Trine Lembrecht Jørgensen

Comorbidity in elderly cancer patients in relation to overall and cancer-specific mortality

Background:Aims of this study were to describe the prevalence of comorbidity in newly diagnosed elderly cancer cases compared with the background population and to describe its influence on overall and cancer mortality.Methods:Population-based study of all 70+ year-olds in a Danish province diagnosed with breast, lung, colorectal, prostate, or ovarian cancer from 1 January 1996 to 31 December 2006. Comorbidity was measured according to Charlsons comorbidity index (CCI). Prevalence of comorbidity in newly diagnosed cancer patients was compared with a control group by conditional logistic regression, and influence of comorbidity on mortality was analysed by Cox proportional hazards method.Results:A total of 6325 incident cancer cases were identified. Elderly lung and colorectal cancer patients had significantly more comorbidity than the background population. Severe comorbidity was associated with higher overall mortality in the lung, colorectal, and prostate cancer patients, hazard ratios 1.51 (95% CI 1.24–1.83), 1.41 (95% CI 1.14–1.73), and 2.14 (95% CI 1.65–2.77), respectively. Comorbidity did not affect cancer-specific mortality in general.Conclusion:Colorectal and lung cancer was associated with increased comorbidity burden in the elderly compared with the background population. Comorbidity was associated with increased overall mortality in elderly cancer patients but not consistently with cancer-specific mortality.

Comorbidity and survival after early breast cancer. A review.

INTRODUCTION Survival after breast cancer is determined by disease related factors such as stage at diagnosis, patient characteristics, e.g., age, and treatment. AIM To review evidence published during the last ten years on the effect of comorbidity on survival after early breast cancer. METHODS A search in Pubmed with keywords, breast neoplasm, comorbidity, and survival, was performed. A total of 18 studies published between 2000 and August 2010 was included in this review. RESULTS All 18 studies demonstrated that comorbidity had a significant impact on survival after breast cancer with poorer survival among patients with one or more comorbid conditions. The effect of comorbidity persisted after adjustment for age at diagnosis and stage of disease. Older patients with comorbidity were less likely to receive therapy according to guidelines. CONCLUSION Presence of comorbidity at diagnosis is an important prognostic factor in early breast cancer, irrespective of age and stage of disease.

Significance of age and comorbidity on treatment modality, treatment adherence, and prognosis in elderly ovarian cancer patients

BACKGROUND Age is associated with poor prognosis in ovarian cancer patients. Reasons could be increased comorbidity, more advanced stage, or nonoptimal surgery or chemotherapy. Objectives of this study were to evaluate the significance of comorbidity and age ≥70 years on receiving cytoreductive surgery, standard combination chemotherapy (TC), adherence to TC treatment, and prognosis. METHODS A retrospective cohort study of all women registered in a nation-wide database with ovarian or peritoneal cancer in 2005-2006. Logistic regression was employed for determining the predictive value of age and comorbidity (ASA score) on receiving cytoreductive surgery and TC, and on adhering to TC. Kaplan-Meier method and Cox proportional hazards analysis were employed for survival analyses. RESULTS Of 961 patients, 348 (36.2%) were elderly. Age ≥70 years was independently predictive of not receiving surgery, OR 0.2(95% CI 0.1-0.5) and TC treatment, OR 0.03 (95% CI 0.01-0.1). Comorbidity was also independently predictive of not receiving standard treatment: OR for receiving surgery with ASA score of ≥3 was 0.2 (95% CI 0.1-0.5), and for receiving TC it was 0.03 (95% CI 0.01-0.1). Overall, age ≥70 was a poor prognostic factor in OS and PFS, but the effect of age ceased after 16 months. Comorbidity was a poor prognostic factor throughout the study period but with time-varying effect. For patients treated with TC, age was not a prognostic factor, whereas ASA score ≥3 was. CONCLUSION Elderly patients and patients with comorbidity less often receive optimal surgical and medical treatment. For those receiving optimal treatment, age ≥70 is not an independent poor prognostic factor, whereas severe comorbidity is.

