Stewart-Treves syndrome in an older woman successfully treated by metronomic chemotherapy: case report and literature survey.

The authors present the case of a 94-year-old woman suffering from a right arm angiosarcoma developed after primary breast cancer and treated with success by oral metronomic chemotherapy based on daily low doses of cyclophosphamide and prednisone. The case description is followed by a short review of actual knowledge on the subject.

Incidence of falls and fall-related injuries and their predictive factors in frail older persons with cancer: a multicenter study.

BACKGROUND: Falls and fall-related injuries are a major public health problem. Data on falls in older persons with cancer is limited and robust data on falls within those with a frailty profile are missing. The aim of this study is to investigate the incidence and predictive factors for falls and fall-related injuries in frail older persons with cancer. METHODS: This study is a secondary data analysis from data previously collected in a large prospective multicenter observational cohort study in older persons with cancer in 22 Belgian hospitals (November 2012-February 2015). Patients ≥70 years with a malignant tumor and a frailty profile based on an abnormal G8 score were included upon treatment decision and evaluated with a Geriatric Assessment (GA). At follow-up, data on falls and fall-related injuries were documented. RESULTS: At baseline 2141 (37.2%) of 5759 included patients reported at least one fall in the past 12 months, 1427 patients (66.7%) sustained an injury. Fall-related data of 3681 patients were available at follow-up and at least one fall was reported by 769 patients (20.9%) at follow-up, of whom 289 (37.6%) fell more than once and a fall-related injury was reported by 484 patients (62.9%). Fear of falling was reported in 47.4% of the patients at baseline and in 55.6% of the patients at follow-up. In multivariable analysis, sex and falls history in the past 12 months were predictive factors for both falls and fall-related injuries at follow-up. Other predictive factors for falls, were risk for depression, cognitive impairment, dependency in activities of daily living, fear of falling, and use of professional home care. CONCLUSION: Given the high number of falls and fall-related injuries and high prevalence of fear of falling, multifactorial falls risk assessment and management programs should be integrated in the care of frail older persons with cancer. Further studies with long-term follow-up, subsequent impact on cancer treatment and interventions for fall prevention, and integration of other important topics like medication and circumstances of a fall, are warranted. TRIAL REGISTRATION: B322201215495.

Efficacy and safety of chronomodulated irinotecan, oxaliplatin, 5-fluorouracil and leucovorin combination as first- or second-line treatment against metastatic colorectal cancer: Results from the International EORTC 05011 Trial.

The triplet combination of irinotecan, oxaliplatin and fluorouracil is an active frontline regimen in metastatic colorectal cancer, but scarce data exist on its use as salvage treatment. We aimed at assessing its safety and efficacy profiles with its circadian-based administration (chronoIFLO5) as either first- or second-line treatment, within the time-finding EORTC 05011 trial. Five-day chronoIFLO5 was administered every 3 weeks in patients with PS 0, 1 or 2. It consisted of chronomodulated irinotecan (180 mg/sqm), oxaliplatin (80 mg/sqm) and fluorouracil-leucovorin (2800 and 1200 mg/sqm, respectively). For our study, toxicity and antitumour activity were evaluated separately in first- and second-line settings. Primary endpoints included Grade 3-4 toxicity rates, best objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). One-hundred forty-nine and 44 patients were treated in first-line and second-line settings, respectively, with a total of 1138 cycles with median relative dose intensities of about 90%. Demographics were comparable in the two groups. Thirty-six (24.7%) and 10 (22.2%) patients experienced at least one episode of severe toxicity in first line and second line, respectively. Frontline chronoIFLO5 yielded an ORR of 62.3% [95% CI: 54.2-70.4] and resulted in median PFS and OS of 8.7 months [7.5-9.9] and 19.9 months [15.4-24.5]. Corresponding figures in second line were 37.5% [22.5-52.5], 6.7 months [4.8-8.9] and 16.3 months [11.8-20.8]. International and prospective evaluation revealed the favourable safety and efficacy profiles of chronoIFLO5, both as frontline and as salvage treatment against metastatic colorectal cancer. In particular, encouraging activity in second line was observed, with limited haematological toxicity.

Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228).

BACKGROUND: The hepatic artery infusion (HAI) of irinotecan, oxaliplatin and 5-fluorouracil with intravenous cetuximab achieved outstanding efficacy in previously treated patients with initially unresectable liver metastases from colorectal cancer. This planned study aimed at the identification of pharmacogenetic predictors of outcomes. METHODS: Circulating mononuclear cells were analysed for 207 single-nucleotide polymorphisms (SNPs) from 34 pharmacology genes. Single-nucleotide polymorphisms passing stringent Hardy-Weinberg equilibrium test were tested for their association with outcomes in 52 patients (male/female, 36/16; WHO PS, 0-1). RESULTS: VKORC1 SNPs (rs9923231 and rs9934438) were associated with early and objective responses, and survival. For rs9923231, T/T achieved more early responses than C/T (50% vs 5%, P=0.029) and greatest 4-year survival (46% vs 0%, P=0.006). N-acetyltransferase-2 (rs1041983 and rs1801280) were associated with up to seven-fold more macroscopically complete hepatectomies. Progression-free survival was largest in ABCB1 rs1045642 T/T (P=0.026) and rs2032582 T/T (P=0.035). Associations were found between toxicities and gene variants (P<0.05), including neutropenia with ABCB1 (rs1045642) and SLC0B3 (rs4149117 and rs7311358); and diarrhoea with CYP2C9 (rs1057910), CYP2C19 (rs3758581), UGT1A6 (rs4124874) and SLC22A1 (rs72552763). CONCLUSION: VKORC1, NAT2 and ABCB1 variants predicted for HAI efficacy. Pharmacogenetics could guide the personalisation of liver-targeted medico-surgical therapies.

Fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancer.

BACKGROUND: Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the early occurrence of chemotherapy-induced symptoms correlated with circadian disruption would selectively hinder the efficacy of chronotherapy. METHODS: Fatigue and weight loss (FWL) were considered to be associated with circadian disruption based on previous data. Patients with metastatic colorectal cancer (n = 543) from an international phase 3 trial comparing FOLFOX2 with chronoFLO4 were categorized into 4 subgroups according to the occurrence of FWL or other clinically relevant toxicities during the initial 2 courses of chemotherapy. Multivariate Cox models were used to assess the role of toxicity on the time to progression (TTP) and overall survival (OS). RESULTS: The proportions of patients in the 4 subgroups were comparable in both treatment arms (P = .77). No toxicity was associated with TTP or OS on FOLFOX2. The median OS on FOLFOX2 ranged from 16.4 (95% confidence limits [CL], 7.2-25.6 months) to 19.8 months (95% CL, 17.7-22.0 months) according to toxicity subgroup (P = .45). Conversely, FWL, but no other toxicity, independently predicted for significantly shorter TTP (P < .0001) and OS (P = .001) on chronoFLO4. The median OS on chronoFLO4 was 13.8 months (95% CL, 10.4-17.2 months) or 21.1 months (95% CL, 19.0-23.1 months) according to presence or absence of chemotherapy-induced FWL, respectively. CONCLUSIONS: Early onset chemotherapy-induced FWL was an independent predictor of poor TTP and OS only on chronotherapy. Dynamic monitoring to detect early chemotherapy-induced circadian disruption could allow the optimization of rapid chronotherapy and concomitant improvements in safety and efficacy.

Linking clinical and population-based data in older patients with cancer in Belgium: Feasibility and clinical outcomes.

