Physical activity and checkpoint inhibition: association with toxicity and survival.

BACKGROUND: Although animal experiments suggest beneficial effects of physical activity (PA) on antitumor immunity, little is known about the effects of PA on immune checkpoint inhibitor (ICI) toxicity and effectiveness in humans. We assessed the association of PA with immune-related adverse events (irAE) and survival in patients undergoing ICI. METHODS: Patients receiving ICI who completed the Dutch short questionnaire to assess health enhancing physical activity (SQUASH) questionnaire at the start of treatment as part of the prospective UNICIT study in an academic hospital were included. PA was quantified by calculating total metabolic equivalent task hours per week (total PA) and hours per week of moderate- to vigorous-intensity PA during sport and leisure time (MVPA-SL). Associations of PA with severe irAE occurrence within 1 year and overall survival (OS) were evaluated using logistic regression and Cox proportional hazard regression, respectively, with adjustment for probable confounders. RESULTS: In total, 251 patients were included, with a median follow-up of 20 months. Moderate and high levels of total PA were associated with lower odds of severe irAE occurrence compared to low levels of total PA (adjusted OR: 0.34 [95% CI = 0.12 to 0.90] and 0.19 [95% CI = 0.05 to 0.55], respectively). Moderate and high levels of total PA were also associated with prolonged survival (adjusted HR: 0.58 [95% CI = 0.32 to 1.04] and 0.48 [95% CI = 0.27 to 0.89], respectively). Similar associations were observed in patients who performed more MVPA-SL. CONCLUSIONS: Higher physical activity levels at the start of ICI treatment are associated with lower risk of severe irAEs and probably prolonged survival. Randomized controlled trials are needed to investigate whether patients indeed benefit from increasing PA levels after diagnosis.

Frailty and checkpoint inhibitor toxicity in older patients with melanoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs) that range from mild to life-threatening. Age itself does not seem to be a predictor for the occurrence of irAEs. It is unknown whether frailty plays a role in the occurrence of irAEs. Therefore, the authors assessed whether irAEs and their sequelae occur more often in frail patients than in fit patients according to the Geriatric 8 (G8) assessment. METHODS: Patients with melanoma aged 70 years and older who were about to start ICI therapy and were screened with the G8 assessment were enrolled in this prospective, observational study. Patients were classified by the G8 as either fit or frail. The primary outcome was the occurrence of grade ≥3 irAEs. RESULTS: In total, 92 patients were included for statistical analyses, 26 (29%) of whom were classified as frail. Grade ≥3 irAEs occurred in 20% of patients. There was no significant difference in the occurrence of grade ≥3 irAEs between fit and frail patients (17% vs 27%; P = .26). Frail patients were admitted to the hospital because of irAEs significantly more often than fit patients (29% vs 54%; P = .02) and showed a trend toward increased length of hospitalization (5 vs 8 days; P = .06) and more frequent use of immunosuppressants or ICI discontinuation for irAEs (36% vs 58%; P = .06). CONCLUSIONS: Although frailty appears to be unrelated to the occurrence of severe irAEs, it is an indicator of irAE-related adverse sequelae, such as hospital admission. Screening for frailty can be of added value in the shared decision-making process for older patients who qualify for ICI treatment.

Functional decline after surgery in older patients with head and neck cancer.

INTRODUCTION: In addition to classical endpoints such as survival and complication rates, other outcomes such as quality of life and functional status are increasingly recognized as important endpoints, especially for elderly patients. However, little is known about the long-term effect of surgery with regard to these other outcomes. Our aim is to investigate the functional status and self-reported health status of patients ≥ 70 years one year after surgery for head and neck cancer. METHODS: We present one-year follow-up data of patients ≥ 70 year who underwent surgery for HNC. During an interview by telephone, functional status was evaluated by using the Katz-15 Index of Independence questionnaire including six items covering basic Activities of Daily Living (ADL) and nine items covering Instrumental Activities of Daily Living (IADL). Measurements were compared with those obtained preoperatively. RESULTS: In total, 126 patients were included and eventually we collected follow-up data of 68 patients. There was a statistically significant decrease in functional status on the total Katz-15 and on the IADL questionnaire scores one year after surgery (mean 1.34 versus 2.42,p-value 0.00 and mean 1.21 versus 1.94,p-value 0.00). There was no significant change concerning ADL dependence (p-value 0.18) and cognitive status (p-value 0.11). The self-reported health status improved postoperatively, although not statistically significantly so (mean 67.36 versus 71.25,p-value 0.12). CONCLUSION: Approximately-one year after surgery for HNC, there is a significant decline in functional status indicating a higher level of dependency.

