The development of biological therapy is based on growing knowledge regarding the molecular changes required in cells for the development and progression of cancer to occur. Molecular targeted therapy is designed to inhibit the major molecular pathways identified as essential for a specific development. This information, in turn, has led to new opportunities for the treatment of cancer. Normal cells, however, are also dependent on these pathways to maintain their function and, consequently, their survival. Interfering with this function in normal cells may result in the risk of serious adverse effects. One serious adverse effect is the risk of cardiovascular dysfunction. Some targeted therapies, eg, treatment with monoclonal antibodies or angiogenesis inhibitors, have shown an increased risk of cardiac events. Their influence on the cardiovascular system, however, seems to be transient, but there is scarce information about their long-term effects for general use. Previous experience with long-term survivors, in whom the risk for cardiac disease seems to increase in subsequent years, has led to concern about patients treated with molecular therapy. This review assesses the currently available knowledge about the risk of cardiotoxicity in targeted therapy for general use.

The development of biological therapy is based on growing knowledge regarding the molecular changes required in cells for the development and progression of cancer to occur. Molecular targeted therapy is designed to inhibit the major molecular pathways identified as essential for a specific development. This information, in turn, has led to new opportunities for the treatment of cancer. Normal cells, however, are also dependent on these pathways to maintain their function and, consequently, their survival. Interfering with this function in normal cells may result in the risk of serious adverse effects. One serious adverse effect is the risk of cardiovascular dysfunction. Some targeted therapies, eg, treatment with monoclonal antibodies or angiogenesis inhibitors, have shown an increased risk of cardiac events. Their influence on the cardiovascular system, however, seems to be transient, but there is scarce information about their long-term effects for general use. Previous experience with long-term survivors, in whom the risk for cardiac disease seems to increase in subsequent years, has led to concern about patients treated with molecular therapy. This review assesses the currently available knowledge about the risk of cardiotoxicity in targeted therapy for general use.

7504 Background: Surgery is not generally considered standard of care in preoperative pathological verified spread to N2 mediastinal lymph nodes in NSCLC. Methods: Previously untreated histologically verified NSCLC stages T1-3N2M0 were randomized to reg. A (Paclitaxel 225 mg/m2 + Carboplatin AUC6 day 1 q 3 wks for 3 courses, followed by surgery with ipsilateral mediastinal lymph node sampling followed by radiotherapy 2Gy x 30 fractions, 5F/W) or reg. B: same as A without surgery (sequential chemo-radiotherapy). 406 pts were needed to detect a 10% 5-year survival increase with 80% power and type 1-error of 5%. The study was approved by ethical committees. Pts gave informed consent. Results: 170 pts were randomized to A and 171 to B from 1998-2009 when study closed due to concomitant chemo-radiotherapy becoming standard instead of sequential treatment. Median age was 61 years (range 33-76 yrs), 59% were males, 43% had performance status 0. Stages T1N2M0, T2N2M0, and T3N2M0 occurred in 19%, 60%, and 21%, respectively. Adenocarcinoma (ADC) and squamous cell carcinoma occurred in 50% and 29%, respectively. In reg. A, surgery was possible in 132 out of 170 pts (78%), 121 pts (71%) had complete resection while 11 pts (6%) had incomplete resection. Pathological-surgical stage pT0 occurred in 4%. Median progression free survival (PFS), OS and 5-years survival rate were 10 mths, 17 mths, and 20% for A (+ surgery) compared to 8 mths (p=0.144), 15 mths (p=0.172), and 16% (p=0.310) for B, respectively. ADC pts had better OS in A than in B (HR 0.60; p=0.002), and 5-year survivals 20% and 7% (p=0.017) respectively. Stage T1N2 had better OS in A than in B (HR 0.47; p=0.010), 5-year survivals 36% and 17%. Conclusions: There were no statistical overall significant advantage for surgery in addition to chemo-radiotherapy (A) compared to chemo-radiotherapy alone (B) but ADC pts and pts with T1N2 had significantly improved OS and 5-year survival rates in the surgery arm. Current standard treatment for T1-3N2M0 NSCLC is concomitant chemo-radiotherapy which was not used in this study, hence conclusions should be further tested with use of such treatment as reference arm.