INTRODUCTION: Geriatric screening and geriatric assessment (GS/GA) have proven their benefits in the care for older patients with cancer. However, less is known about the predictive value of GS/GA for outcomes. To research this, clinical data on GS/GA can be enriched with population-based data. In this article we describe the methods and feasibility of data linkage, and first clinical outcomes (GS/GA results and overall survival). MATERIALS AND METHODS: A large cohort study consisting of patients aged ≥70 years with a new cancer diagnosis was established using linked data from clinical and population-based databases. Clinical data were derived from a previous prospective study where older patients with cancer were screened with G8, followed by GA in case of an abnormal result (GS/GA study; 2009-2015). These data were linked to cancer registration data from the Belgian Cancer Registry (BCR), reimbursement data of the health insurance companies (InterMutualistic Agency, IMA), and hospital discharge data (Technical Cell, TCT). Cox regression analyses were conducted to evaluate the prognostic value of the G8 geriatric screening tool. RESULTS: Of the 8067 eligible patients with a new cancer diagnosis, linkage of data from the GS/GA study and data from the BCR was successful for 93.7%, resulting in a cohort of 7556 patients available for the current analysis. Further linkage with the IMA and TCT database resulted in a cohort of 7314 patients (96.8%). Based on G8 geriatric screening, 67.9% of the patients had a geriatric risk profile. Malnutrition and functional dependence were the most common GA-identified risk factors. An abnormal baseline G8 score (≤14/17) was associated with lower overall survival (adjusted HR [aHR] = 1.62 [1.50-1.75], p < 0.001). DISCUSSION: Linking clinical and population-based databases for older patients with cancer has shown to be feasible. The GS/GA results at cancer diagnosis demonstrate the vulnerability of this population and the G8 score showed prognostic value for overall survival. The established cohort of almost 8000 patients with long-term follow-up will serve as a basis in the future for detailed analyses on long-term outcomes beyond survival.

End-of-Life Care in the Last Three Months before Death in Older Patients with Cancer in Belgium: A Large Retrospective Cohort Study Using Data Linkage.

This study aims to describe end-of-life (EOL) care in older patients with cancer and investigate the association between geriatric assessment (GA) results and specialized palliative care (SPC) use. Older patients with a new cancer diagnosis (2009-2015) originally included in a previous multicentric study were selected if they died before the end of follow-up (2019). At the time of cancer diagnosis, patients underwent geriatric screening with Geriatric 8 (G8) followed by GA in case of a G8 score ≤14/17. These data were linked to the cancer registry and healthcare reimbursement data for follow-up. EOL care was assessed in the last three months before death, and associations were analyzed using logistic regression. A total of 3546 deceased older patients with cancer with a median age of 79 years at diagnosis were included. Breast, colon, and lung cancer were the most common diagnoses. In the last three months of life, 76.3% were hospitalized, 49.1% had an emergency department visit, and 43.5% received SPC. In total, 55.0% died in the hospital (38.5% in a non-palliative care unit and 16.4% in a palliative care unit). In multivariable analyses, functional and cognitive impairment at cancer diagnosis was associated with less SPC. Further research on optimizing EOL healthcare utilization and broadening access to SPC is needed.

Long-term health-care utilisation in older patients with cancer and the association with the Geriatric 8 screening tool: a retrospective analysis using linked clinical and population-based data in Belgium.

BACKGROUND: Little evidence is available on the long-term health-care utilisation of older patients with cancer and whether this is associated with geriatric screening results. We aimed to evaluate long-term health-care utilisation among older patients after cancer diagnosis and the association with baseline Geriatric 8 (G8) screening results. METHODS: For this retrospective analysis, we included data from three cohort studies for patients (aged ≥70 years) with a new cancer diagnosis who underwent G8 screening between Oct 19, 2009 and Feb 27, 2015, and who survived more than 3 months after G8 screening. The clinical data were linked to cancer registry and health-care reimbursement data for long-term follow-up. The occurrence of outcomes (inpatient hospital admissions, emergency department visits, use of intensive care, contacts with general practitioner [GP], contacts with a specialist, use of home care, and nursing home admissions) was assessed in the 3 years after G8 screening. We assessed the association between outcomes and baseline G8 score (normal score [>14] or abnormal [≤14]) using adjusted rate ratios (aRRs) calculated from Poisson regression and using cumulative incidence calculated as a time-to-event analysis with the Kaplan-Meier method. FINDINGS: 7556 patients had a new cancer diagnosis, of whom 6391 patients (median age 77 years [IQR 74-82]) met inclusion criteria and were included. 4110 (64·3%) of 6391 patients had an abnormal baseline G8 score (≤14 of 17 points). In the first 3 months after G8 screening, health-care utilisation peaked and then decreased over time, with the exception of GP contacts and home care days, which remained high throughout the 3-year follow-up period. Compared with patients with a normal baseline G8 score, patients with an abnormal baseline G8 score had more hospital admissions (aRR 1·20 [95% CI 1·15-1·25]; p<0·0001), hospital days (1·66 [1·64-1·68]; p<0·0001), emergency department visits (1·42 [1·34-1·52]; p<0·0001), intensive care days (1·49 [1·39-1·60]; p<0·0001), general practitioner contacts (1·19 [1·17-1·20]; p<0·0001), home care days (1·59 [1·58-1·60]; p<0·0001), and nursing home admissions (16·7% vs 3·1%; p<0·0001) in the 3-year follow-up period. At 3 years, of the 2281 patients with a normal baseline G8 score, 1421 (62·3%) continued to live at home independently and 503 (22·0%) had died. Of the 4110 patients with an abnormal baseline G8 score, 1057 (25·7%) continued to live at home independently and 2191 (53·3%) had died. INTERPRETATION: An abnormal G8 score at cancer diagnosis was associated with increased health-care utilisation in the subsequent 3 years among patients who survived longer than 3 months. FUNDING: Stand up to Cancer, the Flemish Cancer Society.