Long-term use of metformin and colorectal cancer risk in type II diabetics: a population-based case-control study

In vitro and animal studies indicate that metformin prevents colorectal cancer (CRC). Epidemiological studies, however, have been equivocal. We undertook this study to assess whether metformin prevents CRC in individuals with type II diabetes. We performed a nested case–control study restricted to Danish citizens with type II diabetes. Data were collected from four Danish nationwide registries. Cases were type II diabetics with a primary CRC between 2000 and 2009, and controls were sampled among subjects with type II diabetes. Long‐term exposure to metformin was defined by the redeeming of prescriptions for a cumulative dose of 2000 g within 5 years prior to the index date. To control for potential confounders, we used unconditional logistic regression. We generated adjusted odds ratios (OR) for the association between metformin and CRC and performed subanalyses for selected subgroups and for the dose–response relation. We identified 2088 cases and 9060 controls during the study period. The association between long‐term metformin use and CRC gave an adjusted OR at 0.83 (95% CI 0.68–1.00). A protective effect on CRC with long‐term use of metformin was only evident for women (OR 0.66 vs. 0.99 for men). There was a significant dose–response association of metformin use >250 defined daily dose (DDD) and for the duration of metformin use >1 year. We found an indication of a protective effect of long‐term metformin use against CRC in type II diabetics, although this effect was only seen in women.

Bevacizumab in combination with cetuximab and irinotecan after failure of cetuximab and irinotecan in patients with metastatic colorectal cancer

Abstract Background. The efficacy and safety of concurrent administration of irinotecan with the two monoclonal antibodies cetuximab and bevacizumab as fourth line therapy in heavily pretreated patients with metastatic colorectal cancer were evaluated. Patients and methods. Patients with metastatic colorectal cancer who had progressed on therapy with 5-FU, oxaliplatin and irinotecan in the first and second line setting and on the combination of irinotecan and cetuximab in third line setting independent of their KRAS mutation status, were treated with irinotecan and cetuximab combined with bevacizumab in a dosage of 5 mg/kg. All drugs were administered every second week. Results. From January 2007 to November 2008 27 patients were treated with cetuximab, irinotecan and bevacizumab. The triple-combination was well tolerated. Progression free survival (PFS) was 8.3 months and median overall survival (mOS) was 12.0 months. Two patients without KRAS mutation (7%) obtained a partial response and 17 (63%) had stable disease for at least two months. A retrospective KRAS mutation analysis revealed that there was a trend toward longer PFS and mOS in patients without KRAS mutations compared to patients with KRAS mutations with a PFS of 8.9 vs. 5.1 months and a mOS of 12.7 vs. 9.0 months. Conclusion. Bevacizumab is safe to add to irinotecan and cetuximab with a toxicity profile that seems to be similar to what would be expected from the agents alone. The results indicate that adding bevacizumab to irinotecan and cetuximab in a fourth line setting may induce a high rate of disease control in heavily pretreated patients with metastatic colorectal cancer.

Addition of sunitinib to cetuximab and irinotecan in patients with heavily pre-treated advanced colorectal cancer

Abstract Results of continuous sunitinib, in combination with cetuximab and irinotecan every other week (SIC) for compassionate use in heavily pre-treated patients with mCRC are presented. Patients and methods. Patients with mCRC resistant to oxaliplatin, irinotecan, 5-FU and cetuximab received SIC at two Danish oncologic departments. The regimen consisted of sunitinib given as a continuous-dosing in combination with cetuximab and irinotecan every other week (CetIri). The first six patients started with a daily oral dose of sunitinib of 12.5 mg. Subsequent patients started at a daily dose of 25 mg with the possibility to escalate to 37.5 mg. Results. Twenty-nine patients received SIC. No patient had an objective response, but 13 patients had subjective relief and 42% had stable disease. The median time to progression was 3.2 months and median overall survival was 7.4 months. Fatigue and leukopenia were the most frequently reported severe adverse event (18% grade 3 and 18% grade 3/4, respectively). Discussion. Sunitinib continuous-dosing with 25 mg/day can safely be combined with CetIri administered every other week.

