Sex and Gender in Ageing and Longevity: Highlights From an International Course.

Gender medicine is a multidisciplinary science and represents an important perspective for pathophysiological and clinical studies in the third millennium. Here, it is provided an overview of the topics discussed in a recent course on the Role of Sex and Gender in Ageing and Longevity. The paper highlights three themes discussed in the course, i.e., the interaction of gender/sex with, i) the pathophysiology of age-related diseases; ii), the role of genetics and epigenetics in ageing and longevity and, iii) the immune responses of older people to pathogens, vaccines, autoantigens, and allergens. Although largely unexplored, it is clear that sex and gender are modulators of disease biology and treatment outcomes. It is becoming evident that men and women should no longer be considered as subgroups, but as biologically distinct groups of patients deserving consideration for specific therapeutic approaches.

Cancer in the older person.

Cancer in the older person is an increasingly common problem, due to the progressive prolongation of the life-expectancy of the Western population. This article reviews the mechanisms associating aging and cancer, age-related changes in cancer biology, assessment of the older person to estimate life-expectancy, treatment tolerance, and medical and social conditions that may interfere with cancer treatment, effectiveness of cancer prevention and cancer treatment in older individuals. A comprehensive geriatric assessment (CGA) is commonly used to predict life-expectancy and functional reserve and to unearth conditions that may jeopardize cancer prevention and treatment. In the interest of cost and time, shortened forms of CGA are being explored. Chemoprevention of cancer is a promising form of prevention that at present has no conclusive clinical indications. Early diagnosis of breast and colon cancer through screening of asymptomatic patients at risk may be beneficial for individuals with a life-expectancy of 5 years or longer. Early detection of lung cancer in ex-smokers is undergoing clinical trials, as this disease is becoming more and more common. Age should not prevent appropriate treatment of cancer in older individuals, especially in those with adequate life-expectancy and functional reserve. The National Cancer Center Network (NCCN) has issued a series of guidelines to minimize the toxicity and promote the effectiveness of cancer in older patients. Important interventions include prevention of neutropaenic infections with filgrastim and peg-filgrastim, prevention of anaemia with epoietin or darbepoietin, and prevention and early management of mucositis.

Supportive care of the older cancer patient.

Aging is associated with decreased functional reserve of multiple organ systems and with changes in the pharmacokinetics and pharmacodinamics of drugs. Older individuals express enhanced susceptibility to the complications of cytotoxic chemotherapy, especially to myleotoxicity, mucositis, cardiotoxicity and neurotoxicity. The management of older individuals with chemotherapy involves then prevention of these complications. General precautions include proper patient selection, based on the comprehensive geriatric assessment (CGA), dose adjustment for agents that are renally excreted to the patient creatinine clearance and maintenance of hemoglobin levels > or =12 g/dl. Filgrastim and pegfilgrastim proved effective in reducing by 50-75% the risk of neutropenic fever in older individuals treated with CHOP and CHOP-like chemotherapy and should be used for the prophilaxis of infections. When feasible, the oral agent capecitabine, should be used in lieu of intravenous fluorinated pyrimidines, to prevent mucositis. In patients at risk of cardiomyopathy from anthracyclines, dexrazoxane or liposomal compounds may be indicated. When toxicity is properly prevented, cytotoxic chemotherapy may be as effective in older individuals as it is in the younger ones.

Use of growth factors in the elderly patient with cancer: a report from the Second International Society for Geriatric Oncology (SIOG) 2001 meeting.

Over 70% of the total incidence of cancer recorded in Europe in 1996 was in the elderly population (> or =60 years). Despite such high statistics, elderly cancer patients have often been denied the treatment that younger patients routinely receive. The response of elderly cancer patients to full-dose chemotherapy treatment in several neoplasms is similar to that of younger patients, demonstrating that age should not be a barrier to the administration of potentially curative or palliative chemotherapy. In order to provide optimal treatment to elderly cancer patients, management guidelines are recommended which take into account various factors, such as the physical well-being of the patient, the type of malignancy and any conditions that may hamper compliance with chemotherapy. The evidence-based guidelines of the National Comprehensive Cancer Network (NCCN) in the US recommend that the safest and most effective treatment of cancer in older individuals may be achieved by proper patient selection based on comprehensive geriatric assessment, dose adjustment of renally excreted drugs, prophylactic use of haematopoietic growth factors in patients treated with chemotherapy of dose-intensity comparable to cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) and maintenance of haemoglobin levels > or =12 g/l. The objective of this article is to report the conclusions of the meeting of the International Society of Geriatric Oncology (SIOG) in September 2001, including the need for geriatric assessment to tailor the management of patients to their personal circumstances and general health and the importance of evidence-based guidelines for the management of elderly cancer patients cannot be over-estimated.