Prediction of overall survival through circadian rest-activity monitoring during chemotherapy for metastatic colorectal cancer.

The clinical relevance of circadian rhythm modifications in patients on chemotherapy is unknown. Even so, circadian parameter I

Functional status in older patients with cancer and a frailty risk profile: A multicenter observational study.

INTRODUCTION: Functional status (FS) and frailty are significant concerns for older adults, especially those with cancer. Data on FS (Activities of Daily Living [ADL]; Instrumental Activities of Daily Living [IADL]) and its evolution during cancer treatment in older patients and a frailty risk profile are scarce. Therefore, this study examines FS and its evolution in older patients with cancer and a frailty risk profile and investigates characteristics associated with functional decline. MATERIAL AND METHODS: This secondary data-analysis, focusing on FS, uses data from a large prospective multicenter observational cohort study. Patients ≥70 years with a solid tumor and a frailty risk profile based on the G8 screening tool (score ≤ 14) were included. A geriatric assessment was performed including evaluation of FS based on ADL and IADL. At approximately three months of follow-up, FS was reassessed. Univariable and multivariable logistic regression analyses were used to identify predictive factors for functional decline in ADL and IADL. RESULTS: Data on ADL and IADL were available at baseline and follow-up in 3388 patients. At baseline 1886 (55.7%) patients were dependent for ADL, whereas 2085 (61.5%) patients were dependent at follow-up. Functional decline was observed in 23.6% of patients. For IADL 2218 (65.5%) patients were dependent for IADL, whereas 2591 (76.5%) patients were dependent at follow-up. Functional decline in IADL was observed in 41.0% of patients. In multivariable analysis, disease stage III or IV, comorbidities, falls history in the past twelve months, and FS measured by IADL were predictive factors for functional decline in both ADL and IADL. Other predictive factors for functional decline in ADL were polypharmacy, Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) score 2-4, and cognitive impairment, and for functional decline in IADL were female sex, fatigue, and risk for depression. DISCUSSION: Functional impairments are frequent in older persons with cancer and a frailty risk profile, and several characteristics are identified that are significantly associated with functional decline. Therefore, FS is an essential part of the geriatric assessment which should be standard of care for this patient population. Next step is to proceed with directed interventions with the aim to limit the risk of functional decline as much as possible.

Unplanned hospitalizations in older patients with cancer: Occurrence and predictive factors.