The treatment of two major diseases in the Western world, cancer and heart disease, has improved significantly in recent years. Today, many more cancers are curable than in previous years. Cancer treatment often consists of chemotherapy, radiation therapy, and now also targeted therapy. All three types of treatment can lead to an increased risk of developing or of worsening a pre-existent cardiovascular disease either during the treatment, immediately afterward, or several years after cessation of therapy. Anthracyclines, a class of drugs that are also known as anthracycline antibiotics, and the drug cisplatin have contributed to the success of cancer treatment. However, these agents can cause cardiovascular disease during treatment, and studies have shown that the risk of disease persists for many years after treatment stops. Irradiation contributes significantly to this risk when the cardiovascular system is part of the radiation field. If the targeted therapy also inhibits the genes responsible for maintaining the function of the cardiovascular system, development of cardiovascular symptoms is inevitable. Therefore, it is essential to have a cardiovascular endpoint in trials with targeted therapy. When treatment stops, however, the effect on the cardiovascular system appears to cease, but it is not known whether the long-term risk of developing cardiovascular disease increases. Combined, these factors indicate that close cooperation between oncologists and cardiologists is essential to optimally benefit patients with cancer.

Anthracyclines are important in the treatment of numerous malignant diseases but the use is limited by a risk of heart failure (CHF). LVEF (left ventricular ejection fraction) measurements by radionuclide ventriculography with multiple gated acquisition (MUGA) is often used for cardiac monitoring. However, diastolic variables have been proposed as sensitive supplements. It was hypothesized that a change in diastolic filling variables measured by MUGA could identify individuals after epirubicin treatment (ET) in risk of developing heart failure. A retrospective analysis of registered raw data. Individuals completing high-dose ET for breast cancer were selected from a 2-year period. All had MUGA-scans performed prior to and after ET and were observed clinically for late development of CHF. Eleven of 34 individuals developed CHF. A significant LVEF-reduction was recorded after ET with only minor changes in diastolic parameters. Development of CHF was related to dose, entry-blood pressure and inversely to post-epirubicin LVEF. Risk of CHF was high if LVEF <50% (Hazard ratio 3.31). Epirubicin induces considerable decrease in LVEF and a high risk of CHF. The risk of CHF is significantly higher if LVEF is reduced after ET. Diastolic MUGA-variables seem to add little information to conventional measurements of LVEF.

BACKGROUND:Current recommendations that cancer patients receive a maximum cumulative dose of 900 mg/m(2) epirubicin are based on the risk of epirubicin-mediated cardiotoxicity and do not take into account the competing risk of death from cancer. Here, we identify risk factors for cardiotoxicity and overall mortality and determine the cumulative dose of epirubicin that yields a 5% risk for cardiotoxicity for cancer patients from different risk backgrounds.METHODS:Data were collected from 1097 consecutive anthracycline-naive patients treated for metastatic breast cancer with epirubicin. Patients who developed congestive heart failure classified as New York Heart Association class 2 or higher were recorded as having cardiotoxicity. Independent Cox multiple regression analyses for cardiotoxicity and for overall mortality were followed by competing risks analysis, with cardiotoxicity as the primary event and death from all other causes as the competing event. All statistical tests were two-sided.RESULTS:A total of 11.4% of patients developed cardiotoxicity. Risk factors for cardiotoxicity included increased cumulative dose of epirubicin (hazard ratio per every 100 mg/m(2) administered = 1.40, 95% confidence interval = 1.21 to 1.61), patient age, predisposition to cardiac disease, history of mediastinal irradiation, or antihormonal treatment for metastatic disease. Risk factors for death from all other causes (including breast cancer) included lesser dosages of epirubicin, increased tumor burden, prior use of adjuvant chemotherapy, and patient age. The cumulative dosage of epirubicin that carries a 5% risk of cardiotoxicity was lower than previously assumed and was dependent on risks of both cardiotoxicity and overall mortality.CONCLUSION:Maximum cumulative dosages of epirubicin are presented that confer a 5% risk of cardiotoxicity for patients with different sets of risk factors.

