Prescribing Exercise to Cancer Patients Suffering from Increased Bone Fracture Risk Due to Metastatic Bone Disease or Multiple Myeloma in Austria-An Inter- and Multidisciplinary Evaluation Measure.

INTRODUCTION: In the current absence of specific functional fracture risk assessment technology, the planning of physical exercise interventions for cancer patients suffering from increased bone fracture risk remains a serious clinical challenge. Until a reliable, solely technical solution is available for the clinician, fracture risk assessment remains an inter- and multidisciplinary decision to be made by various medical experts. The aim of this short paper is depicting how this challenge should be approached in the clinical reality according to Austrian experts in cancer rehabilitation, presenting the best-practice model in Austria. Following referral from the specialist responsible for the primary cancer treatment (oncologist, surgeon, etc.), the physiatrist takes on the role of rehabilitation case manager for each individual patient. Fracture risk assessment is then undertaken by specialists in radiology, orthopedics, oncology, and radiation therapy, with the result that the affected bone regions are classified as being at highly/slightly/not increased fracture risk. Following internal clearance, exercise planning is undertaken by a specialist in exercise therapy together with the physiatrist based on the individual's fracture risk assessment. In the case in which the patient shows exercise limitations due to additional musculoskeletal impairments, adjuvant physical modalities such as physiotherapy should be prescribed to increase exercisability. CONCLUSION: Exercise prescription for cancer patients suffering from increased fracture risk is an inter- and multidisciplinary team decision for each individual patient.

Cancer rehabilitation: current trends and practices within an Austrian University Hospital Center.

Background: Cancer rehabilitation has the goal to improve functional status, quality of life, participation, and can improve quality of patient-centered programs and health care efficiencies. In Austria, inpatient cancer rehabilitation is well established but outpatient rehabilitation has not yet established well.Methods: The present article is describing current rehabilitation in practice and focuses on cancer rehabilitation in Austria, namely bringing together a descriptive account of current trends and practices within an Austrian University Hospital Center (General Hospital of Vienna linked to the Medical University of Vienna) and the Comprehensive Cancer Centre (CCC) Vienna, Austria.Results: Cancer Rehabilitation in the described Austrian University Hospital Center is well developed due to the help of all different clinics dealing with cancer patients and of the opinion leaders of the CCC Vienna. The Department of Physical Medicine, Rehabilitation, and Occupational Medicine of the Medical University of Vienna as a part of the CCC Vienna with his "Pioneer-Status" and the described milestones has been integrated in the national cancer rehabilitation concept of our country from the beginning.Conclusions: Also in Austria, Physical Medicine and Rehabilitation with competencies in diagnostic and therapy as well as of coordination of the multiprofessional and interdisciplinary rehabilitation teams is an important part of cancer rehabilitation.Implications for rehabilitationCancer rehabilitation is an important part in the treatment and care of cancer patients with the goal to improve functional status, quality of life, and participationCancer rehabilitation helps cancer survivors to be integrated in their normal live, namely to increase social participation and/or workabilityThe field of Physical Medicine and Rehabilitation with competencies in diagnostic and therapy as well as of coordination of the multi-professional and interdisciplinary rehabilitation teams is an important part of cancer rehabilitationInterventions and treatment approaches from the field of Physical Medicine and rehabilitation include the application of Physical Modalities like electrotherapy, thermotherapy, balneology and climatic therapy, phototherapy, and mechanotherapy Cancer rehabilitation has to be early integrated into the cancer care continuum.

Cancer rehabilitation in Austria--aspects of Physical Medicine and Rehabilitation.

In Austria, cancer rehabilitation is an important issue in the management of cancer patients. Survival rates and survival time of cancer patients are increasing, and cancer rehabilitation is an important part in the treatment and care of cancer patients with the goal to improve functional status, quality of life, and (social) participation. Today, in Austria there are approximately 600 beds for inpatient rehabilitation. The field of outpatient rehabilitation will maybe be expanded after evaluating the existing pilot projects. Beside other specialities, the field of Physical Medicine and Rehabilitation (PM&R) plays an important role in cancer rehabilitation. In cancer rehabilitation, especially activating modalities from PM&R such as exercise are very important and well-accepted parts to improve functional status, quality of life, and participation of patients.

Impact of HER-2-targeted therapy on overall survival in patients with HER-2 positive metastatic breast cancer.