BACKGROUND: This study aims to investigate the occurrence of unplanned hospitalizations in older patients with cancer and to determine predictive factors. METHODS: A prospective Belgian multicentre (n = 22), observational cohort study was performed. Patients ≥70 years with a malignant tumor were included. Patients underwent G8 screening followed by geriatric assessment (GA) if abnormal at baseline and were followed for unplanned hospitalizations at approximately three months. Uni- and multivariable regression models were performed to determine predictive factors associated with unplanned hospitalizations in older patients with an abnormal G8. RESULTS: In total, 7763 patients were included in the current analysis of which 2409 (31%) patients with a normal G8 score and 5354 (69%) with an abnormal G8 score. Patients with an abnormal G8 were hospitalized more frequently than patients with a normal G8 (22.9% versus 12.4%; p < 0.0001). Reasons for unplanned hospitalizations were most frequently cancer related (25.7%) or cancer therapy related (28%). In multivariable analysis, predictive factors for unplanned hospitalizations in older patients with cancer and an abnormal G8 were female gender, absence of surgery, chemotherapy, ADL dependency, malnutrition and presence of comorbidities. CONCLUSION: Older patients with cancer and an abnormal G8 screening present a higher risk (23%) for unplanned hospitalizations. Predictive factors for these patients were identified and include not only patient and treatment related factors but also GA related factors.

The use of chemotherapy regimens carrying a moderate or high risk of febrile neutropenia and the corresponding management of febrile neutropenia: an expert survey in breast cancer and non-Hodgkin's lymphoma.

BACKGROUND: The use of chemotherapy regimens with moderate or high risk of febrile neutropenia (defined as having a FN incidence of 10% or more) and the respective incidence and clinical management of FN in breast cancer and NHL has not been studied in Belgium. The existence of a medical need for G-CSF primary and secondary prophylaxis with these regimens was investigated in a real-life setting. METHODS: Nine oncologists and six hematologists from different Belgian general hospitals and university centers were surveyed to collect expert opinion and real-life data (year 2007) on the use of chemotherapy regimens with moderate or high risk of febrile neutropenia and the clinical management of FN in patients aged <65 years with breast cancer or NHL. Data were retrospectively obtained, over a 6-month observation period. RESULTS: The most frequently used regimens in breast cancer patients (n = 161) were FEC (45%), FEC-T (37%) and docetaxel alone (6%). In NHL patients (n = 39), R-CHOP-21 (33%) and R-ACVBP-14 (15%) were mainly used. Without G-CSF primary prophylaxis (PP), FN occurred in 31% of breast cancer patients, and 13% had PSN. After G-CSF secondary prophylaxis (SP), 4% experienced further FN events. Only 1 breast cancer patient received PP, and did not experience a severe neutropenic event. Overall, 30% of chemotherapy cycles observed in breast cancer patients were protected by PP/SP. In 10 NHL patients receiving PP, 2 (20%) developed FN, whereas 13 (45%) of the 29 patients without PP developed FN and 3 (10%) PSN. Overall, 55% of chemotherapy cycles observed in NHL patients were protected by PP/SP. Impaired chemotherapy delivery (timing and/or dose) was reported in 40% (breast cancer) and 38% (NHL) of patients developing FN. Based on oncologist expert opinion, hospitalization rates for FN (average length of stay) without and with PP were, respectively, 48% (4.2 days) and 19% (1.5 days). Similar rates were obtained from hematologists. CONCLUSIONS: Despite the studied chemotherapy regimens being known to be associated with a moderate or high risk of FN, upfront G-CSF prophylaxis was rarely used. The observed incidence of severe neutropenic events without G-CSF prophylaxis was higher than generally reported in the literature. The impact on medical resources used is sizeable.

Interest for a Systematic Rehabilitation Program Including Physical Exercise and Lifestyle Accompaniment for Women Recently Treated for Early Breast Cancer: A Comparative Study.

BACKGROUND/AIM: A prospective non-randomized study was performed on 68 women who had recently undergone curative treatment (surgery +/- adjuvant radio/chemotherapy) for breast cancer. PATIENTS AND METHODS: Patients were distributed into 2 subgroups, control (C) group (n=21) and experimental (E) group (n=47). The last group participated in a 12-week rehabilitation program associating physical activity and psychoeducational workshops, including management of stress, diet, and sleep disorders. RESULTS: Despite the initial imbalance between the groups (patients from C group were older and had received less chemotherapy than those from the E group), at the end of the rehabilitation program, we observed a significant improvement in global health feeling and in objective physical tests (distance covered in 6 min and objective measures of ergospirometry), and a decrease in pathological fatigue, while these different items remained quite stable over time in the control group. CONCLUSION: It is suggested to recommend structured rehabilitation to any patient who does not have a contraindication to it. In addition, the scientific literature encourages us to extend the spectrum of oncological rehabilitation to pathologies other than breast cancer.

