Hormone Receptor-Positive/HER2-Positive Breast Cancer: Hormone Therapy and Anti-HER2 Treatment: An Update on Treatment Strategies.

Hormone receptor (HR)-positive/HER2-positive breast cancer represents a distinct subtype expressing estrogen and progesterone receptors with an overexpression of HER2. Approximately 14% of female breast cancer cases are HER2-positive, with the majority being HR-positive. These tumors show a cross-talk between the hormonal and HER2 pathways; the interaction has implications for the treatment options for the disease. In this review, we analyze the biology of HR-positive/HER2-positive breast cancer and summarize the evidence concerning the standard of care options both in neoadjuvant/adjuvant settings and in advanced disease. Additionally, we focus on new trials and drugs for HR-positive/HER2-positive breast cancer and the new entity: HER2-low breast cancer.

CDK4/6 inhibition in hormone receptor-positive/HER2-negative breast cancer: Biological and clinical aspects.

A dysregulated cell division, one of the key hallmarks of cancer, results in uncontrolled cellular proliferation. This aberrant process, mediated by a dysregulated cell-cycle machinery and overactivation of cyclin-dependent kinase (CDK) 4 and 6, can potentially promote tumorigenesis. The clinical application of CDK 4/6 inhibitors, developed to inhibit cell-cycle progression, in the treatment regimens of breast cancer (BC) patients is expanding. Currently, three agents, ribociclib, palbociclib, and abemaciclib, are approved for treating patients with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic BC. In addition, abemaciclib is FDA and EMA-approved for patients with hormone receptor-positive HER2-negative, node-positive, early BC at high risk of recurrence. Emerging data suggest potential anti-tumor effects beyond cell cycle arrest, providing novel insights into the agent's mechanisms of action. As a result, a broader application of the CDK4/6 inhibitors in patients with cancer is achieved, contributing to enhanced optimized treatment in the adjuvant and neoadjuvant settings. Herein, the immunomodulatory activities of CDK4/6 inhibitors, their impact on the cell's metabolic state, and the effect on the decision of the cell to undergo quiescence or senescence are discussed. Moreover, this review provides an update on clinical trial outcomes and the differences in the underlying mechanisms between the distinct CDK4/6 inhibitors.

CDK4/6 inhibitors in the treatment of metastatic breast cancer: Focus on toxicity and safety.

The development of oral cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, including palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for patients with hormone-receptor-positive (HR+) and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (BC). When combined with an aromatase inhibitor or fulvestrant, these agents have been approved as first-line therapy in the metastatic setting. Abemaciclib has also gained FDA approval for patients with HR-positive, HER2-negative, node-positive, early BC at high risk of recurrence. Moreover, ribociclib has recently improved disease-free survival in patients with stage II or III HR+/HER2-negative early BC. CDK4/6 inhibitors have favorable safety profiles. However, the available agents have different toxicity profiles that must be clearly discussed with the patients for optimal clinical decisions. This manuscript aims to review CDK4/6 inhibitor-related treatment-associated adverse events, identify risk factors for intolerable adverse events, and assess their safety in special patient populations such as the elderly and those with renal insufficiency. Enhanced knowledge and understanding of CDK4/6 inhibitor-related toxicities can improve treatment strategies and ultimately enhance patient care.

Primary Tumor Shrinkage and the Effect on Metastatic Disease and Outcomes in Patients With Advanced Kidney Cancer With Intermediate or Poor Prognosis Treated With Nivolumab Plus Ipilimumab or Cabozantinib.