Purpose: To report the clinical outcome in 1000 patients with prostate cancer treated with external beam radiotherapy and high-dose-rate 192-Iridium brachytherapy boost in a single institution.

To report the long-term results for treatment of localized carcinoma of the prostate using high dose rate (HDR) brachytherapy, conformal external beam radiotherapy (3D EBRT) and neo-adjuvant hormonal therapy (TAB). From 1998 through 1999, 154 patients with localized prostate cancer were entered in the trial. Biologically no evidence of disease (bNED) was defined at PSA levels < 2 µg/l. In order to compare the results of this treatment with other treatment modalities, the patient's pre-treatment data were used to calculate the estimated 5-year PSA relapse free survival using Kattan's nomograms for radical prostatectomy (RP) and 3D EBRT. After 6 years of follow-up, 129 patients remain alive. The actual 5-year relapse-free survival is 84%. None of the patients demonstrated clinical signs of local recurrence. The median PSA at follow-up among the relapse-free patients was 0.05 µg/l. Among the 80 patients who presented with clinical stage T3 tumours, 55 (68%) were relapse-free. The expected 5-year relapse-free survival using nomograms for RP and 3D EBRT was 54% and 70%, respectively. Late rectal toxicity RTOG grade 3 occurred in 1% of the patients. Late urinary tract toxicity RTOG grade 3 developed in 4% of the patients. Combined treatment, utilizing HDR, 3D EBRT and TAB, produces good clinical results. Rectal toxicity is acceptable. Urinary tract toxicity, most likely can be explained by the fact that during the first years of this treatment, no effort was made to localize the urethra, which was assumed to be in the middle of the prostate.

Self-reported symptoms including urinary, bowel and sexual side effects were investigated prospectively at multiple assessment points before and after combined radiotherapy of prostate cancer including HDR brachytherapy and neoadjuvant androgen deprivation therapy. Between April 2000 and June 2003, patients with predominantly advanced localized prostate tumours subjected to this treatment were asked before treatment and on follow-up visits to complete a questionnaire covering urinary, bowel and sexual problems. The mainly descriptive analyses included 525 patients, responding to at least one questionnaire before or during the period 2–34 months after radiotherapy. Adding androgen deprivation before radiotherapy significantly worsened sexual function. During radiotherapy, urinary, bowel and sexual problems increased and were reported at higher levels up to 34 months, although there seemed to be a general tendency to less pronounced irritative bowel and urinary tract symptoms over time. No side effects requiring surgery were reported. Classic late irradiation effects such as mucosal bleeding were demonstrated mainly during the second year after therapy, but appear less pronounced in comparison with dose escalated EBRT series. In conclusion, despite the high radiation dose given, the toxicity seemed comparable with that of other series but long term (5–10 years) symptom outcome has to be determined.

In order to identify factors predictive of central nervous system (CNS) metastasis, we reviewed the histories of 579 patients treated with epirubicin-based chemotherapy for metastatic breast cancer. Statistical analysis included Kaplan-Meier survival plots, Cox's regression analysis and competing risk analysis using the cumulative incidence. Median follow-up-time was 137 months (range 0-183+). In this period, one hundred and twenty-four patients (21.4%) developed CNS metastasis. Lung, liver, and lymph node metastases and oestrogen receptor negative or unknown tumor were predictive as well. However, increased pretreatment lactate dehydrogenase (LDH) concentration in serum above the upper normal limits was the strongest single risk factor and should therefore be measured. The risk of CNS metastasis differed considerably among risk groups. Patients without risk factors had a cumulative incidence on 9%, compared to a cumulative incidence of 42%, when the serum LDH concentration was elevated to more than twice the upper normal limits.