Sex-dependent least toxic timing of irinotecan combined with chronomodulated chemotherapy for metastatic colorectal cancer: Randomized multicenter EORTC 05011 trial.

The least toxic time (LTT) of irinotecan varied by up to 8 hours according to sex and genetic background in mice. The translational relevance was investigated within a randomized trial dataset, where no LTT stood out significantly in the whole population. 130 male and 63 female eligible patients with metastatic colorectal cancer were randomized to receive chronomodulated Irinotecan with peak delivery rate at 1 of 6 clock hours staggered by 4 hours on day 1, then fixed-time chronomodulated Fluorouracil-Leucovorin-Oxaliplatin for 4 days, q3 weeks. The sex-specific circadian characteristics of grade (G) 3-4 toxicities were mapped with cosinor and time*sex interactions confirmed with Fisher's exact test. Baseline characteristics of male or female patients were similar in the six treatment groups. Main grade 3-4 toxicities over six courses were diarrhea (males vs females, 39.2%; vs 46.0%), neutropenia (15.6% vs 15.0%), fatigue (11.5% vs 15.9%), and anorexia (10.0% vs 7.8%). They were reduced following irinotecan peak delivery in the morning for males, but in the afternoon for females, with statistically significant rhythms (P < .05 from cosinor) and sex*timing interactions (Fisher's exact test, diarrhea, P = .023; neutropenia, P = .015; fatigue, P = .062; anorexia, P = .032). Irinotecan timing was most critical for females, with grades 3-4 ranging from 55.2% of the patients (morning) to 29.4% (afternoon) for diarrhea, and from 25.9% (morning) to 0% (afternoon) for neutropenia. The study results support irinotecan administration in the morning for males and in the afternoon for females, in order to minimize adverse events without impairing efficacy.

The prognostic value of patient-reported Health-Related Quality of Life and Geriatric Assessment in predicting early death in 6769 older (≥70 years) patients with different cancer tumors.

OBJECTIVES: We aimed to determine the prognostic value of baseline Health-Related Quality Of Life (HRQOL) and geriatric assessment (GA) to predict three-month mortality in older patients with cancer undergoing treatment. METHODS: Logistic regressions analysed HRQOL, as measured with the EORTC Global Health Status (GHS) scale, and geriatric information prognostic for early mortality controlling for oncology variables. The assessment was established with the odds ratio (OR), 95% confidence interval (CI) and level of significance set at p < 0.05. Discriminative power was evaluated with area under the curve (AUC). RESULTS: In total, 6769 patients were included in the study, of whom 1259 (18.60%) died at three months. Our model showed higher odds of early death for patients with lower HRQOL (GHS, OR 0.98, 95% CI 0.98-0.99; p < 0.001), a geriatric risk profile (G8 Screening Tool, 1.94, 1.14-3.29; p = 0.014), cognitive decline (Mini Mental State Examination, 1.41, 1.15-1.72; p = 0.001), being at risk for malnutrition (Mini Nutritional Assessment-Short Form, 1.54, 1.21-1.98; p = 0.001), fatigue (Visual Analogue Scale for Fatigue, 1.45, 1.16-1.82; p = 0.012) and comorbidities (Charlson Comorbidity index, 1.23, 1.02-1.49; p = 0.033). Additionally, older age, poor ECOG PS and being male increased the odds of early death, although the magnitude differed depending on tumor site and stage, and treatment (all p < 0.05). Predictive accuracy increased with 3.7% when including HRQOL and GA in the model. CONCLUSION: The results suggest that, in addition to traditional clinical measures, HRQOL and GA provide additional prognostic information for early death, but the odds differ by patient and tumor characteristics.

Health related quality of life in older patients with solid tumors and prognostic factors for decline.