BACKGROUND: Immune checkpoint inhibitor (ICI)-based combinations have become the first-line standard of care in metastatic renal cell carcinoma (mRCC), but their activity on the primary tumor is still one of the most debated issues. PATIENTS AND METHODS: The aim of our analysis was to evaluate the primary tumor's response to first-line therapy with cabozantinib or nivolumab+ipilimumab, and its correlation with metastatic response and with patient outcomes. RESULTS: Sixty-seven mRCC patients met the criteria for inclusion in the final analysis (30 treated with cabozantinib and 37 with nivolumab+ipilimumab). In the overall population, the primary tumor control rate (PTCR) was 90.9%; no complete responses (CR) were achieved. A significant correlation was found between the baseline size of the primary tumor's longest diameter and its response according to RECIST v1.1 criteria at the time of the second radiological assessment (rs = -0.351; P = .049). Moreover, a significant correlation between the type of primary tumor response and the response of the metastases was observed in the overall population (rs = 0.50; two-sided P < 0.001). There was also a significant correlation between primary tumor response and 1-year survival rate (P = .002), even when adjusted for the IMDC prognostic group and type of therapy (HR = 8.70; 95%CI, 2.52-30.05; P = .001). CONCLUSION: Extension of the primary tumor did not affect patient survival, while its response was significantly related to the response on metastatic disease and survival. No significant differences in terms of primary tumor shrinkage were identified between treatment with nivolumab+ipilimumab or cabozantinib in this cohort.

Molecular-Biology-Driven Treatment for Metastatic Colorectal Cancer.

BACKGROUND: Metastatic CRC (mCRC) is a molecular heterogeneous disease. The aim of this review is to give an overview of molecular-driven treatment of mCRC patients. METHODS: A review of clinical trials, retrospective studies and case reports was performed regarding molecular biomarkers with therapeutic implications. RESULTS: RAS wild-type status was confirmed as being crucial for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies and for rechallenge strategy. Antiangiogenic therapies improve survival in first- and second-line settings, irrespective of RAS status, while tyrosine kinase inhibitors (TKIs) remain promising in refractory mCRC. Promising results emerged from anti-HER2 drugs trials in HER2-positive mCRC. Target inhibitors were successful for BRAFV600E mutant mCRC patients, while immunotherapy was successful for microsatellite instability-high/defective mismatch repair (MSI-H/dMMR) or DNA polymerase epsilon catalytic subunit (POLE-1) mutant patients. Data are still lacking on NTRK, RET, MGMT, and TGF-ß, which require further research. CONCLUSION: Several molecular biomarkers have been identified for the tailored treatment of mCRC patients and multiple efforts are currently ongoing to increase the therapeutic options. In the era of precision medicine, molecular-biology-driven treatment is the key to impro patient selection and patient outcomes. Further research and large phase III trials are required to ameliorate the therapeutic management of these patients.

Timing of the negative effects of trastuzumab on cardiac mechanics after anthracycline chemotherapy.

Trastuzumab (TZB) has been shown to be extremely effective in breast cancer patients over-expressing HER-2, but careful cardiac monitoring is required when TZB is administered with anthracyclines, since the combination can increase its toxicity. Myocardial deformation indexes associated with speckle tracking echocardiography (STE) have proven to be very sensitive in identifying early myocardial dysfunction. An observational, prospective study was designed to assess TZB-induced cardiac damage using STE in patients with HER-2 positive breast cancer who had been sequentially treated with TZB following epirubicin (EPI). Conventional echocardiographic parameters and STE deformation indexes (longitudinal, radial, and circumferential strain/strain rate and apical rotation) were analyzed at baseline, after each EPI treatment, and 1 week after every other dose of TZB administration until 1 year follow up, in order to focus on the timing and extent of myocardial impairment. In the forty-five enrolled patients, a reduction in subendocardial function after EPI treatment was observed by a significant impairment of the global longitudinal strain/strain rate (GLS/SR), while a significant increase in the activity of the subepicardial fibers was highlighted by an increase in apical rotation. After the second TZB dose, a sudden reduction of the apical rotation was seen, together with circumferential and radial strain/SR. Most importantly, the extent to which the apical rotation increased and decreased was found to strictly correlate with the GLS reduction at follow up. We found that after EPI therapy, subendocardial function was impaired, even while a compensatory increase in apical rotation occurred. Following TZB treatment, we observed impairment in apical rotation, which seems to be the first sign of global LV dysfunction predicting GLS reduction found at the end of treatment.

Treatment of irradiated expanders: protective lipofilling allows immediate prosthetic breast reconstruction in the setting of postoperative radiotherapy.

