Study protocol for a comparative randomized controlled trial of Tai Chi and conventional exercise training on alleviating depression in older insomniacs.

Background: Insomnia and depression are prevalent mental disorders that are often comorbid among older adults. Lifestyle intervention strategies incorporating Tai Chi or conventional exercise have been shown to alleviate symptoms of insomnia and depression. However, the comparative efficacy of these exercise modalities in individuals with both disorders has yet to be determined. Therefore, the aim of this study is to examine the efficacy of Tai Chi and conventional exercise for reducing depressive symptoms in older adults with chronic insomnia and depressive symptoms, when compared to a health education control. Methods: This study is a prospective, assessor-blinded, three-arm, parallel group, randomized controlled trial. Older adults aged ≥60 years with a diagnosis of chronic insomnia and depressive symptoms will be randomly assigned to a Tai Chi, conventional exercise or health education control condition on a 1:1:1 basis. Interventions will last for 3 months, with a 6-month follow-up period. The primary outcome is depressive symptoms, assessed using the Hospital Anxiety and Depression Scale. Secondary outcomes include subjective sleep quality, 7-day actigraphy, 7-day sleep diary, anxiety symptoms, quality of life, medication usage and physical function. All measurements will be conducted at baseline, 3 months and 9 months by outcome assessors who are blinded to group allocation. Discussion: This study will compare the efficacy of Tai Chi and conventional exercise in improving depression outcomes in older adults with chronic insomnia and depressive symptoms. Our results will shed light on the clinical potential of these interventions for combating insomnia and depression in older adults.

Effects of volume-matched once-weekly and thrice-weekly high-intensity interval training (HIIT) on body adiposity in adults with central obesity: Study protocol for a randomized controlled trial.

Objective: This study aims to examine the comparative effects of 75 min of volume-matched once-weekly and thrice-weekly high-intensity interval training (HIIT) on body adiposity in adults with central obesity. Methods: This assessor-blinded, three-arm, randomized controlled trial will recruit 315 physically inactive adults with central obesity (aged ≥18 years, body mass index ≥23, waist circumference ≥90 cm for men and ≥80 cm for women). Participants will be randomly allocated to the once-weekly HIIT, thrice-weekly HIIT or usual care control group. Participants in the HIIT groups will receive weekly exercise training sessions for 16 weeks, prescribed either once or three times weekly. Each HIIT session will consist of a supervised program of four 4-min high-intensity intervals at 85%-95% peak heart rate (HRpeak) interspersed with 3-min active recovery intervals at 50%-70% HRpeak. Participants in the once-weekly HIIT group will perform the 25-min HIIT bout three times with a break between each 25-min HIIT bout. The usual care control group will receive bi-weekly health education classes. The outcome assessments will be conducted at baseline, 16 weeks (post-intervention) and 32 weeks (follow-up). The primary outcome will be total body adiposity assessed by dual-energy X-ray absorptiometry (DXA). The secondary outcome measures will include markers of cardiovascular and metabolic health (body composition, cardiorespiratory fitness, blood pressure, and blood lipids), mental health, cognitive performance, health-related quality of life, sleep quality, habitual physical activity, diet, medication, adverse events and adherence to the intervention. Impact of the project: The findings from this study are expected to consolidate the therapeutic efficacy of HIIT for the management of central obesity and inform the comparative compliance, feasibility and suitability of once-weekly and thrice-weekly HIIT as exercise strategies to manage obesity. In particular, the present study is expected to provide a novel perspective on the utility of low-frequency HIIT (i.e., once-weekly) as an effective and sustainable exercise strategy to tackle the obesity pandemic. The anticipated findings will hold substantial translational value by informing public health policies and enhancing exercise compliance in the physically inactive obese population. Trial registration: ClinicalTrials.gov (NCT04887454).