The role of myelopoietic growth factors in managing cancer in the elderly.

More than 50% of all malignancies are diagnosed in patients aged > 65 years and most cancer-related deaths occur in this population. Misconceptions about prognosis and treatment contribute to the undertreatment of elderly cancer patients and consequent poor outcomes. Although older patients have been excluded from cancer treatment trials in the past, response rates to chemotherapy in a variety of common cancers in otherwise healthy elderly patients are comparable to those attained in younger patients. Lower functional reserve in many organ systems alters the pharmacokinetics of chemotherapeutic drugs as well as the patient's response to treatment-induced toxicity. Except for myelosuppression and mucositis, otherwise fit elderly cancer patients are not at significantly enhanced risk of toxicity to chemotherapy. Severe neutropenia and related infection are encountered much more frequently during the treatment of elderly as compared with younger cancer patients. These lead to treatment delays, dose reductions and higher hospitalisation rates. Myelopoietic growth factor support reduces myelosuppression and the associated risk of severe infection, thereby allowing delivery of chemotherapy at full dose intensity. Beneficial responses to granulocyte colony-stimulating factor (G-CSF; filgrastim) in elderly patients have been found in aggressive non-Hodgkin's lymphoma with standard cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) therapy and acute myeloid leukaemia (AML) during induction and consolidation chemotherapy. Granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim) has been found to reduce myelosuppression in elderly AML patients receiving induction but not consolidation chemotherapy. These prophylactic treatments produce significant cost benefits because of the reduced hospitalisation and antibiotic use associated with neutropenia. To maximise positive outcomes, elderly patients should be included in clinical trials of new cancer agents. Since myelosuppression is the main risk factor for elderly patients undergoing chemotherapy, optimisation of growth factor support and the development of more effective and safer myelopoietic agents may improve success rates and reduce adverse events. Such information will lead to better management of cancer in older patients.

Cancer chemotherapy in the older cancer patient.

This article reviews the principles of systemic cancer treatment in older individuals. These include: assessment of physiologic age with a comprehensive geriatric assessment (CGA), adjustment of chemotherapy doses to the patient's renal function, and prevention of myelotoxicity with hemopoietic growth factors. Other complications that become more common with age include mucositis, peripheral neuropathy and cardiomyopathy. Two chronic complications of chemotherapy become more common with age, including myelodysplasia and chronic cardiomyopathy. The goal of systemic cancer treatment in the older person should include prolongation of active life-expectancy and compression of morbidity in addition to prolongation of survival and symptom management.

Gemcitabine-based doublets versus single-agent therapy for elderly patients with advanced nonsmall cell lung cancer: a Literature-based Meta-analysis.

BACKGROUND: : Although platinum-based combinations are considered the best option of care for patients with advanced nonsmall cell lung cancer (NSCLC), single-agent therapy is the preferred treatment for older patients. Since the late 1990s, various combinations of third-generation agents (gemcitabine [G], vinorelbine, docetaxel, and paclitaxel) have been tested, yielding contradictory results. The authors of this report performed a literature-based meta-analysis to assess the efficacy and tolerability of G-based doublets compared with single-agent chemotherapy for elderly patients with NSCLC. METHODS: : Data from all published, randomized, phase 3 trials that compared a G-based doublet with a third-generation single agent in elderly patients were collected from electronic databases (Medline and the Cochrane Central Register of Controlled Trials), relevant reference lists, and abstract books. Pooled odds ratios (ORs) were calculated for the 1-year survival rate, the overall response rate (ORR), and grade 3 and 4 toxicities. RESULTS: : Four eligible trials (1436 patients) were selected from 442 studies that initially were identified. A significant difference in ORR favoring G-based doublets over single agents was observed (OR, 0.65; 95% confidence interval [95% CI], 0.51-0.82 [P < .001]), whereas the trend toward an improved 1-year survival rate was not significant (OR, 0.78; 95% CI, 0.57-1.06 [P = .169]). Grade 3 and 4 toxicities did not differ significantly except for thrombocytopenia (OR, 1.76; 95% CI, 1.12-2.76 [P = .014]). CONCLUSIONS: : G-based doublets appeared to be effective and feasible compared with single agents in the treatment of elderly patients with advanced NSCLC who were not suitable for full-dose, platinum-based chemotherapy. Further prospective, elderly specific, phase 3 trials will be necessary. Cancer 2009. (c) 2009 American Cancer Society.