BACKGROUND: Immediate two-stage prosthetic breast reconstruction in the setting of postmastectomy radiotherapy (PMRT) currently is hardly achieved with the fast-track expander exchange proposed by Cordeiro and colleagues or the delayed-immediate breast reconstruction proposed by Kronowitz and Robb. Each of these techniques has important drawbacks and complications. To overcome these problems, the authors in 2011 described lipofilling on irradiated expanders in patients undergoing unplanned PMRT (Cagliari University Hospital [CUH] protocol) for early breast cancers with specific risk factors. The authors report their experience after expanding the use of such a protocol for any immediate expander/implant reconstruction in a patient undergoing PMRT. METHODS: The timing for advanced breast cancer involves immediate reconstruction with a tissue expander, complete tissue expansion, radiotherapy (RT) after neoadjuvant chemotherapy starting 2-3 months after mastectomy, one or two fresh fat-grafting sessions at least 6 weeks after RT, and an expander-implant exchange with anterior capsulectomy at least 3 months after the completion of fat grafting. The timing for early breast cancers with specific risk factors involves immediate reconstruction with a tissue expander, complete tissue expansion during postoperative chemotherapy, RT 6 months after mastectomy, one or two fat-grafting sessions 6 weeks after RT, and an expander-implant exchange with anterior capsulectomy at least 3 months after the completion of fat grafting. From 2008 to 2012, 16 patients undergoing total mastectomy and immediate expander-implant breast reconstruction with subsequent PMRT were treated according to the CUH protocol. RESULTS: The results have been extremely encouraging, with rates of ulceration and implant exposure in the radiotreated area dropping to 0 %. These results were retrospectively compared with those for a control group of 16 patients who underwent immediate implantation of an expander. In this latter group, the extrusion rate of the implant in the end was 31.25 %, and this was statistically significant (p < 0.03). The shape and symmetry also were significantly better in the lipofilled patients. CONCLUSION: Protective lipofilling on irradiated expanders appears to be a valid technique for avoiding ulceration and implant exposure after PMRT while allowing a complete expansion. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Long-term, up to 18 months, protective effects of the angiotensin II receptor blocker telmisartan on Epirubin-induced inflammation and oxidative stress assessed by serial strain rate.

PURPOSE: The primary objective of the present study was to show the long lasting cardioprotective activity, at different time-points, up to 18 month-follow-up, of telmisartan in preserving the systolic function (assessed as Strain Rate-SR) in cancer patients treated with EPI both in the adjuvant and metastatic setting; the secondary objective was to confirm the correlation of the cardioprotective activity of telmisartan with a reduction of inflammation and oxidative stress induced by EPI. METHODS: Phase II single blind placebo-controlled randomized trial. Sample size 50 patients per arm: based on a pre-planned interim analysis for early stopping rules, the study was discontinued for ethical reasons at 49 patients. Cardiovascular disease-free patients with cancer at different sites eligible for EPI-based treatment randomized to: telmisartan n = 25 or placebo n = 24. Echocardiography Tissue Doppler imaging (TDI) strain and strain rate was performed, serum levels of proinflammatory cytokines (IL-6, TNF-α) and oxidative stress (reactive oxygen species, ROS) were assessed at baseline, every 100 mg/m(2) EPI dose and at 6-, 12- and 18-month follow-up (FU). RESULTS: Significant SR peak reduction in both arms was observed at t2 (cumulative dose EPI 200 mg/m(2)) vs t0. Conversely, at t3, t4, 6-, 12- and 18-month FU SR increased towards normal range in the telmisartan arm, while in the placebo arm SR remained significantly lower. Differences between SR changes in the placebo and telmisartan arm were significant from t3 up to 18 month-FU. IL-6 and ROS increased significantly in the placebo arm at t2 but did not change in the telmisartan arm. A significant (p < 0.05) correlation between changes of SR vs IL-6 and ROS was observed. CONCLUSIONS: Our results suggest that the protective effect of telmisartan is long lasting, probably by ensuring a permanent (at least up to 18-month FU) defense against chronic or late-onset types of anthracycline-induced cardiotoxicity.

