, both factors had increased significantly by 29% (IGF1) and 19% (IGFBP3), with the highest increase being observed in the dose-intensified group. Correlations with patient and tumor characteristics revealed a relatively higher increase in both parameters in premenopausal patients, patients with lower-grade tumors, more positive lymph nodes, larger tumor volume, and positive hormone receptor status. No correlation was found with the HER2 expression of the tumors.

Clinical value of bisphosphonates in cancer therapy.

The therapeutic opportunities for an improved management of malignant bone disease are currently extensively studied. The conventional management of symptomatic bone lesions in patients with advanced cancer involves various combinations of local and systemic standard anticancer therapies and the symptomatic treatment of skeletal complications. In recent years, bisphosphonates have demonstrated high efficacy to avoid skeletal complications from metastatic bone lesions and to prevent cancer treatment-induced bone loss. Especially in the treatment of patients with bone metastases, secondary to breast cancer, a widespread use of bisphosphonates has been established. With the development of highly potent new-generation bisphosphonates, such as zoledronate, the therapeutic opportunities for bisphosphonates are going to expand. Several current studies have investigated the benefit of zoledronate therapy for bone metastases from a variety of tumor types, including prostate cancer, lung and renal cell cancer and multiple myeloma. Furthermore, bisphosphonates have been shown to significantly reduce antineoplastic therapy-induced bone loss. According to recently published data, it is suggested that bisphosphonates not only play a role in the inhibition of osteoclast-mediated bone resorption, but also have antitumor effects inhibiting tumor cell proliferation, adhesion and invasion, as well as angiogenesis and induction of apoptosis. Further preclinical and clinical investigations are necessary to elucidate the role of bisphosphonates, and large randomized clinical trials should be conducted to confirm the clinical value of bisphosphonates for the prevention of relapse, as well as for the maintainance of net bone density, e.g. during aromatase inhibitor therapy.

The amino-terminal propeptide (PINP) of type I collagen is a clinically valid indicator of bone turnover and extent of metastatic spread in osseous metastatic breast cancer.

BACKGROUND: The efficacy control for the treatment of bone metastases in breast cancer is difficult and usually initiated later and with longer time between treatment cycles than the restaging of visceral or soft tissue metastases. The amino-terminal propeptide (PINP) of type I collagen as a biochemical indicator of bone turnover might facilitate early and valid disease surveillance. The utility of total PINP was investigated in metastatic breast cancer patients, with or without bone metastases (for monitoring of therapy). The results were compared to the established markers, osteocalcin and beta-carboxyterminal telopeptide (CTX) or crosslaps concentration. PATIENTS AND METHODS: Baseline serum samples of 51 patients with metastastic breast cancer under chemotherapy were investigated. In total, 38 patients had been diagnosed with bone metastases while 13 had no evidence of metastastic spread to the bone. All the patients with bone spread received bisphosphonates in addition to systemic chemotherapy and/or antibody therapy or hormonal treatment. Osteocalcin, CTX and PINP levels were measured on an Elecsys 2010 analyzer (electrochemiluminescence immunoassay--ECLIA). The normal cut-off values were: osteocalcin < 41.3 pg/ml, CTX < 1008 pg/ml and PINP < 95 ng/ml. Based on overall treatment outcome, the patients were grouped as responders (CR/PR), with stable disease (SD) or displaying primary progression (PD). RESULTS: The baseline levels of PINP were significantly higher in patients with bone metastases (median: 92.8 ng/ml) than in those without (median: 63.2 ng/ml, p = 0.044). Patients with more than seven bone metastases had significantly higher PINP levels (median: 149.7 ng/ml) than those with fewer than seven (median: 67.6 ng/ml, p = 0.04). Significant differences were also found for osteocalcin and CTX, at p = 0.02 and p = 0.04, respectively, although the median levels remained under the normal cut-off levels. In terms of response assessment of bone spread, the PINP concentrations decreased in responders from 194.3 ng/ml to 100.4 ng/ml (p = 0.23). In patients with SD, PINP remained at the same level of approximately 70 ng/ml (p = 0.16), but increased in patients with PD from 83.4 ng/ml to 176.5 ng/ml (p = 0.14). These trends rather than statistical difference were probably due to the limited patient cohort. No differences were found for the serum concentrations of PINP, CTX and osteocalcin between post- and pre-menopausal women. CONCLUSION: The PINP levels of the osseous metastatic breast cancer patients were elevated at baseline in comparison to those without bone involvement; the levels correlated to the number of bone metastases but were independent of the menopausal status. Thus, the levels of PINP under therapy might correlate with the response to therapy. Osteocalcin and CTX did not show similar sensitivity for the surveillance of bone metastases.