Upon disease progression on trastuzumab-based therapy, patients with HER-2 positive metastatic breast cancer (MBC) may switch to lapatinib or continue on trastuzumab. We aimed to assess the impact of both strategies on overall survival (OS) in all patients treated for HER-2 positive MBC at the Medical University Vienna from 1999 until 2009. A total of 201 patients were identified from a breast cancer data base. Of these 115 (57.2%) received multiple lines of trastuzumab-based therapy, whereas 58 (28.9%) were treated with a single line. A control group of 28 patients (13.9%) had never received trastuzumab as they were treated before 1999, when trastuzumab was registered. OS from diagnosis of metastatic disease was defined as primary study endpoint. Trastuzumab significantly prolonged OS in HER-2 positive MBC (41 versus 13 months; p < 0.001). Administration of multiple lines further improved OS; this, however, did not reach statistical significance (47 versus 28 months; p = 0.069). Positive estrogen receptor (ER) status (HR 1.6; 95% CI 1.13-2.27) was associated with better outcome compared to negative estrogen receptor status (p = 0.02). Addition of lapatinib did not improve OS significantly in patients with prior trastuzumab-based therapy (62 versus 47 months; p = n.s.). Patients receiving lapatinib after diagnosis of BM, however, experienced an improvement of OS (22 versus 5 months; p = 0.022). Trastuzumab improves OS in patients with HER-2 positive MBC with further nonsignificant improvement when administered in multiple lines. Lapatinib did not further improve OS in the entire population; however, lapatinib might improve OS in patients with BM.

Concomitant docetaxel plus gemcitabine versus sequential docetaxel followed by gemcitabine in anthracycline-pretreated metastatic or locally recurrent inoperable breast cancer patients: a prospective multicentre trial of the Central European Cooperative Oncology Group (CECOG).

Docetaxel (D) plus gemcitabine (G) is an active combination in anthracycline pre-treated breast cancer. Impact of sequential administration of these drugs is unclear. This trial aimed to compare concomitant DG with sequential D --> G. Patients were randomised to eight cycles of gemcitabine 1,000 mg/m2 on days 1 + 8 plus docetaxel 75 mg/m2 on day 8, or 4 cycles of docetaxel 100 mg/m2 on day 1, followed by four cycles of gemcitabine 1,250 mg/m2 on days 1 + 8, in a 21-day schedule. Time to progression (TTP) was defined as primary endpoint; secondary endpoints were overall response rate (ORR), response duration (RD), overall survival (OS) and toxicity. Due to poor recruitment, the trial was terminated after 100 of a pre-planned 430 patients. Patient characteristics were well balanced. No significant difference was observed in terms of TTP, ORR, RD and OS. Grade 3/4 adverse events encompassed leucopoenia (29 vs.68%, P < 0.001), neutropoenia (49 vs. 83%, P < 0.001) and febrile neutropoenia (4 vs. 9%, n.s.), all favouring D --> G. No difference in efficacy was observed between concomitant and sequential treatment. D --> G produced significantly more episodes of haematological toxicity due to the administration of docetaxel at 100 mg/m2 without GCSF support.

Predicting for activity of second-line trastuzumab-based therapy in her2-positive advanced breast cancer.

BACKGROUND: In Her2-positive advanced breast cancer, the upfront use of trastuzumab is well established. Upon progression on first-line therapy, patients may be switched to lapatinib. Others however remain candidates for continued antibody treatment (treatment beyond progression). Here, we aimed to identify factors predicting for activity of second-line trastuzumab-based therapy. METHODS: Ninety-seven patients treated with > 1 line of trastuzumab-containing therapy were available for this analysis. Her2-status was determined by immunohistochemistry and re-analyzed by FISH if a score of 2+ was gained. Time to progression (TTP) on second-line therapy was defined as primary study endpoint. TTP and overall survival (OS) were estimated using the Kaplan-Meier product limit method. Multivariate analyses (Cox proportional hazards model, multinomial logistic regression) were applied in order to identify factors associated with TTP, response, OS, and incidence of brain metastases. p values < 0.05 were considered to indicate statistical significance. RESULTS: Median TTP on second-line trastuzumab-based therapy was 7 months (95% CI 5.74-8.26), and 8 months (95% CI 6.25-9.74) on first-line, respectively (n.s.). In the multivariate models, none of the clinical or histopthological features could reliably predict for activity of second-line trastuzumab-based treatment. OS was 43 months suggesting improved survival in patients treated with trastuzumab in multiple-lines. A significant deterioration of cardiac function was observed in three patients; 40.2% developed brain metastases while on second-line trastuzumab or thereafter. CONCLUSION: Trastuzumab beyond progression showed considerable activity. None of the variables investigated correlated with activity of second-line therapy. In order to predict for activity of second-line trastuzumab, it appears necessary to evaluate factors known to confer trastuzumab-resistance.

Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial.

PURPOSE: The primary objective of this randomized phase III study was to show significant difference in median time to progression (TTP) in patients with advanced NSCLC treated with single-agent gemcitabine maintenance therapy versus best supportive care following gemcitabine plus cisplatin initial first-line therapy. PATIENTS AND METHODS: Chemonaive patients with stage IIIB/IV NSCLC received gemcitabine 1,250 mg/m(2) (days 1 and 8) plus cisplatin 80 mg/m(2) (day 1) every 21 days. Patients achieving objective response or disease stabilization following initial gemcitabine plus cisplatin therapy were randomized (2:1 fashion) to receive maintenance gemcitabine (1,250 mg/m(2) on days 1 and 8 every 21 days) plus best supportive care (GEM arm), or best supportive care only (BSC arm). RESULTS: Between November 1999 and November 2002, we enrolled 352 patients (median age: 57 years; stage IV disease: 74%; Karnofsky performance status (KPS) >80: 41%). Following initial therapy, 206 patients were randomized and treated with gemcitabine (138) or best supportive care (68). TTP throughout the study period was 6.6 and 5 months for GEM and BSC arms, respectively, while values for the maintenance period were 3.6 and 2.0 months (for p < 0.001 for both). Median overall survival (OS) throughout study was 13.0 months for GEM and 11.0 months for BSC arms (p = 0.195). The toxicity profile was mild, with neutropenia being most common grade 3/4 toxicities. CONCLUSION: Maintenance therapy with gemcitabine, following initial therapy with gemcitabine plus cisplatin, was feasible, and produced significantly longer TTP compared to best supportive care alone. Further studies are warranted to establish the place of maintenance chemotherapy in patients with advanced NSCLC.

The efficacy of trastuzumab in Her-2/neu-overexpressing metastatic breast cancer is independent of p53 status.

PURPOSE: Her-2/neu and p53-mediated signalling have been shown to interact at various cellular levels. However, the clinical relevance of p53 alterations in patients receiving trastuzumab for Her-2/neu-overexpressing metastatic breast cancer (MBC) remains unknown. The present study was performed to corroborate previous in vitro findings from our laboratory showing that trastuzumab induces growth arrest and apoptosis in a p53-independent manner. METHOD: Retrospective immunohistochemical (IHC) analysis for p53 protein expression was carried out on tumour specimens from 104 patients receiving trastuzumab-based treatment for Her-2/neu-overexpressing MBC at a single institution. p53 status was correlated with response (R) and clinical benefit (CB), median progression-free survival (PFS) time and overall survival (OAS) time in univariate and multivariate analyses. RESULTS: Characteristics were similar between p53-negative and p53-positive tumours (all P>0.05). In univariate analyses, R (39% vs 26%, P=0.208), CB (70% vs 57%, P=0.218), PFS (6.2 months vs 4.2 months, P=0.186) and OAS (23.8 months vs 23.2 months, P=0.650) were similar for p53-positive tumours and p53-negative tumours, respectively. In multivariate analyses, p53 status was not a significant predictor of R, CB, PFS or OAS (all P>0.05). CONCLUSIONS: p53 status, as determined by IHC, is not a predictor of the clinical efficacy of trastuzumab-based treatment in patients with Her-2/neu-overexpressing MBC.

Gemcitabine, epirubicin, and paclitaxel versus fluorouracil, epirubicin, and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: a Central European Cooperative Oncology Group International, multicenter, prospective, randomized phase III trial.