Dose-response effects of exercise and caloric restriction on visceral adiposity in overweight and obese adults: a systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: To determine and compare the dose-response effects of exercise and caloric restriction on visceral adipose tissue in overweight and obese adults, while controlling for the weekly energy deficit induced by the interventions. METHODS: PubMed, Embase, CINAHL and Web of Science were searched for randomised controlled trials comparing exercise or caloric restriction against eucaloric controls in overweight or obese adults. The primary outcome was the change in visceral fat measured by CT or MRI. Meta-analyses and meta-regressions were performed to determine the overall effect size (ES) and the dose-dependent relationship of exercise and caloric restriction on visceral fat. Heterogeneity, risk of bias and the certainty of evidence were also assessed. RESULTS: Forty randomised controlled trials involving 2190 participants were included. Overall, exercise (ES -0.28 (-0.37 to -0.19); p<0.001; I2=25%) and caloric restriction (ES -0.53 (-0.71 to -0.35); p<0.001; I2=33%) reduced visceral fat compared with the controls. Exercise demonstrated a dose-response effect of -0.15 ((-0.23 to -0.07); p<0.001) per 1000 calories deficit per week, whereas the effect of caloric restriction was not dose-dependent (ES 0.03 (-0.12 to 0.18); p=0.64). Most of the studies showed a moderate risk of bias. CONCLUSIONS: These findings support the dose-dependent effects of exercise to reduce visceral fat in overweight and obese adults. Caloric restriction did not demonstrate a dose-response relationship, although this may be attributed to the smaller number of studies available for analysis, compared with exercise studies. PROSPERO REGISTRATION NUMBER: CRD42020210096.

Comparative effectiveness of exercise, antidepressants and their combination in treating non-severe depression: a systematic review and network meta-analysis of randomised controlled trials.

OBJECTIVE: To assess the comparative effectiveness of exercise, antidepressants and their combination for alleviating depressive symptoms in adults with non-severe depression. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Embase, MEDLINE, PsycINFO, Cochrane Library, Web of Science, Scopus and SportDiscus. ELIGIBILITY CRITERIA: Randomised controlled trials (1990-present) that examined the effectiveness of an exercise, antidepressant or combination intervention against either treatment alone or a control/placebo condition in adults with non-severe depression. STUDY SELECTION AND ANALYSIS: Risk of bias, indirectness and the overall confidence in the network were assessed by two independent investigators. A frequentist network meta-analysis was performed to examine postintervention differences in depressive symptom severity between groups. Intervention drop-out was assessed as a measure of treatment acceptability. RESULTS: Twenty-one randomised controlled trials (n=2551) with 25 comparisons were included in the network. There were no differences in treatment effectiveness among the three main interventions (exercise vs antidepressants: standardised mean differences, SMD, -0.12; 95% CI -0.33 to 0.10, combination versus exercise: SMD, 0.00; 95% CI -0.33 to 0.33, combination vs antidepressants: SMD, -0.12; 95% CI -0.40 to 0.16), although all treatments were more beneficial than controls. Exercise interventions had higher drop-out rates than antidepressant interventions (risk ratio 1.31; 95% CI 1.09 to 1.57). Heterogeneity in the network was moderate (τ2=0.03; I2=46%). CONCLUSIONS: The results suggest no difference between exercise and pharmacological interventions in reducing depressive symptoms in adults with non-severe depression. These findings support the adoption of exercise as an alternative or adjuvant treatment for non-severe depression in adults. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD4202122656.

Effectiveness of Exercise, Cognitive Behavioral Therapy, and Pharmacotherapy on Improving Sleep in Adults with Chronic Insomnia: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