Randomized phase III clinical trial of a combined treatment with carnitine + celecoxib ± megestrol acetate for patients with cancer-related anorexia/cachexia syndrome.

BACKGROUND & AIMS: A phase III, randomized non-inferiority study was carried out to compare a two-drug combination (including nutraceuticals, i.e. antioxidants) with carnitine + celecoxib ± megestrol acetate for the treatment of cancer-related anorexia/cachexia syndrome (CACS): the primary endpoints were increase of lean body mass (LBM) and improvement of total daily physical activity. Secondary endpoint was: increase of physical performance tested by grip strength and 6-min walk test. METHODS: Sixty eligible patients were randomly assigned to: arm 1, L-carnitine 4 g/day + Celecoxib 300 mg/day or arm 2, L-carnitine 4 g/day + celecoxib 300 mg/day + megestrol acetate 320 mg/day, all orally. All patients received as basic treatment polyphenols 300 mg/day, lipoic acid 300 mg/day, carbocysteine 2.7 g/day, Vitamin E, A, C. Treatment duration was 4 months. Planned sample size was 60 patients. RESULTS: The results did not show a significant difference between tre atment arms in both primary and secondary endpoints. Analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) increased significantly in both arms as well as physical performance assessed by 6MWT. Toxicity was quite negligible and comparable between arms. CONCLUSIONS: The results of the present study showed a non-inferiority of arm 1 (two-drug combination) vs arm 2 (two-drug combination + megestrol acetate). Therefore, this simple, feasible, effective, safe, low cost with favorable cost-benefit profile, two-drug approach could be suggested in the clinical practice to implement CACS treatment.

Long-term protective effects of the angiotensin receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress and myocardial dysfunction.

Chronic inflammation, oxidative stress and the renin-angiotensin system (RAS) play a significant role in chemotherapy-induced cardiotoxicity (CTX). Telmisartan (TEL), an antagonist of the angiotensin II type-1 receptor, was found to reduce anthracycline (ANT)-induced CTX. We carried out a phase II placebo (PLA)-controlled randomized trial to assess the possible role of TEL in the prevention of cardiac subclinical damage induced by epirubicin (EPI). Forty-nine patients (mean age ± SD, 53.0±8 years), cardiovascular disease-free with cancer at different sites and eligible for EPI-based treatment, were randomized to one of two arms: TEL n=25; PLA n=24. A conventional echocardiography equipped with Tissue Doppler imaging, strain and strain rate (SR) was performed, and serum levels of proinflammatory cytokines, IL-6 and TNF-α, and oxidative stress parameters, reactive oxygen species (ROS) and glutathione peroxidase were determined. All assessments were carried out at baseline, after every 100 mg/m(2) of EPI dose and at the 12-month follow-up (FU). A significant reduction in the SR peak both in the TEL and PLA arms was observed at t(2) (cumulative dose of 200 mg/m(2) of EPI) in comparison to t(0). Conversely, at t(3) (300 mg/m(2) EPI), t(4) (400 mg/m(2) EPI) and the 12-month FU, the SR increased reaching the normal range only in the TEL arm, while in the PLA arm the SR remained significantly lower as compared to t(0) (baseline). The differences between SR changes in the PLA and TEL arms were significant from 300 mg/m(2) EPI (t(3)) up to the 12-month FU. Serum levels of IL-6 increased significantly in the PLA arm at 200 mg/m(2) EPI (t(2)) in comparison to baseline, but remained unchanged in the TEL arm. The same trend was demonstrated for ROS levels which significantly increased at t(2) vs. baseline in the PLA arm, while remained unchanged in the TEL arm. The mean change in ROS and IL-6 at t(2) was significantly different between the two arms. In the present study, we confirmed at the 3-month FU a trend toward a decrease in ROS and IL-6 from t(2) in the PLA arm. Our results suggest that TEL is able to reverse acute (early) EPI-induced myocardial dysfunction and to maintain later a normal systolic function up to the 12-month FU. These effects are likely to be due to different mechanisms, RAS blockade and prevention of chronic inflammation/oxidative stress.