BACKGROUND: The objectives of this phase III trial were to compare the time to progressive disease (TtPD), overall response rate (ORR), overall survival, and toxicity of gemcitabine, epirubicin, and paclitaxel (GET) versus fluorouracil (FU), epirubicin, and cyclophosphamide (FEC) as first-line therapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Female patients aged 18 to 75 years with stage IV and measurable MBC were enrolled and randomly assigned to either gemcitabine (1,000 mg/m(2), days 1 and 4), epirubicin (90 mg/m(2), day 1), and paclitaxel (175 mg/m(2), day 1) or FU (500 mg/m(2), day 1), epirubicin (90 mg/m(2), day 1), and cyclophosphamide (500 mg/m(2), day 1). Both regimens were administered every 21 days for a maximum of eight cycles. RESULTS: Between October 1999 and November 2002, 259 patients (GET, n = 124; FEC, n = 135) were enrolled. Baseline characteristics were well balanced across treatment arms. After a median of 20.4 months of follow-up, median TtPD was 9.1 months and 9.0 months in the GET and FEC arms, respectively (P = .557). The ORR was 62.3% in the GET arm (n = 114) and 51.2% in the FEC arm (n = 129; P = .093). Grade 3 and 4 toxicities, including neutropenia, thrombocytopenia, anemia, stomatitis, neurosensory toxicity, and allergy, occurred significantly more often in the GET arm. CONCLUSION: No significant differences in terms of TtPD and ORR were observed between the two treatment arms. Treatment-related toxicity was higher in the GET arm.

Single-agent trastuzumab versus trastuzumab plus cytotoxic chemotherapy in metastatic breast cancer: a single-institution experience.

Trastuzumab has shown significant single-agent activity in patients with Her-2/neu overexpressing metastatic breast cancer, and increased response rates, progression-free and overall survival when added to standard chemotherapy. Despite higher response rates, the combination with chemotherapy has higher toxicity and it remains unknown whether single-agent trastuzumab is equally effective as the combined treatment in terms of progression-free and overall survival. We therefore carried out a retrospective multivariate analysis of 117 patients with Her-2/neu overexpressing metastatic breast cancer who were treated with trastuzumab with or without chemotherapy at a single institution between November 1999 and December 2003. Response rates tended to be higher in patients receiving trastuzumab in combination with chemotherapy (34 versus 8%, p=0.060). However, this did not translate into a benefit in progression-free survival: median (95% confidence interval) progression-free survival was 6.2 (4.45-7.95) months in patients receiving trastuzumab plus chemotherapy versus 4.2 (1.77-6.63) months in those receiving single-agent trastuzumab (p=0.560). Likewise, no significant difference in overall survival was observed: 27.0 (19.9-34.0) versus 23.1 (16.2-30.0) months (p=0.809). We conclude that in the absence of extensive visceral involvement necessitating a higher response rate, single-agent trastuzumab may be a safe and less-toxic alternative to its combined use with other chemotherapy agents. This needs to be confirmed in prospective randomized trials.

Monitoring of serum Her-2/neu predicts histopathological response to neoadjuvant trastuzumab-based therapy for breast cancer.

BACKGROUND: This prospective pilot study was performed to elucidate whether early changes in serum levels of the Her-2/neu extracellular domain (ECD) reflect histopathological response to trastuzumab-based neoadjuvant therapy in patients with Her-2/neu-overexpressing breast cancer. PATIENTS AND METHODS: ECD levels were measured throughout neoadjuvant trastuzumab-based treatment in 16 patients using a Her-2/neu Microtiter ELISA. RESULTS: In 9 (56%) patients with Her-2/neu shedding tumors (ECD > 15 ng/ml), ECD values (in % of baseline) of non-responders vs. responders were 117% vs. 55% on day 8 (p=0.014), 157% vs. 58% on day 22 (p=0.061) and 114% vs. 46% at restaging (p=0.049). CONCLUSION: Serial monitoring of serum Her-2/neu ECD levels may represent a valuable tool to predict pathological response to trastuzumab-based neoadjuvant therapy in patients with Her-2/neu-overexpressing tumors.

Monitoring of serum Her-2/neu predicts response and progression-free survival to trastuzumab-based treatment in patients with metastatic breast cancer.