Despite the well-established treatment effectiveness of exercise, cognitive behavioral therapy for insomnia (CBT-I), and pharmacotherapy on improving sleep, there have been no studies to compare their long-term effectiveness, which is of clinical importance for sustainable management of chronic insomnia. This study compared the long-term effectiveness of these three interventions on improving sleep in adults with chronic insomnia. MEDLINE, PsycINFO, Embase, and SPORTDiscus were searched for eligible reports. Trials that investigated the long-term effectiveness of these three interventions on improving sleep were included. The post-intervention follow-up of the trial had to be ≥6 months to be eligible. The primary outcome was the long-term effectiveness of the three interventions on improving sleep. Treatment effectiveness was the secondary outcome. A random-effects network meta-analysis was carried out using a frequentist approach. Thirteen trials were included in the study. After an average post-intervention follow-up period of 10.3 months, both exercise (SMD, -0.29; 95% CI, -0.57 to -0.01) and CBT-I (-0.48; -0.68 to -0.28) showed superior long-term effectiveness on improving sleep compared with control. Temazepam was the only included pharmacotherapy, which demonstrated superior treatment effectiveness (-0.80; -1.25 to -0.36) but not long-term effectiveness (0.19; -0.32 to 0.69) compared with control. The findings support the use of both exercise and CBT-I for long-term management of chronic insomnia, while temazepam may be used for short-term treatment.

Physical Activity Interventions to Alleviate Depressive Symptoms in Children and Adolescents: A Systematic Review and Meta-analysis.

Importance: Depression is the second most prevalent mental disorder among children and adolescents, yet only a small proportion seek or receive disorder-specific treatment. Physical activity interventions hold promise as an alternative or adjunctive approach to clinical treatment for depression. Objective: To determine the association of physical activity interventions with depressive symptoms in children and adolescents. Data Sources: PubMed, CINAHL, PsycINFO, EMBASE, and SPORTDiscus were searched from inception to February 2022 for relevant studies written in English, Chinese, or Italian. Study Selection: Two independent researchers selected studies that assessed the effects of physical activity interventions on depressive symptoms in children and adolescents compared with a control condition. Data Extraction and Synthesis: A random-effects meta-analysis using Hedges g was performed. Heterogeneity, risk of bias, and publication bias were assessed independently by multiple reviewers. Meta-regressions and sensitivity analyses were conducted to substantiate the overall results. The study followed the PRISMA reporting guideline. Main Outcomes and Measures: The main outcome was depressive symptoms as measured by validated depression scales at postintervention and follow-up. Results: Twenty-one studies involving 2441 participants (1148 [47.0%] boys; 1293 [53.0%] girls; mean [SD] age, 14 [3] years) were included. Meta-analysis of the postintervention differences revealed that physical activity interventions were associated with a reduction in depressive symptoms compared with the control condition (g = -0.29; 95% CI, -0.47 to -0.10; P = .004). Analysis of the follow-up outcomes in 4 studies revealed no differences between the physical activity and control groups (g = -0.39; 95% CI, -1.01 to 0.24; P = .14). Moderate study heterogeneity was detected (Q = 53.92; df = 20; P < .001; I2 = 62.9% [95% CI, 40.7%-76.8%]). The primary moderator analysis accounting for total physical activity volume, study design, participant health status, and allocation and/or assessment concealment did not moderate the main treatment effect. Secondary analyses demonstrated that intervention (ie, <12 weeks in duration, 3 times per week, unsupervised) and participant characteristics (ie, aged ≥13 years, with a mental illness and/or depression diagnosis) may influence the overall treatment effect. Conclusions and Relevance: Physical activity interventions may be used to reduce depressive symptoms in children and adolescents. Greater reductions in depressive symptoms were derived from participants older than 13 years and with a mental illness and/or depression diagnosis. The association with physical activity parameters such as frequency, duration, and supervision of the sessions remains unclear and needs further investigation.

Physical activity and exercise for cancer-related cognitive impairment among individuals affected by childhood cancer: a systematic review and meta-analysis.