Phase II study of vinorelbine/cetuximab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck progressing after at least two chemotherapy regimens.

The aim of the present study was to identify a potentially effective new treatment regimen for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck in disease progression after at least two previous chemotherapy regimens. The "novel" regimen was Cetuximab administered weekly plus Vinorelbine on days 1, 8, 15 every 28days. The regimen was administered to patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck previously treated with surgery, radiotherapy or both and progressing after at least two chemotherapy regimens. Twenty-four patients with histologically confirmed tumors of oral cavity, oropharynx, hypopharynx and larynx were enrolled. All patients were stage IV and 91.6% had an ECOG PS 0-1. After 3 cycles of treatment 23 patients (95.8%) were evaluable for response: 4 patients had partial response; 12 stable disease and 7 progressive disease. Disease control rate was 69.5%. At a median follow-up of 21.3months, the median progression-free survival was 5.8months. Median duration of response was 5.2months. At May 2010, 11/24 (45.8%) patients were alive. The safety profile was quite good. The present study shows that the combination of Vinorelbine and Cetuximab in recurrent and/or metastatic squamous cell carcinoma of the head and neck patients is effective, feasible and has a good safety profile. Our findings warrant further investigation in a wider patient population.

Protective effects of the angiotensin II receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress, and early ventricular impairment.

BACKGROUND: Oxidative stress and RAAS play an important role in the occurrence of anthracyclines-induced cardiotoxicity. Telmisartan, an angiotensin II type 1 receptor blocker, inhibits activation of superoxide sources and induces anti-inflammatory effects. METHODS: The possible role of telmisartan in preventing myocardial damage induced by epirubicin (EPI) was investigated. Forty-nine patients free from cardiovascular diseases affected by a variety of solid cancers were examined. Eligible patients were randomized to receive telmisartan (40 mg/d; TEL, n = 25) or placebo (PLA, n = 24) starting 1 week before chemotherapy. Patients were studied by means of echocardiography, tissue Doppler, and strain and strain rate (SR) imaging. We also measured plasma levels of inflammatory and oxidative stress markers. All parameters were assessed at baseline and 7 days after every new EPI dose of 100 mg/m(2). RESULTS: An impairment of the SR peak was observed at the EPI dose of 200 mg/m(2), with no significant differences between TEL and PLA (1.41 +/- 0.31 vs 1.59 +/- 0.36/s). At growing cumulative doses of EPI, SR normalized only in TEL, showing a significant difference in comparison to PLA at EPI doses of 300 mg/m(2) (1.69 +/- 0.42 vs 1.34 +/- 0.18/s, P < .001) and 400 mg/m(2) (1.74 +/- 0.27 vs 1.38 +/- 0.24/s, P < .001). Moreover, a significant increase in reactive oxygen species and interleukin-6 was found in PLA; but these remained unchanged in TEL. CONCLUSIONS: We confirmed that EPI-induced cardiotoxicity is primarily related to the inactivation of the cardiac antioxidant defenses. In addition, we showed that telmisartan can reduce EPI-induced radical species, antagonize the inflammation, and reverse the early myocardial impairment.

Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia.

PURPOSE: A phase III, randomized study was carried out to establish the most effective and safest treatment to improve the primary endpoints of cancer cachexia-lean body mass (LBM), resting energy expenditure (REE), and fatigue-and relevant secondary endpoints: appetite, quality of life, grip strength, Glasgow Prognostic Score (GPS) and proinflammatory cytokines. PATIENTS AND METHODS: Three hundred thirty-two assessable patients with cancer-related anorexia/cachexia syndrome were randomly assigned to one of five treatment arms: arm 1, medroxyprogesterone (500 mg/day) or megestrol acetate (320 mg/day); arm 2, oral supplementation with eicosapentaenoic acid; arm 3, L-carnitine (4 g/day); arm 4, thalidomide (200 mg/day); and arm 5, a combination of the above. Treatment duration was 4 months. RESULTS: Analysis of variance showed a significant difference between treatment arms. A post hoc analysis showed the superiority of arm 5 over the others for all primary endpoints. An analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) significantly increased in arm 5. REE decreased significantly and fatigue improved significantly in arm 5. Appetite increased significantly in arm 5; interleukin (IL)-6 decreased significantly in arm 5 and arm 4; GPS and Eastern Cooperative Oncology Group performance status (ECOG PS) score decreased significantly in arm 5, arm 4, and arm 3. Toxicity was quite negligible, and was comparable between arms. CONCLUSION: The most effective treatment in terms of all three primary efficacy endpoints and the secondary endpoints appetite, IL-6, GPS, and ECOG PS score was the combination regimen that included all selected agents.