Weekly dose-dense cisplatin-epirubicin-paclitaxel administration with granulocyte colony-stimulating factor support does not substantially improve prognosis in extensive disease small-cell lung cancer. A SICOG phase II study.

PURPOSE: The present study was aimed at defining the antitumor activity of the cisplatin-epirubicin-paclitaxel (PET) weekly administration with granulocyte colony-stimulating factor (G-CSF) support in chemonaive small-cell lung cancer patients with extensive disease (ED-SCLC). METHODS: Chemonaive ED-SCLC patients received cisplatin 30 mg/sqm, epirubicin 50 mg/sqm and paclitaxel 120 mg/sqm, weekly, with G-CSF (5 microg/kg from day 3 to 5) support, for a maximum of 12 weeks. RESULTS: Thirty-nine patients were treated, for a total of 354 cycles delivered. Eight complete (21%), and 22 partial responses (56%) were recorded, giving a 77% (95% CI = 61-89%) objective response rate (ORR). After 14 (range, 7-28)-month median follow-up, 24 deaths have occurred. Median progression-free and overall survival were 7 months and 11 months, with 1- and 2-year projected survivals of 45 and 24%, respectively. No toxic deaths occurred. Grade 4 neutropenia and thrombocytopenia occurred in 4 (10%) and 1 (3%) patients, respectively. Only one case of neutropenic sepsis was recorded, while hemorrhagic thrombocytopenia was never observed. Emesis, loss of appetite, mucositis and fatigue were the main nonhematological toxicities, being severe in 9, 8, 4 and 7 patients, respectively. CONCLUSIONS: The weekly PET combination with G-CSF support represents an active therapeutic approach in chemonaive ED-SCLC patients. However, both ORR and median survival does not seem substantially better than those achievable with a standard regimen. In view of that, and in consideration of the relevant nonhematological toxicity, this approach should not be pursued outside clinical trials.

Randomized multicenter Phase II trial of two different schedules of irinotecan combined with capecitabine as first-line treatment in metastatic colorectal carcinoma.

BACKGROUND: The aim of the current randomized Phase II study was to investigate the efficacy and safety of capecitabine combined with irinotecan as first-line treatment in metastatic colorectal carcinoma (CRC). METHODS: A total of 140 patients received capecitabine at a dose of 1250 mg/m(2) twice daily on Days 2-15 and irinotecan at a dose of either 300 mg/m(2) on Day 1 (Arm A) or 150 mg/m(2) on Days 1 and 8 (Arm B) every 3 weeks. During the course of the study, enrollment was continued using lower doses of capecitabine (1000 mg/m(2) twice daily) and irinotecan (Arm A: 240 mg/m(2); Arm B: 120 mg/m(2)) to improve the safety profile of the combinations. RESULTS: Efficacy was evaluable in 134 patients (68 in Arm A, 66 in Arm B). Objective responses were observed in 46% of the patients (8% complete response [CR]), including 47% in Arm A (9% CR; 38% partial response [PR]) and 44% in Arm B (8% CR; 36% PR). The median progression-free survival was 8.3 months in Arm A and 7.6 months in Arm B. Among the first 52 patients treated with the higher doses, the most frequent Grade 3-4 adverse event was diarrhea (27%). The lower doses adopted in the subsequent 88 patients led to better diarrhea control, particularly in Arm A, and significant reductions in the incidence of all-grade hand-foot syndrome and abdominal pain. CONCLUSIONS: The capecitabine and irinotecan combination was a highly active first-line therapy in metastatic CRC. An acceptable safety profile was observed after dose reduction, particularly when irinotecan was administered on 1 day.