PURPOSE: The present pilot study was performed to elucidate whether early changes in serum Her-2/neu extracellular domain (ECD) levels during trastuzumab-based treatment would predict the clinical course of disease in patients with metastatic breast cancer. EXPERIMENTAL DESIGN: Sera from 55 patients with Her-2/neu-overexpressing metastatic breast cancer obtained immediately before each weekly administration of trastuzumab were analyzed by a serum Her-2/neu ELISA. RESULTS: Whereas response rates were significantly higher in patients with elevated (>or=15 ng/ml) ECD levels before initiation of treatment (35% versus 7%, P = 0.045), progression-free and overall survival did not differ significantly between patients with normal and elevated ECD levels. In patients responding to treatment, ECD levels decreased significantly as early as from day 8 of treatment onwards (all P for weekly measurements versus baseline <0.001). In contrast, no significant change in ECD levels was observed in patients with progressive disease. Multiple logistic regression analyses identified kinetics of ECD levels as the only factor that allowed for the accurate prediction of response likelihood as early as from day 8 of trastuzumab-based treatment onwards (P = 0.020). In addition, determination of serial ECD levels allowed for the prediction of the risk for disease progression within the observed period as early as day 15 of treatment (P = 0.010). CONCLUSIONS: Serial monitoring of the ECD may represent a valuable tool for early prediction of the probability of response and progression-free survival to trastuzumab-based treatment and is thus likely to contribute to an optimization of treatment and resource allocation.

Inhibition of tumor cell growth by antibodies induced after vaccination with peptides derived from the extracellular domain of Her-2/neu.

The anti Her-2/neu monoclonal antibody Trastuzumab has strong inhibiting effects on tumor growth in vitro and in vivo and is therefore used for immunotherapy in breast cancer patients. Due to necessity of frequent applications, however, cost intensiveness of Trastuzumab treatment and its limited duration of affectivity, an active immunization inducing a perhaps preventive and long-term immunity to Her-2/neu remains a desirable goal. We attempted to induce anti Her-2/neu antibodies by peptide vaccination and to test their efficacy in inhibiting tumor cell growth in vitro. By computer aided analyses, 7 putative B cell epitopes of Her-2/neu were defined and synthesized. These peptide epitopes were coupled to tetanus toxoid and used for immunization in BALB/c mice. Among these peptides, immunizations with 2 single peptides or a combination of 2 peptides induced anti-peptide antibody levels, primarily of the IgG1 isotype. These antibodies were also directed against the native Her-2/neu antigen, as shown in precipitation assays and ELISA with cell lysates of the Her-2/neu overexpressing breast cancer cell line SK-BR-3. Isolated IgG fractions from immune sera incubated with SK-BR-3 cells led to a moderate inhibition of the tumor cell growth in vitro, as well as to complement dependent cell lyses comparable to that achieved by incubation with Trastuzumab. Moreover, peptide immunization in rabbits generated anti-Her 2-neu IgG that, in contrast to mouse sera, were able to mediate a 31-46% lysis of SK-BR-3 cells in ADCC experiments. We conclude from our data that immunization with Her-2/neu peptides successfully induced humoral immune response with anti-tumor activity in an animal model.

Defect of tumour necrosis factor-alpha (TNF-alpha) production and TNF-alpha-induced ICAM-1-expression in BRCA1 mutations carriers.

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is a potent cytokine secreted primarily by activated cells from the monocyte/macrophage lineage which exhibits various antitumoral effects including the induction of apoptosis, necrosis, activation of lytic effector cells as well as upregulation of the expression of intercellular adhesion molecule-1 (ICAM-1) which is of decisive importance in the interaction with lymphokine activated killer cells. Previous studies from our laboratory have indicated impaired production of TNF-alpha by monocytes as well as decreased expression of ICAM-1 on monocytes derived from patients with various stages of breast cancer. METHODS: In the present experiments, we have assessed spontaneous as well as lipopolysaccharide (LPS)-induced production of TNF-alpha by as well as expression of ICAM-1 on monocytes derived from healthy females with germline mutations of BRCA1 and from healthy age-matched control females. RESULTS: We report that monocytes derived from healthy women with various germline mutations of BRCA1 had significantly decreased spontaneous (p = 0.03) and LPS-induced (p < 0.001) production of TNF-alpha, as compared to monocytes derived from healthy age-matched control females. In contrast, no difference in LPS- or TNF-alpha-induced production of interleukin-6 was found. Whereas unstimulated monocytes derived from healthy women with germline mutations of BRCA1 and from healthy control women had similar expression of ICAM-1, stimulation with cytokines TNF-alpha and/or interleukin-1 led to a significant increase of ICAM-1 expression on monocytes derived from control females only, but not from BRCA1 germline mutation carriers (p < 0.001). CONCLUSION: We conclude that the presence of germline mutations of BRCA1 was associated with a selective deficiency in spontaneous and LPS-induced production of TNF-alpha and of TNF-alpha-induced ICAM-1 expression on peripheral blood monocytes.