Phase II nonrandomized study of the efficacy and safety of COX-2 inhibitor celecoxib on patients with cancer cachexia.

Chronic inflammation is one of the main features of cancer cachexia. Experimental and clinical studies showed that cyclooxygenase-2 inhibitors, such as celecoxib, may be beneficial in counteracting major symptoms of this devastating syndrome. We carried out a prospective phase II clinical trial to test the safety and effectiveness of an intervention with the COX-2 inhibitor celecoxib (300 mg/day for 4 months) on key variables of cachexia (lean body mass, resting energy expenditure, serum levels of proinflammatory cytokines, and fatigue) in patients with advanced cancer at different sites. A sample of 24 patients was enrolled from January to December 2008 and all were deemed assessable. A significant increase of lean body mass and a significant decrease of TNF-alpha were observed. Moreover, an improvement of grip strength, quality of life, performance status, and Glasgow prognostic score was shown. There were no grade 3/4 toxicities. Patient compliance was very good; no patient had to reduce the celecoxib dosage nor interrupt treatment. Our results showed that the COX-2 selective inhibitor celecoxib is an effective single agent for the treatment of cancer cachexia. Although the treatment of cancer cachexia, a multifactorial syndrome, is more likely to yield success with a multitargeted approach; in the present study, we were able to show that a treatment, such as celecoxib, addressing a single target, albeit very important as chronic inflammation, could have positive effects. Therefore, phase III clinical trials are warranted to test the efficacy and safety of celecoxib.

Palonosetron plus dexamethasone effectively prevents acute and delayed chemotherapy-induced nausea and vomiting following highly or moderately emetogenic chemotherapy in pre-treated patients who have failed to respond to a previous antiemetic treatment: comparison between elderly and non-elderly patient response.

Aim of the present phase II non-randomized study was to verify whether palonosetron might be able to prevent acute and especially delayed CINV for either HEC or MEC, starting from the second chemotherapy cycle, in patients who had failed to respond to a different antiemetic 5-HT(3) antagonist during the first cycle. Stratification factor was age <65 years vs. > or =65 years of patients included. Forty-seven cancer patients (23 elderly and 24 non-elderly) scheduled to receive HEC or MEC regimens who had experienced CINV grade 3-4 during the first chemotherapy course and for whom the same course of chemotherapy regimen was further scheduled were enrolled. Complete response (CR) and complete control (CC) rates for the acute, delayed and overall phases of CINV were not significantly different between elderly and non-elderly patients. Palonosetron was safe: only grade 1-2 toxicities were observed with a peak of 12.9% for asthenia with no significant difference between elderly and non-elderly patients. In conclusion, single dose palonosetron (250 microg) should be considered a safe and effective second generation 5-HT(3) antagonist in the prevention of nausea and vomiting induced by HEC or MEC, irrespective of patients' age.

Persistence, up to 18 months of follow-up, of epirubicin-induced myocardial dysfunction detected early by serial tissue Doppler echocardiography: correlation with inflammatory and oxidative stress markers.