Strontium-89 is an established alternative for the alleviation of bone pain in prostate cancer. There are few data evaluating the effect on pain of palliative chemotherapy. The aim of this randomized phase II study was to assess and compare the analgesic efficacy of strontium-89 and chemotherapy (FEM=5-FU, epirubicin, and mitomycin C) in 35 patients with disseminated, hormone-refractory prostate cancer suffering from persisting bone pain despite analgesic treatment. In order to minimize the risk for imbalances regarding the two patient groups, a double-blind randomization was performed. A significant reduction in pain intensity and pain frequency was registered in both patient groups (P < 0.01 in both groups after 3 weeks). Side effects were generally mild in the strontium-89 group and significantly more severe in the FEM group. The effect of FEM on pain is surprising as chemotherapy has generally only limited effect on tumor growth in bone metastases due to prostate cancer. A possible explanation is that FEM has an inhibitory activity on the inflammatory component of metastases.

Given the demand for interventions that may prevent the development of persistent musculoskeletal pain problems, we investigated the effects of a cognitive-behavioral program in a group of non-patients with neck or back pain symptoms. Two hundred and fifty-three people selected from a population study were invited to participate. These people had experienced four or more episodes of relatively intense spinal pain during the past year but had not been out of work more than 30 days. Participants were randomly assigned to either a cognitive-behavioral group intervention or a treatment as usual comparison group. The experimental group received a standardized six-session program, provided by a trained therapist according to a manual. A significant overall analysis at the 1-year follow-up showed that the cognitive-behavioral group produced better results on 26 of the 33 outcome variables. Group comparisons indicated that the cognitive-behavioral group, relative to the comparison group, had significantly better results with regard to fear-avoidance beliefs, number of pain-free days, as well as the key variable of sick leave. Participation in the cognitive behavioral group reduced the risk for long-term sick leave during the follow-up by threefold. Thus, despite the strong natural recovery rate for back pain, the cognitive-behavioral intervention produced a significant preventive effect with regard to disability.

Current estimates of the prevalence and consequences of neck and back pain vary greatly between studies. It is not known whether this variance is due to differences in methodology, or if it depends on the dynamics of the problem over time. The aim of this study was consequently an attempt to replicate and extend the findings of a previous epidemiological study using the same methodology on a new population. A survey of 3000 35–45 year olds, selected at randon, was conducted to determine the prevalence, site, frequency and intensity of the pain as well as any work loss or health‐care utilization. The response rate was 69% and an analysis of non‐responders showed that they were very similar to responders, but had a slightly lower prevalence. The results replicated the original study: 73% reported back pain during the past year and the consequences included considerable suffering and functional impairment. Moreover, 17% of those reporting pain had utilized sick leave during the past year for the problem, while an additional 14% had been off work but had not used sick leave. Sufferers averaged 3.5 health‐care visits during the past year. However, the consumption of resources was highly skewed and about 6% of the sufferers accounted for over 50% of the costs. It was concluded that when the same selection criteria and assessment techniques are employed, the results found are quite similar. This implies that much of the huge variation in reported prevalence rates and consequences of back pain may be due to methodological differences. This underscores the need for standardized methods.

In a controlled prospective randomized study the regimen doxorubicin (A) 40 mg/m(2) + melphalan (M) 0.4 mg/kg was compared with A+M+cisplatin (C) 50 mg/m(2) given every four weeks in advanced ovarian cancer, FIGO stage III or IV and with serous or anaplastic histology. From 1981 to 1983, 300 patients entered the study and 295 patients were evaluable for response, toxicity and long-term survival. All patients were followed for at least 10 years. The majority of patients had large residual tumours >2 cm. Patients treated with MAC had a higher response rate compared with patients treated with MA (76% vs, 50%, p<0.01) and treatment with MAC resulted in significantly more pathological complete responders than MA. There was a significant difference in median duration of response (19 months vs. 13 months, p<0.006) and in median survival time (26 months vs. 19 months, p=0.05). After 5- and 10 years a significant difference in progression-free and overall survival was found. The independent prognostic factors in this study were residual tumour after primary surgery, treatment with MAC, tumour grade, ascites, and stage, objective and subjective side effects were significantly worse with MAC, although tolerable. In conclusion, this study shows that incorporating C into MA improves the duration of progression-free survival and overall survival in women with incompletely resected Stage III or Stage IV ovarian epithelial cancer. A 5- and 10-year survival of 25% and 18%, respectively, is impressive.