OBJECTIVES: This study aims to investigate health-related quality of life (HRQOL) at baseline and at follow-up in older patients with cancer and to determine prognostic factors for HRQOL decline. METHODS: A prospective Belgian multicentre (n = 22) study was performed. Patients ≥70 years with a malignant tumor and abnormal G8 (≤14/17) screening tool were included. Patients underwent geriatric assessment (GA) and HRQOL evaluation with follow up at three months. Uni- and multivariate regression models were performed to determine factors associated (p < .05) with baseline HRQOL and HRQOL decline at follow-up. RESULTS: Results reflect data collected from 3673 patients. A multivariate analysis showed that younger patients, and those with poor Eastern Cooperative Oncology Group - Performance Status (ECOG-PS), specific tumor types (gastrointestinal, gynaecological and thorax) and higher stage had lower baseline HRQOL. In addition worse functional status and presence of pain, fatigue, depression and malnutrition were associated with lower baseline HRQOL. During treatment (n = 2972), improvement in HRQOL was observed in 1037 patients (35%) and a decline in 838 patients (28.2%). In multivariate analysis, stage and presence of baseline comorbidities, pain, fatigue or malnutrition were associated with HRQOL evolution. CONCLUSION: Baseline HRQOL in older patients with cancer and an abnormal G8 depends on tumor and age related parameters. During follow-up, HRQOL improved in one third of patients, indicating that they may benefit from cancer treatment while one quarter demonstrated a HRQOL decline for which prognostic factors were identified.

Implications of circadian clocks for the rhythmic delivery of cancer therapeutics.

The circadian timing system controls drug metabolism and cellular proliferation over the 24 h through molecular clocks in each cell, circadian physiology, and the suprachiasmatic nuclei--a hypothalamic pacemaker clock that coordinates circadian rhythms. As a result, both the toxicity and efficacy of over 30 anticancer agents vary by more than 50% as a function of dosing time in experimental models. The circadian timing system also down-regulates malignant growth in experimental models and possibly in cancer patients. Programmable-in-time infusion pumps and rhythmic physiology monitoring devices have made possible the application of chronotherapeutics to more than 2000 cancer patients without hospitalization. This strategy first revealed the antitumor efficacy of oxaliplatin against colorectal cancer. In this disease, international clinical trials have shown a five-fold improvement in patient tolerability and near doubling of antitumor activity through the chronomodulated, in comparison to constant-rate, delivery of oxaliplatin and 5-fluorouracil-leucovorin. Here, the relevance of the peak time, with reference to circadian rhythms, of the chemotherapeutic delivery of these cancer medications for achieving best tolerability was investigated in 114 patients with metastatic colorectal cancer and in 45 patients with non-small cell lung cancer. The incidence of severe adverse events varied up to five-fold as a function of the choice of when during the 24 h the peak dose of the medications was timed. The optimal chronomodulated schedules corresponded to peak delivery rates at 1 a.m. or 4 a.m. for 5-fluorouracil-leucovorin, at 1 p.m. or 4 p.m. for oxaliplatin, and at 4 p.m. for carboplatin. Sex of patient was an important determinant of drug schedule tolerability. This finding is consistent with recent results from a chronotherapy trial involving 554 patients with metastatic colorectal cancer, where sex also predicted survival outcome from chronotherapy, but not conventional drug delivery. Ongoing translational studies, mathematical modeling, and technology developments are further paving the way for tailoring cancer chronotherapeutics to the main rhythmic characteristics of the individual patient. Targeting therapeutic delivery to the dynamics of the cross-talk between the circadian clock, the cell division cycle, and pharmacology pathways represents a new challenge to concurrently improve the quality of life and survival of cancer patients through personalized cancer chronotherapeutics.

Pharmacokinetics of Irinotecan, Oxaliplatin and 5-Fluorouracil During Hepatic Artery Chronomodulated Infusion: A Translational European OPTILIV Study.