A phase II, open, nonrandomized trial was carried out in a group of epirubicin-treated cancer patients with the aim of detecting early preclinical changes that are predictive of the risk for heart failure. Thirty-one patients (male/female ratio, 8/23; mean age +/- standard deviation, 59 +/- 14 years) with tumors at different sites and scheduled to be treated with an epirubicin-based chemotherapy regimen, were enrolled. We prospectively evaluated the acute (1 week after) and late (3, 6, 12, and 18 months of follow-up) effects of epirubicin administration. A significant impairment in systolic left ventricular (LV) function was observed at a cumulative epirubicin dose of 200 mg/m(2). This was shown by a reduction in the strain rate (SR) peak in comparison with baseline and persisted throughout the treatment and follow-up, up to 18 months; strain (Sigma) remained unchanged. The Sm wave showed a progressive reduction that became significant only at the 18-month follow-up. On TDI the E(m)/A(m) ratio declined at the 200-mg/m(2) cumulative epirubicin dose versus baseline and persisted throughout the treatment and up to the 18-month follow-up. On conventional echocardiography the E/A ratio declined significantly only at the 300-mg/m(2) cumulative epirubicin dose. Interleukin (IL)-6, soluble IL-6 receptor, and reactive oxygen species (ROS) increased significantly at the 200-mg/m(2) dose, and IL-6 was persistently high at the 300- and 400-mg/m(2) doses, returning to within baseline values during follow-up. ROS, after the peak reached at the 200-mg/m(2) dose, returned to within baseline values. A significant inverse correlation between DeltaSR and the increase in both IL-6 and ROS was observed. A multiple regression analysis showed that both the IL-6 and ROS variables were independent and strongly predictive of DeltaSR. The clinical meaningfulness of our findings warrants further investigations on a larger number of patients for a longer period of follow-up.

Randomized phase III clinical trial of five different arms of treatment for patients with cancer cachexia: interim results.

OBJECTIVE: In April 2005 a phase III randomized study was started to establish which was the most effective and safest treatment of cancer-related anorexia/cachexia syndrome and oxidative stress in improving identified primary endpoints: increase of lean body mass, decrease of resting energy expenditure (REE), increase of total daily physical activity, decrease of interleukin-6 and tumor necrosis factor-alpha, and improvement of fatigue assessed by the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF). METHODS: All patients were given as basic treatment polyphenols plus antioxidant agents alpha-lipoic acid, carbocysteine, and vitamins A, C, and E, all orally. Patients were then randomized to one of the following five arms: 1) medroxyprogesterone acetate/megestrol acetate; 2) pharmacologic nutritional support containing eicosapentaenoic acid; 3) L-carnitine; 4) thalidomide; or 5) medroxyprogesterone acetate/megestrol acetate plus pharmacologic nutritional support plus L-carnitine plus thalidomide. Treatment duration was 4 mo. The sample comprised 475 patients. RESULTS: By January 2007, 125 patients, well balanced for all clinical characteristics, were included. No severe side effects were observed. As for efficacy, an interim analysis on 125 patients showed an improvement of at least one primary endpoint in arms 3, 4, and 5, whereas arm 2 showed a significant worsening of lean body mass, REE, and MFSI-SF. Analysis of variance comparing the change of primary endpoints between arms showed a significant improvement of REE in favor of arm 5 versus arm 2 and a significant improvement of MFSI-SF in favor of arms 1, 3, and 5 versus arm 2. A significant inferiority of arm 2 versus arms 3, 4, and 5 for the primary endpoints lean body mass, REE, and MFSI-SF was observed on the basis of t test for changes. CONCLUSION: The interim results obtained thus far seem to suggest that the most effective treatment for cancer-related anorexia/cachexia syndrome and oxidative stress should be a combination regimen. The study is still in progress and the final results should confirm these data.

Early epirubicin-induced myocardial dysfunction revealed by serial tissue Doppler echocardiography: correlation with inflammatory and oxidative stress markers.