Validation of the G8 screening tool in older patients with cancer considered for surgical treatment.

BACKGROUND: The Geriatric 8 (G8) has proven to be one of the most sensitive frailty-screening tools for older patients with cancer undergoing systemic treatment. In this study we validated whether the G8 is also suitable for identifying impairments in their comprehensive geriatric assessment (CGA) in older patients with cancer undergoing surgery. Thereby, we investigated the differences in postoperative outcomes between the fit and frail patients classified by the G8. METHODS: Patients ≥70 years with a surgery indication because of a (suspected) malignant disease were prospectively enrolled. In all patients, a CGA was performed. The G8 results were assessed in parallel. The diagnostic value of the G8 was determined by comparing the result with the CGA as a reference test. Deficits in CGA was defined as ≥ two impairments of the CGA. Postoperative complications were retrospectively obtained from the medical record and compared between the fit and frail patients. RESULTS: In total, 143 patients were enrolled. The sensitivity, specificity, and negative predictive value of the G8 were 82% (95% CI 70-91), 63% (95% CI 52-73), and 85% (95% CI 75-91). In the patients with an impaired G8, a significantly prolonged hospital stay, higher rate of delirium, and higher 1-year mortality rate were seen. CONCLUSION: The G8 is a simple and useful screening tool for identifying deficits in CGA in older patients with cancer requiring surgery. Second, we concluded that patients with an impaired G8 are more at risk for a complicated recovery from surgery.

Predictive value of each geriatric assessment domain for older patients with cancer: A systematic review.

BACKGROUND: A geriatric assessment (GA) is increasingly used to help guide treatment decisions in older patients with cancer. However, there is no consensus regarding which domains should be included in the GA. In addition, the field of geriatric oncology moves very fast and as a result many new studies have been published since the last review in 2015. Therefore, the objective of this systematic review is to evaluate which domains of the GA could predict patient-related treatment outcomes of older patients with cancer and thereby should be included in a GA. METHODS: A systematic literature search was performed for publications in English or Dutch between September 2006 and July 2017 addressing the association between individual domains of the GA and mortality, postoperative complications, or systemic treatment-related outcomes in older patients with cancer. RESULTS: Eight different domains were evaluated in 46 publications, namely functional status, nutritional status, cognition, mood, physical function, fatigue, social support, and falls. All eight domains were predictive for at least one of the investigated outcomes but the results were quite variable across studies. Physical function and nutritional status were the domains most often associated with mortality and systemic treatment-related outcomes, and the domain physical function was most often associated with postoperative complications. CONCLUSION: Overall, this review demonstrates that the GA should minimally consist of physical function and nutritional status, when the aim is to predict patients-related outcomes of older patients with cancer, although the results are quite heterogeneous. For the other domains, the findings are too inconsistent to draw conclusions about their overall predictive ability.

Lenalidomide maintenance after nonmyeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible: results of the HOVON 76 Trial.

To improve the outcome of allogeneic stem cell transplantation (allo-SCT) in multiple myeloma as part of first-line treatment, we prospectively investigated the feasibility and efficacy of lenalidomide maintenance. Patients started maintenance 1 to 6 months after nonmyeloablative allo-SCT. Lenalidomide was dosed 10 mg on days 1 to 21 of a 28-day schedule for a total of 24 cycles. Peripheral blood samples were taken to evaluate immune modulating effects. Thirty-five eligible patients were enrolled, and 30 started with lenalidomide. After 2 cycles, 14 patients (47%) had to stop treatment, mainly because of the development of acute graft versus host disease (GVHD). In total, 13 patients (43%) stopped treatment because of development of GVHD, 5 patients (17%) because of other adverse events, and 5 patients (17%) because of progression. Responses improved in 37% of patients, and the estimated 1-year progression-free survival from start of maintenance was 69% (90% confidence interval, 53%-81%). Lenalidomide increased the frequency of human leukocyte antigen-DR(+) T cells and regulatory T cells, without correlation with clinical parameters. In conclusion, lenalidomide maintenance 10 mg daily after nonmyeloablative allo-SCT with unmanipulated graft in multiple myeloma patients is not feasible, mainly because of the induction of acute GVHD. This trial was registered at www.trialregister.nl as #NTR1645.