BACKGROUND: Individuals affected by childhood cancer can have cognitive dysfunction that persists into adulthood and negatively affects quality of life. In this study, we aimed to evaluate the effects of physical activity and exercise on cognitive function among individuals affected by childhood cancer. METHODS: In this systematic review and meta-analysis, we searched seven databases (CINAHL Plus, Cochrane Library, Embase, MEDLINE, PsycINFO, SPORTDiscus, and Web of Science) and two clinical trial registries (ClinicalTrials.gov and the International Clinical Trials Registry Platform) for randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs) published (or registered) from database inception to Jan 30, 2022, with no language restrictions. We included studies that compared the effects of physical activity or exercise interventions with controls (no intervention or usual care) on cognitive function among individuals diagnosed with any type of cancer at age 0-19 years. Two reviewers (JDKB and FR) independently screened records for eligibility and searched references of the selected studies; extracted study-level data from published reports; and assessed study risk of bias of RCTs and NRSIs using the Cochrane risk of bias tool for randomised trials (RoB 2) and Risk Of Bias In Non-randomised Studies-of Interventions (ROBINS-I) tools, certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach, and any adverse events. We used intention-to-treat data and unpublished data if available. Cognitive function was assessed by standardised cognitive performance measures (primary outcome) and by validated patient-reported measures (secondary outcome). A random-effects meta-analysis model using the inverse-variance and Hartung-Knapp methods was used to calculate pooled estimates (Hedges' g) and 95% CI values. We estimated the heterogeneity variance by the restricted maximum likelihood method and calculated I2 values to measure heterogeneity. We examined funnel plots and used Egger's regression test to assess for publication bias. This study is registered with PROSPERO, CRD42021261061. FINDINGS: We screened 12 425 titles and abstracts, which resulted in full-text assessment of 131 potentially relevant reports. We evaluated 22 unique studies (16 RCTs and six NRSIs) with data on 1277 individuals affected by childhood cancer and low-to-moderate risk of bias. Of the 1277 individuals, 674 [52·8%] were male and 603 [47·2%] were female; median age at study start was 12 (IQR 11-14) years, median time since the end of cancer treatment was 2·5 (IQR -1·1 to 3·0) years, and median intervention period was 12 [IQR 10-24] weeks. There was moderate-quality evidence that, compared with control, physical activity and exercise improved cognitive performance measures (five RCTs; Hedges' g 0·40 [95% CI 0·07-0·73], p=0·027; I2=18%) and patient-reported measures of cognitive function (13 RCTs; Hedges' g 0·26 [0·09-0·43], p=0·0070; I2=40%). No evidence of publication bias was found. Nine mild adverse events were reported. INTERPRETATION: There is moderate-certainty evidence that physical activity and exercise improves cognitive function among individuals affected by childhood cancer, which supports the use of physical activity for managing cancer-related cognitive impairment. FUNDING: Research Impact Fund of Research Grants Council of the Hong Kong University Grants Committee (R7024-20) and Seed Fund for Basic Research of the University of Hong Kong. COPYRIGHT: © 2022 Published by Elsevier Ltd. All rights reserved.

Maintenance immunotherapy in recurrent ovarian cancer: long term follow-up of a phase II study.

OBJECTIVES: Vascular endothelial growth factor (VEGF), a mediator of tumor-associated immunodeficiency, plays a key role in angiogenesis and is a prognostic factor in advanced ovarian cancer (AOC). Previously, we showed that low-dose interleukin-2 (IL-2) and 13-cis-retinoic acid (RA) improved the tumor-associated immunodeficiency and decreased VEGF in patients with AOC. Here, we report long term follow-up of a group of patients with platinum-sensitive AOC who were treated with IL-2 and RA. METHODS: Sixty-five patients with AOC who had a clinical benefit from second line chemotherapy and elevated serum levels of VEGF were entered into the study from 04/98 to 04/05. Therapy consisted of low-dose subcutaneous IL-2 and oral RA, administered on intermittent schedules for up to 5 years. RESULTS: A statistically significant improvement in lymphocyte and NK counts and a decrease in VEGF levels were observed with respect to baseline values among the 65 evaluable patients. Five-year progression-free survival and overall survival rate were 29% and 38%, respectively. CONCLUSIONS: These data show that patients treated with low-dose IL-2 and RA have a statistically significant improvement in their lymphocyte and NK counts, a decrease in VEGF, and seem to have an improved clinical outcome.

Liposomal pegylated doxorubicin and oxaliplatin as salvage chemotherapy in patients with metastatic gastric cancer treated earlier.