A phase II, open, nonrandomized trial was carried out in a group of epirubicin-treated patients with cancer at different sites with the aim of detecting early preclinical changes that are predictive of the risk for heart failure. All patients underwent conventional echocardiography, as well as tissue Doppler imaging (TDI) with strain (sigma) and strain rate (SR), a very accurate technique for detecting minimal changes in cardiac left ventricular (LV) function. Moreover, echocardiographic changes identified during epirubicin treatment were compared with those of a series of biochemical markers of both myocardial damage and inflammation/oxidative stress. Sixteen patients (male-to-female ratio, 3:13; mean age +/- standard deviation, 56 +/-3 years; range, 27-75 years) with histologically confirmed tumors at different sites, scheduled to be treated with an epirubicin-based chemotherapy regimen, were enrolled in the study. A significant impairment in systolic LV function was observed after 200 mg/m2 of epirubicin; this was shown by a lower SR peak compared with baseline (1.82 +/- 0.57/second versus 1.45 +/- 0.44/second), whereas sigma remained unchanged. The following significant changes in LV diastolic function occurred only after 300 mg/m2 of epirubicin: a decrease in conventional early/late diastolic (E/A) velocities (1.16 +/- 0.31 versus 0.93 +/- 0.24) and a reduction in both the E(m) wave in the basal portion of the interventricular septum (8.86 +/- 1.73 cm/second versus 7.51 +/- 2.30 cm/second) and in the E(m)/A(m) ratio (1.09 +/- 0.51 versus 0.83 +/- 0.51), as measured using the TDI technique. No significant changes in LV ejection fraction were observed. Baseline values of brain natriuretic peptide, troponin I, myoglobin, and creatine kinase-myocardial subfraction were within the normal range and no significant changes were observed throughout the study. Levels of interleukin (IL)-6 and its soluble receptor (sIL-6R) and reactive oxygen species increased significantly, whereas glutathione peroxidase (GPx) levels decreased significantly, after 200 mg/m2 of epirubicin. Significant correlations between the reduction in the SR peak (deltaSR) after 200 mg/m2 of epirubicin and the increase in IL-6 and ROS and decrease in GPx were observed. The multiple regression analysis showed that the only independent predictive variable for deltaSR was ROS level. Our data show that: (a) subtle cardiac abnormalities may occur at epirubicin doses significantly below those known to be potentially clinically harmful and (b) the earliest myocardial impairment affects LV systolic rather than diastolic function. Early contractility impairment during epirubicin treatment was associated with high levels of ROS and markers of inflammation. The clinical meaningfulness of our findings warrants further investigations in a larger number of patients for a longer period of follow-up.

Efficacy of l-carnitine administration on fatigue, nutritional status, oxidative stress, and related quality of life in 12 advanced cancer patients undergoing anticancer therapy.

OBJECTIVE: Fatigue is a multidimensional symptom that is described in terms of perceived energy, mental capacity, and psychological status: it can impair daily functioning and lead to negative effects on quality of life. It is one of the most common side effects of chemotherapy and radiotherapy. In recent studies, l-carnitine (LC) supplementation has been demonstrated to be able to improve fatigue symptoms in patients with cancer. METHODS: In the present study we tested the efficacy and safety of LC supplementation in a population of patients who had advanced cancer and developed fatigue, high blood levels of reactive oxygen species, or both. As outcome measures we evaluated fatigue and quality of life in relation to oxidative stress, nutritional status, and laboratory variables, mainly levels of reactive oxygen species, glutathione peroxidase, and proinflammatory cytokines. From March to July 2004, 12 patients who had advanced tumors (50% at stage IV) at different sites were enrolled (male-to-female ratio 2:10, mean age 60 y, range 42-73). Patients were only slightly anemic (hemoglobin 10.9 g/dL) and hemoglobin levels did not change after treatment. LC was administered orally at 6 g/d for 4 wk. All patients underwent antineoplastic treatment during LC supplementation. RESULTS: Fatigue, as measured by the Multidimensional Fatigue Symptom Inventory-Short Form, decreased significantly, particularly for the General and Physical scales, and for quality of life in each subscale of quality of life in relation to oxidative stress. Nutritional variables (lean body mass and appetite) increased significantly after LC supplementation. Levels of reactive oxygen species decreased and glutathione peroxidase increased but not significantly. Proinflammatory cytokines did not change significantly. CONCLUSION: Improvement of symptoms with respect to fatigue and quality of life in relation to oxidative stress may be explained mainly by an increase in lean body mass, which may be considered the most important nutritional or functional parameter in assessing the cachectic state of patients. In this view, fatigue with related symptoms can well be considered an important constituent of cancer-related anorexia cachexia syndrome.