Response to targeted therapy in urachal adenocarcinoma.

We report the case of a young woman diagnosed with metastatic urachal carcinoma. A multimodal approach was used for the management of this patient. Due to disease progression despite surgery and two different chemotherapy regimens (neoadjuvant capecitabine + irinotecan + oxaliplatin and docetaxel + cisplatin after surgery), treatment with sunitinib was eventually started. Treatment with sunitinib resulted in stable disease and improvement of symptoms. Sunitinib was discontinued due to the occurrence of metrorrhagia, and restarted one week later. Disease eventually progressed and the patient died 18 months after the onset of symptoms. This is the first report on the use of sunitinib for the management of urachal carcinoma and provides initial evidence supporting the use of targeted therapy in this setting.

Medical treatment of small cell lung cancer: state of the art and new development.

INTRODUCTION: Small cell lung cancer (SCLC) is a rapidly progressive disease that accounts for approximately 15% of all lung cancers. Chemotherapy remains the cornerstone of treatment of SCLC, but in the last two decades, its progress has reached a plateau. Although a significant sensitivity to chemotherapy and radiotherapy is a feature of SCLC, an early development of drug resistance unavoidable occurs during the course of the disease. Second-line treatment for relapsed patients remains a very challenging setting, with a limited clinical benefit. AREAS COVERED: A thorough analysis of various therapeutic strategies reported in literature for SCLC treatment was performed. This review includes novel therapeutic approaches such as maintenance or consolidation treatments, new chemotherapy agents and targeted therapy. EXPERT OPINION: Against this background, there is a desperate need for the development of novel active drugs. Among these, amrubicin has also shown more favourable antitumor activity, and is the most promising at present. Concerning targeted agents, these have failed to demonstrate effectiveness for SCLC and a better understanding of the molecular mechanisms is clearly needed. In the future, further investigations are required to clarify the role of novel anti-angiogenic or pro-apoptotic agents and hedgehog pathway inhibitors.

A randomized phase III clinical trial of a combined treatment for cachexia in patients with gynecological cancers: evaluating the impact on metabolic and inflammatory profiles and quality of life.

OBJECTIVES: Gynecological neoplastic disease progression is characterized by specific energy metabolism alterations and by symptoms including fatigue, anorexia, nausea, anemia, and immunodepression, which result in a cachexia syndrome and a marked decrease in patient quality of life (QoL). Therapeutic protocols associated with appropriate and effective psychological and social support systems are essential to counteract the symptoms of neoplastic disease in incurable patients. METHODS: A phase III randomized study was performed to establish the most effective and safest treatment to improve the key symptoms in advanced gynecological cancer patients, i.e., lean body mass (LBM), resting energy expenditure (REE), fatigue, and QoL. In addition, the impact of the treatment arms on the main metabolic and inflammatory parameters, including C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α, leptin, reactive oxygen species (ROS), and glutathione peroxidase, was evaluated. The change in the Glasgow Prognostic Score (GPS) during treatment was also assessed. A total of 104 advanced-stage gynecological cancer patients were enrolled and randomly assigned to receive either megestrol acetate (MA) plus l-carnitine, celecoxib, and antioxidants (arm 1) or MA alone (arm 2). The treatment duration was 4 months. RESULTS: The combination arm was more effective than arm 2 with respect to LBM, REE, fatigue, and global QoL. As for the secondary efficacy endpoints, patient appetite increased, and ECOG PS decreased significantly in both arms. The inflammation and oxidative stress parameters IL-6, TNF-α, CRP, and ROS decreased significantly in arm 1, while no significant change was observed in arm 2. CONCLUSIONS: The combined treatment improved both immunometabolic alterations and patient QoL. Multimodality therapies for cachexia ideally should be introduced within a context of "best supportive care" that includes optimal symptom management and careful psychosocial counseling.

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.

Oxytocin both increases proliferative response of peripheral blood lymphomonocytes to phytohemagglutinin and reverses immunosuppressive estrogen activity.