Clopidogrel–Paclitaxel Drug–Drug Interaction: A Pharmacoepidemiologic Study

Paclitaxel is mainly eliminated by CYP2C8 in the liver. CYP2C8 is strongly inhibited by the clopidogrel metabolite acyl‐β‐D‐glucuronide. To determine if this interaction has clinical relevance, we identified 48 patients treated with clopidogrel and paclitaxel using databases and a prescription register. Peripheral sensory neuropathy was retrospectively evaluated from medical charts and compared to that of 88 age‐ and sex‐matched controls treated with paclitaxel and low‐dose aspirin. By a cumulative dose of 1,500 mg paclitaxel, 35% of the patients had developed severe neuropathy. The overall hazard ratio between clopidogrel use and severe paclitaxel neuropathy was 1.7 (95% confidence interval, 0.9–3.0). Among those receiving a high‐dose paclitaxel regimen, the hazard ratio was 2.3 (95% confidence interval, 1.1–4.5). Our study indicates that clopidogrel is associated with a clinically relevant increased risk of neuropathy in patients treated with high‐dose paclitaxel.

Can we predict toxicity and efficacy in older patients with cancer? Older patients with colorectal cancer as an example

Colorectal cancer is a disease of the elderly. As older and frail patients are under-represented in clinical trials, most of the evidence available on treatment of older metastatic colorectal patients with cancer originates from pooled analyses of the older patients included in large prospective clinical trials and from community-based studies. The aging process is highly individual and cannot be based on the chronological age alone. It is characterised by a decline in organ function with an increased risk of comorbidity and polypharmacy. These issues can result in an increased susceptibility to the complications of both the disease and treatment. Therefore, evaluation of performance status and the chronological age alone is not sufficient, and additionally assessment must be included in the treatment decision process. In the present review, we will focus on clinical aspects of treating older and frail metastatic colorectal patients with cancer, but also on the present knowledge on how to select and tailor therapy for this particular group of patients. Trial registration number EudraCT 2014-000394-39, pre-results.

It’s time to move forward in geriatric oncology

The greatest risk factor of developing malignancy is aging. In the Nordic countries, approximately 45% of newly diagnosed cancer patients and the major part of cancer survivors are aged 70 years or older [1,2]. However, most studies are conducted in highly selected groups of younger patients without significant comorbidity, and results from these studies set the standard of treatment for all cancer patients. It has been shown that whereas 67% of newly diagnosed cancer patients in the US are 65 years or older, only 33% of patients in oncologic clinical trials are in this age group. This distribution has not changed throughout the past decade [3,4]. This is also seen in the Nordic countries [5]. This fact raises concerns that many older patients will be undertreated because physicians worry they might not tolerate standard treatment regimens. Others might suffer from severe treatment toxicity due to frailty, not found by a routine examination. For quite some years now, there has been a special and increasing clinical interest in geriatric oncology. Aging is a heterogeneous process that involves a progressive decline in the functional reserve of multiple organs and systems, which increases the susceptibility to stress caused by disease, treatment, and complications to both [6]. The course of this process is highly individual, and a person’s functional status cannot be established on chronological age alone [7]. Recognizing these issues, there has been a major interest in developing tools for identifying patients who might and might not tolerate and benefit from routine oncologic treatment. In 2000, the International Society of Geriatric Oncology (SIOG) was founded. The goal of SIOG is to ‘‘foster the development of health professionals in the field of geriatric oncology, in order to optimize treatment of older adults with cancer’’ (www.siog.org). A comprehensive geriatric assessment (CGA) is defined as ‘‘a multidimensional, interdisciplinary diagnostic process focusing on determining an older person’s medical, psychosocial, and functional capabilities to develop a coordinated and integrated plan for treatment and long-term follow-up’’. In a non-oncologic geriatric population, a CGA can detect frailty and additionally CGA creates opportunities to improve functional status thus improving physical function, overall survival, and quality of life [8]. In older oncologic patients, a CGA identifies problems that are not found by a routine history or physical examination [9], but it also has potential to predict treatment-related toxicity and mortality [10,11]. However, most studies are small, retrospective and/or with very heterogeneous study populations, and further prospective studies in larger and more homogenous groups are warranted to establish the most important predictive parameters and their cut-off points. In two reviews of the literature on CGA in geriatric oncology up to 2012, it has not been possible to conduct a meta-analysis on the effect of a CGA on treatment toxicity and overall survival. This is due to the heterogeneity of both populations and the assessment methods used [12,13]. A CGA is time consuming, and many screening tools and models have been developed and tested to find patients in need of a CGA or simply to replace it. Up until now, no screening tool has been found adequate to replace a full CGA, and an SIOG expert panel could not recommend one over another [14]. Comparing results of a full CGA and various screening tools, the G8 and VES-13 and especially a combination of both, seem to have the highest sensitivity and specificity. Some studies have found G8 and VES-13 to predict both toxicity to chemotherapy and prognosis but again; others have not. An important point is that a CGA performed in collaboration with a geriatric specialist includes an intervention aimed at improving the patients’ condition, and this intervention might make the difference for the patient. As a physician in a busy everyday clinic, however, a quick tool that could help us differentiate the patients who would tolerate chemotherapy and benefit from it, from those who would not, would be invaluable. Published in this issue of Acta Oncologica is a prospective cohort study by Aaldriks et al., ‘‘Prognostic factors for the feasibility of chemotherapy and the Geriatric Prognostic Index (GPI) as risk profile for mortality before chemotherapy in the Elderly’’. A CGA was performed in 496 senior cancer patients before starting chemotherapy in four different hospitals during almost six years. The authors developed a three-item screening tool for prediction of chemotherapy feasibility and one for determining patient prognosis (GPI). The domains evaluated in this GA were nutritional status, cognitive status, co-medication, functional status, and psychosocial status. The authors found