The combination of hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil and oxaliplatin with intravenous cetuximab has safely achieved prolonged survival in colorectal cancer patients with extensive liver metastases and prior treatment. Systemic exposure to the drugs or their main metabolites was determined during the first course of chronomodulated triplet HAI in 11 patients and related to toxicities after one or three courses. Consistent trends were found between the area under the plasma concentration-time curve (AUC) values of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN38; a bioactive metabolite), total oxaliplatin and platinum ultrafiltrate (P-UF), on the one hand, and subsequent leukopenia severity, on the other hand. Moreover, the maximum plasma concentration (C max) and the AUC of P-UF significantly predicted grades of diarrhoea (p = 0.004 and 0.017, respectively) and anaemia (p = 0.001 and 0.008, respectively) after the first course. Systemic drug exposure helps explain both the adverse events and the low rate of extrahepatic progression-a usual drawback of HAI chemotherapy-thus supporting upfront testing of the regimen. Systems optimization of chronomodulated HAI delivery could further reduce adverse events.

Recurrence dynamics of breast cancer according to baseline body mass index.

BACKGROUND: In cancer follow-up, in addition to the evaluation of survival probabilities, there is a fundamental need of assessing recurrence dynamics for optimal disease management. Although the time-dependent effect of the oestrogen receptor (ER) status of the tumour has already been described, so far no factor has proven to disentangle the multi-peak behaviour observed for breast cancer recurrences. Here, we aimed at investigating whether adiposity at diagnosis, reflected by increased patient's body mass index (BMI), could be associated with breast cancer recurrence patterns over time after primary cancer therapy. METHODS: We retrieved BMI from 734 of 777 patients with node-positive breast cancer from a phase III randomised clinical trial, which compared different chemotherapy regimens and had a median follow-up of 15.4 years. Cumulative incidence estimation as well as piecewise exponential models were carried out to estimate the distant recurrence dynamics, in all patients, as well as in subgroups based on the ER status, with the ER-positive group being further split according to the menopausal status. RESULTS: In patients with ER-negative breast cancer, time-dependent analyses revealed that the hazard of late relapses could mainly be attributed to the overweight and obese patients. Within the subgroup of premenopausal patients with ER-positive tumours, obesity was associated with an early high narrow peak of distant recurrences followed by another main peak after 5 years of follow-up. The risk for overweight patients was intermediate between obese and normal-weight patients. In the postmenopausal subgroup of patients with ER-positive tumours, the distant recurrence rate was significantly more elevated in the overweight patients compared to the other BMI categories, and a second late peak of recurrences was also observed for the obese patients. CONCLUSION: These results demonstrate that the patient's BMI at diagnosis is associated with cancer recurrence dynamics. Patient adiposity should therefore be central to the exploration of late adjuvant treatment modalities.

Objective response to chemotherapy as a potential surrogate end point of survival in metastatic breast cancer patients.

PURPOSE: To assess the validity of objective response to chemotherapy as a surrogate end point for survival in metastatic breast cancer. PATIENTS AND METHODS: We carried out a meta-analysis on individual data from 2,126 metastatic breast cancer patients who were enrolled onto 10 randomized trials comparing standard versus intensified epirubicin-containing chemotherapy. RESULTS: The intensified chemotherapy was associated with a significantly higher tumor response rate compared with standard chemotherapy (pooled odds ratio for nonresponse, 0.60; 95% CI, 0.51 to 0.72). The intensified regimens also led to better (although not significant) survival (pooled odds ratio, 0.94; 95% CI, 0.86 to 1.04; P = .22). Tumor response was a highly significant predictor of survival (P < .0001). When tumor response was introduced in the Cox model, the hazard ratio in favor of experimental treatment changed from 0.94 to 1.005 (95% CI, 0.91 to 1.11; P = .92), indicating that no residual effect of the experimental treatment on survival was present once tumor response was adjusted for. This suggests that the overall survival benefit of intensified epirubicin was a result of the increase in response rate. The median survival time of patients with complete response and partial response was 28.8 months (95% CI, 25.4 to 45.3 months) and 21.3 months (95% CI, 19.2 to 22.4 months), respectively; whereas, the median survival time of patients with no response was 14.6 months (95% CI, 13.9 to 15.4 months). CONCLUSION: These results support the hypothesis that the achievement of an objective response to chemotherapy in metastatic breast cancer is associated with a true survival benefit. The potential role of objective response as a surrogate end point for survival in chemotherapy trials of metastatic breast cancer warrants further investigation.