The aim of this study was to evaluate the activity and safety of pegylated liposomal doxorubicin (PLD) and oxaliplatin (LOHP) as salvage chemotherapy in patients with metastatic gastric cancer (MGC) who had earlier been treated with docetaxel, capecitabine, 5-fluorouracil, and leucovorin. Treatment consisted of PLD (40 mg/m(2)) and LOHP (120 mg/m(2)) administered over 2 days, every 3 weeks. Response to therapy was assessed using the Response Evaluation Criteria In Solid Tumors; toxicity was evaluated by the National Cancer Institute common toxicity criteria (version 2.0). Thirty-six patients with pretreated MGC and a mean age of 66 years were recruited for the study. After a median follow-up of 11 months and 202 courses of chemotherapy administered (median, five courses per patient), the overall response rate in the 36 evaluable patients was estimated to be 28%. Grades 3 and 4 hematological toxicities were neutropenia in 44% of patients, grade 2-3 diarrhea in 14% of patients, and grade 2 neuropathy in 12 patients. Median progression-free survival and overall survival were 5.8 and 9.2 months, respectively, with 1-year survival rate of 36%, [95% confidence interval (CI): 21-54%]. Median survival time from the diagnosis of metastatic disease was 31.5 months. Seventy-two percent of patients (n=26) (95% CI: 58-88%) obtained a clinical benefit from this chemotherapy regimen. PLD and LOHP is an active regimen, able to give palliation in a substantial percentage of MCG patients who have been pretreated with taxanes.

Beta-interferon, retinoids and tamoxifen in metastatic breast cancer: long-term follow-up of a phase II study.

Based on a series of in vitro data, including the additive and/or synergistic antiproliferative effect of interferon and tamoxifen on breast cancer cell lines, and on clinical reports, we designed a pilot phase II study to test the activity and toxicity of simultaneous administration of beta-interferon (beta-IFN), retinoids (R) and tamoxifen (TAM) as a salvage therapy in a group of patients with metastatic breast cancer (MBC). Herein we describe the outcome of this cohort of patients after a median follow-up of 150 months. Sixty-five stage IV breast cancer patients, 13 pre-treated with hormones, 38 with chemotherapy and 15 with both, received, as a salvage therapy, TAM, beta-IFN and R. Among 65 evaluable patients, 36 achieved a clinical response (55.5%) (95% c.i. 42-67.7%). Toxicity was moderate and mainly hepatic. Median progression-free and overall survival, which did not show any statistically significant difference in patients with different estrogen and progesterone receptor content, were 43 months and 47.9 months, respectively. In conclusion, the study shows that long-term treatment with TAM, beta-IFN and R in MBC is feasible, has moderate toxicity and seems to give a long-term benefit, irrespective of the receptorial status.

Immunotherapy in patients with less than complete response to chemotherapy.

BACKGROUND: Patients with metastatic solid tumors (MST) with less than a complete response to chemotherapy (L-CR), a depressed immune system and elevated serum vascular endothelial growth factor (VEGF) lack defined treatment options. The primary endpoint evaluated in this study was whether interleukin-2 (IL-2) and 13-cisretinoic acid (RA) treatment reduced VEGF and improved immune function in such patients. Secondary endpoints were objective response, relapse-free survival (RFS), and overall survival (OS). PATIENTS AND METHODS: One hundred consecutive MST patients with L-CR and a mean serum VEGF of 421.0 pg/mm3 were enrolled. Patients self-administered subcutaneous IL-2 1.8 x 10(6) IU/day, and oral RA 0.5 mg/kg/day x 5 days/week for 2 cycles of 3 weeks/month for 1 year and continued until progression. RESULTS: After a median follow-up of 78 months, a statistically significant VEGF decrease and improvements in lymphocyte, NK, and CD4+/CD8+ ratio were observed. Twenty-four patients were converted to a CR; their 5-year RFS and OS rates were each 96%. No WHO grade 3 or 4 toxicities were observed. CONCLUSION: Administration of IL-2/RA to this patient population produced a significant decrease in VEGF, improvement of prognostically relevant immunological parameters, and durable response in 25% of patients.