Chemotherapy-induced febrile neutropenia and use of granulocyte colony-stimulating factors in older cancer patients

Background: Oral mucositis (OM) is a common debiliating adverse effect following high dose chemotherapy prior to bone marrow transplantation. OM often interferes with food intake and lead to malnutrition, weight loss and impaired quality of life. These adverse effects may require intravenous morphine for pain alleviation, Although uncomfortable to the patient, oral cryotherapy with ice chips has been shown to reduce the grade and extent of OM. Purpose: The purpose of the present study is to evaluate whether an intraoral cooling device has the same effectiveness as ice chips when it comes to cooling the oral mucosa. Method: Five healthy volunteers (mean age 36.2 years) chewed ice under surveillance for 30 minutes. Before the start of and immediately after the termination of the ice chewing, the intraoral mucosal temperature was measured using a modified thermometer. The same protocol was used to asses the cooling efficacy obtained by the newly developed intraoral device. Results: No statistical significant differences in cooling of teh oral mucosa (p=0.12) were obtained. The mean surface temperature following cooling was 25.7 degrees Celcius with ice chips and 24.7 degrees Celcius with the cooling device. Conclucion: The cooling device is as effective as ice chips in terms of cooling the oral mucosa. The next step in this research is to use the cooling devise to establish the highest surface temperature of the oral mucosa, during infusion of chemotherapy, that will still result in prevention of oral mucositis.Introduction Lifestyle interventions might be useful in the management of adverse effects of androgen deprivation therapy (ADT) in men with prostate cancer. Objectives To examine the effects of dietary and exercise interventions on quality of life (QoL), metabolic risk factors and androgen deficiency symptoms in men with prostate cancer undergoing ADT. Methods CINAHL, Cochrane library, Medline and PsychINFO were searched to identify randomised controlled trials published from January, 2004 to October, 2014. Data extraction and methodological quality assessment was independently conducted by two reviewers. Meta-analysis was conducted using RevMan® 5.3.5. Results Of 2183 articles retrieved, 11 studies met the inclusion criteria and had low risk of bias.Nine studies evaluated exercise (resistance and/or aerobic and/or counselling) and three evaluated dietary supplementation. Median sample size =79 (33–121) and median intervention duration was 12 weeks (12–24). Exercise improved QoL measures (SMD 0.26, 95%CI −0.01 to 0.53) but not body composition, metabolic risk or vasomotor symptoms. Qualitative analysis indicated soy (or isoflavone) supplementation did not improve vasomotor symptoms; however, may improve QoL. Conclusions Few studies have evaluated the efficacy of lifestyle interventions in the management of adverse effects of ADT. We found inconclusive results for exercise in improving QoL and negative results for other outcomes. For soy-based products, we found negative results for modifying vasomotor symptoms and inconclusive results for improving QoL. Future work should investigate the best mode of exercise for improving QoL and other interventions such as dietary counselling should be investigated for their potential to modify these outcomes.