BACKGROUND: It has been shown that the neurohypophyseal peptide oxytocin is present in the human thymus and in vitro it can mimic interleukin (IL)-2 action in the induction of interferon-gamma production. In the present study, we tested the capacity of oxytocin to modulate the response of peripheral blood mononuclear cells (PBMCs) to phytohemagglutinin (PHA) and its ability to change the membrane expression of IL-2 receptor CD25 and the CD95 activation marker. Furthermore, whether oxytocin was able to reverse the inhibition of PBMC blastic response and CD25 expression induced by estradiol benzoate (E(2)B) was studied. PATIENTS AND METHODS: Fifteen healthy women were studied with a mean age of 33.8 years, no previous pregnancies, all in the early follicular phase of the cycle with normal values of circulating estrogens. RESULTS: The addition of oxytocin (1x10(-10) M, 1x10(-11) M, 1x10(-12) M) significantly increased the PBMC blastic response to PHA as well as the expression of both CD25 and CD95. These results were due to interaction of oxytocin with its specific receptor since the addition of an oxytocin antagonist completely reversed the oxytocin activity. In contrast, E(2)B induced a marked decrease of PHA-stimulated PBMC cell cycle progression and CD25 expression: the inhibitory effect of E(2)B was significantly counteracted by low concentrations of oxytocin. CONCLUSION: The present results support the hypothesis that neuropeptides may act as a link in the network between the immune and the neuroendocrine systems.

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.

Medroxyprogesterone acetate in the management of cancer cachexia.

BACKGROUND: Medroxyprogesterone acetate (MPA) is a synthetic, orally active derivative of the natural steroid hormone progesterone, widely used in oncology both in the endocrine treatment of hormone-related cancers and as supportive therapy in the cachexia syndrome. OBJECTIVE: The anticachectic mechanisms of medroxyprogesterone, beyond its endocrine activity, are described to explain its therapeutic efficacy in the treatment of cachexia. METHODS: After reviewing its pathophysiology and preclinical studies, the main clinical trials on the use of medroxyprogesterone acetate in cancer cachexia, are reviewed. RESULTS/CONCLUSIONS: Progestagens, including MPA, are at present the only approved drugs in Europe for the clinical treatment of cancer-related anorexia/cachexia syndrome. Placebo-controlled trials on the effect of MPA on cachexia have generally reported an improvement of both anorexia and body weight as well as of quality-of-life parameters. However, the weight gain was due to increased body fat, while fat-free mass was not significantly influenced by MPA treatment. Moreover, very recently the combination of MPA with other new anticachectic agents has been suggested as a way of ameliorating their efficacy in the treatment of cachexia.

Carbocysteine: clinical experience and new perspectives in the treatment of chronic inflammatory diseases.

BACKGROUND: Carbocysteine is a muco-active drug with free radical scavenging and anti-inflammatory properties. It is actually approved for clinical use as adjunctive therapy of respiratory tract disorders characterized by excessive, viscous mucus, including chronic obstructive airways disease (COPD). OBJECTIVE: The intriguing antioxidant and anti-inflammatory properties of carbocysteine, beyond its known mucolytic activity, are described to explain its therapeutic efficacy and suggest new clinical uses. METHODS: After reviewing physiology and preclinical studies, human studies on the use of carbocysteine in chronic inflammatory diseases, i.e., COPD and cancer cachexia, are reviewed. RESULTS/CONCLUSIONS: Carbocysteine has been recently recognized as an effective and safe treatment for the long-term management of COPD, able to reduce the incidence of exacerbations and improve patient quality of life. Moreover, carbocysteine was effective in counteracting some symptoms associated with cancer cachexia. Preclinical and clinical studies have demonstrated that the antioxidant and anti-inflammatory properties of carbocysteine are more important than mucolysis itself for its therapeutic efficacy. Therefore, carbocysteine may be able to reverse the oxidative stress associated with several chronic inflammatory diseases, such as cardiovascular diseases and neurodegenerative disorders. Controlled, randomized studies in humans are warranted.

Evidence that human serum with high levels of estrogens interferes with immune system both by decreasing CD25 expression on T-cell and by increasing interleukin-2 availability.

Our study aimed to verify whether serum with high estrogen levels, obtained from infertile women who underwent multiple follicular development, was able to interfere with peripheral blood mononuclear cells proliferative response to phytohemoagglutinin +/- interleukin-2, recombinant interleukin-2 alone and phytohemoagglutinin-stimulated CD25 expression. Blood samples from 10 women were collected at the onset (low estrogen doses), during multiple follicular development (intermediate estrogen doses), and on the day preceding the human chorionic gonadotropin administration (high estrogen doses). Serum with high estrogen doses reduced the proliferative response to phytohemoagglutinin alone and plus recombinant interleukin-2, while increased the proliferative response to recombinant interleukin-2 alone, and reduced the CD25 expression in nonblastic and total lymphocytes. These effects were inhibited by the estrogen receptor antagonist ICI182,780. Inconclusion, estrogens exert a dual effect on immune system: (1) an inhibition of cell-mediated immunity through a reduction of interleukin-2 receptors; (2) an increased proliferative response to interleukin-2.

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.