Maintenance immunotherapy in metastatic breast cancer.

Maintenance chemotherapy provides only a modest survival advantage in metastatic breast cancer (MBC). We have previously shown that a maintenance immunotherapy (MI) regimen based on low-dose interleukin-2 (IL-2) and 13-cis retinoic acid (RA) improved the lymphocyte and natural killer cell (NK) counts, and CD4+/CD8+ ratio in patients with a clinical benefit from chemotherapy. With the aim of improving progression-free survival (PFS), 100 consecutive MBC patients with a clinical benefit from chemotherapy were treated with an MI. Patients with MBC were eligible if they had no evidence of progression after 6-8 courses of epirubicin-paclitaxel induction chemotherapy. Treatment consisted of low-dose IL-2 and oral RA given until progression. The primary endpoint was progression-free survival (PFS); secondary endpoints were toxicity, overall survival (OS), and changes in immunological parameters. From 04/1997 to 04/2002, 100 patients with MBC were enrolled. After a median follow-up of 49 months, median PFS and OS were 37.1 and 57.5 months, respectively. No WHO grade 3 or 4 toxicity was observed; grade 2 cutaneous toxicity and autoimmune reactions occurred in 19 and 16% of patients, respectively. A sustained improvement in lymphocytes, NKs, and in the CD4+/CD8+ ratio was observed, with respect to baseline values. In conclusion, MI with IL-2 and RA in MBC patients who do not progress after 6-8 courses of chemotherapy is well-tolerated, improves lymphocyte, NK, CD4+/CD8+ ratio, and appears to delay disease recurrence. A randomized trial is warranted.

Dose-finding study of docetaxel added to ifosfamide and cisplatin followed by concomitant capecitabine and radiotherapy in the treatment of locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Docetaxel (DOC) is a promising new drug in the management of squamous cell carcinoma of the head and neck. The aim of this phase I study was to determine the toxicity and maximum tolerated dose (MTD) as well as to obtain preliminary data on the activity of DOC combined with fixed doses of ifosfamide (IFO) and cisplatin (CDDP), followed by concomitant capecitabine (C) and radiation therapy in the organ-sparing treatment of patients with locally advanced, inoperable squamous cell carcinoma of the head and neck (A-SCCHN). PATIENTS AND METHODS: Chemotherapy and radiotherapy-naive patients with A-SCCHN were treated in cohorts of three with escalating doses of DOC administered on day 1. The doses of DOC ranged from 40 mg/m2 up to the dose-limiting toxicity (DTL). Fixed doses of IFO (1200 mg/m2) with mesna and CDDP (20 mg/m2) were administered on days 1 to 4, every 4 weeks. Patients who had achieved a response received definitive radiation therapy (6000 cGy) concomitantly with C (1000 mg/m2/day). RESULTS: Twenty-four patients were entered into the study. The MTD of DOC was 70 mg/m2. A total of 99 courses of chemotherapy were given. Grade 3 and 4 hematological toxicities were observed in twelve and nine patients, respectively, while grade 3 gastrointestinal toxicity occurred in four patients. Concomitant C and radiation therapy demonstrated a tolerable toxicity profile. An overall response rate of 83.3% (95% CI: 65.6% to 95.2%) was obtained, with a median time to progression and overall survival of 15.6 and 22.3 months, respectively. CONCLUSION: Out-patient administration of DOC, IFO and CDDP for A-SCCHN was safe and did not affect the ability to administer chemoradiotherapy on schedule. Myelosuppression was the DLT.

Cardiac metastases in malignant fibrous histiocytoma. A case report.

Malignant fibrous histiocytoma metastasizing to the left ventricle is an uncommon form of cardiac malignancy. This report describes a rare case of left ventricular metastases from a malignant fibrous histiocytoma of the posterior compartment of the right thigh, recurring five years after treatment with surgery, hyperthermic perfusion of the limb and radiotherapy. As the patient presented symptoms of cardiac tamponade, open heart surgery was performed through a median sternotomy; however, the tumor was not resectable and only a biopsy was performed. A partial response was obtained with standard and high-dose chemotherapy with peripheral blood progenitor cell transplantation. The response continued to improve with immunotherapy. The patient returned to normal physical activity. He died four years later due to a ventricular arrhythmia.

Interleukin-2 and 13-cis retinoic acid as maintenance therapy in advanced ovarian cancer.

The primary objective was to assess whether low-dose Interleukin-2 (IL-2) and 13-cis-retinoic acid (RA) could decrease serum vascular endothelial growth factor (VEGF) and improve the immune function of patients with advanced ovarian cancer (AOC) responsive to chemotherapy. The secondary end-point was to compare the response of these patients with that of a group of control patients, treated with standard care. Forty-four patients with AOC, responding to chemotherapy and with elevated serum levels of VEGF, were entered into the study from 04/98 to 12/02. After chemotherapy, patients received self-administered subcutaneous IL-2, 1.8x10(6) IU and oral RA, 0.5 mg/kg for 5 days/week for 2 consecutive cycles of 3 weeks, with a 1-week rest, for 1 year and with intermittent schedules for up to 5 years. Eighty-two well-matched controls were selected from a large cohort of patients of similar disease status, treated with standard therapies. A statistically significant decrease of VEGF was observed amongst the 44 evaluable patients. Lymphocyte NK counts and CD4+/CD8+ ratio improved with respect to both baseline values and controls. The progression-free survival (PFS) and overall survival (OS) curves showed a statistically significant improvement in IL-2/RA-treated patients. These preliminary data show that, after chemotherapy for AOC, the administration of low-dose subcutaneous IL-2 and oral RA is feasible, has low toxicity, is cost-effective and improves both PFS and OS.

Paclitaxel plus gemcitabine in advanced non-small cell lung cancer patients with low performance status.

BACKGROUND: The aim was to determine the efficacy and safety of a platinum-free regimen combining gemcitabine and paclitaxel for the treatment of patients with advanced non-small cell lung cancer (NSCLC) and a low performance status (PS). PATIENTS AND METHODS: Patients with histologically confirmed unresectable NSCLC, no previous chemotherapy, measurable lesion and a PS of 2 or 3 according to the Eastern Cooperative Oncology Group (ECOG) scale were elegible. Chemotherapy consisted of paclitaxel 200 mg/m2 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 3 weeks, for a maximum of 8 cycles. RESULTS: Twenty-nine consecutive patients were enrolled. PS was 2 and 3 in 93% and 7% of patients, respectively. A total of 149 courses of chemotherapy were delivered (median 4.6). Responses: complete response 1 (3.4%), partial response 11 (37.9%), stable disease 12 (41.3%), progressive disease 5 (17.2%) (response rate 41.3%, 95% CI. 23.5% to 61.6%). Median time to progression was 8.3 months (range 2.9-31.7); median overall survival was 13.6 months (range 3.2-31.7). Grade 3 leukopenia occurred in 3% of patients, while grade 3 thrombocytopenia was observed in 25% of patients. CONCLUSION: Reasonable response rates and a satisfactory clinical benefit can be obtained with a platinum-free regimen in NSCLC patients with a low PS.

Phase II randomized study of interleukin-2 with or without 13-cis retinoic acid as maintenance therapy in patients with advanced cancer responsive to chemotherapy.

AIM: In a previous phase 1B study, we determined the optimal biological dose of interleukin-2 (IL-2) and 13-cis retinoic acid (RA), given as maintenance therapy to patients with a variety of solid tumors, responding to chemotherapy, with a high risk of relapse. This therapy produced a statistically significant increase of the CD4+/CD8+ ratio, natural killer (NK) and lymphocyte cell counts and a decrease of vascular endothelial growth factor (VEGF). The aim of this phase II randomized study was to verify the role of RA in this drug combination. PATIENTS AND METHODS: One hundred and twelve patients, with locally advanced or metastatic tumors responding to chemotherapy, were randomized to receive IL-2, 1.8 x 10(6) I.U. for 5 days/week for 2 consecutive cycles of 3 weeks, with a 1-week interval (arm A), or the same regimen plus oral RA, 0.5 mg/Kg (arm B). VEGF, the CD4+/CD8+ ratio, NK and tumor markers were assessed every 2 months and response every 4 months. RESULTS: The baseline characteristics were well balanced between the two treatment arms for age, performance status, type of disease, amount of previous chemotherapy and baseline values of NK, CD4+/CD8+ and VEGF. Toxicity was minor in both arms. After a median follow-up of 42 months, all immunological parameters improved in both arms with respect to the baseline values; this improvement was statistically more significant in arm B. There was no statistically significant difference in progression-free and in overall survival between the two arms. CONCLUSION: These data show that low-dose IL-2 and oral RA is more effective than IL-2 alone in improving all known prognostically significant parameters in a variety of solid tumors, including an increase of lymphocytes and a decrease of VEGF.

LH-RH analogues in the treatment of young women with early breast cancer: long-term follow-up of a phase II study.

To prevent premature ovarian failure (POF), high-risk, premenopausal women with early breast cancer were given a luteinizing-hormone releasing hormone (LH-RH) analogue during adjuvant chemotherapy. After an adriamycin-based regimen, patients received radiation therapy concomitant with cyclophosphamide, methotrexate and 5-fluorouracil. An aromatase inhibitor was given to patients positive for the estrogen receptor (ER+). The median age was 43 years (range, 26-45). Among 200 consecutive patients, 46% had no axillary node, and 54% had a mean of 5.4 positive nodes (range, 1-25); 56% were ER+, 44% were estrogen receptor negative (ER-), 13% were triple negative, and 20 had tumors positive for the oncogene, c-erb-B2 (identified with fluorescent in situ hybridization). After a median follow-up of 105 months (range, 65-180), no patient under 40 years old exhibited POF, while 44% of patients over 40 years old exhibited POF. Eight pregnancies were recorded: 7 at term and 1 voluntary interruption. The 10-year disease-free survival and overall survival rates were 85 and 91%, respectively. These data showed that, in premenopausal patients with early breast cancer, the addition of an LH-RH analogue to adjuvant chemotherapy was well tolerated, prevented POF, and was associated with excellent disease-free survival and overall survival rates.

Adjuvant Ovarian Suppression, High-dose Chemotherapy and Immunotherapy for Premenopausal Patients with High-risk Breast Cancer.

BACKGROUND: Premenopausal patients with breast cancer and more than 10 positive axillary nodes (BC>10) have a poor prognosis: In these patients the best adjuvant therapy (CT) has not yet been established. PATIENTS AND METHODS: Forty-two BC>10 received, in sequence, the following adjuvant treatments: luteinizing hormone releasing hormone (LH-RH) analog for 5 years; anthracycline-based induction chemotherapy; radiation therapy; platinum-based high-dose CT, with autologous bone marrow transplantation; immunotherapy with interleukin 2 (IL2) and 13-cis retinoic acid (RA); anastrazole given 5 years to estrogen receptor-positive patients. Primary endpoints of the study were disease-free survival (DFS) and overall (OS) survival. A secondary endpoint was toxicity. RESULTS: The median age of patients was 41 years, and the mean number of positive axillary nodes was 14. Estrogen and progesterone receptors were positive in 57% and 29% of patients respectively, while 14% of patients had triple-negative disease. With a median follow-up of 120 months for patients remaining alive at the end of study, median DFS and OS, had not yet been reached. The 20-year DFS and OS rates were 63.8%, and 81.6%, respectively. One to two years after the end of the therapy, three patients had had four full-term pregnancies. CONCLUSION: Treatment with LH-RH analog, high-dose CT, peripheral blood progenitor cells and IL2 with RA for patients with BC>10 is feasible, has moderate toxicity, while preserving ovarian function, seems to improve the expected DFS and OS for these high-risk patients.