Clinical and biological effects of interleukin 12 in patients with renal cell carcinoma

Il-12 has a number of immunoregulatory properties indicating its therapeutic potential against cancer. The encouraging anti-tumor effects, observed in a variety of animal tumor models, have stimulated the development of Il-12 as a single agent for systemic cytokine therapy of cancer in humans. Metastatic renal cell cancer is one of the few human cancers that are more responsive to immunotherapy than to conventional cytotoxic therapies. Therefore, a phase I study of Il-12 was performed in patients with advanced renal cell cancer. The choice of schedule and route of administration were based on experiments in cynomolgus monkeys. Il-12 in s.c. doses of 0.1 to 1.0 Jlg /kg /day, three times a week, was shown to modulate immune activity without provoking substantial toxicity in these animals. The objective of the study described in chapter 2 was to evaluate the safety and tolerability of subcutaneous IL-12 in humans and establish the pharmacokinetic profile. The observation of a non-linear relationship between dose and drug exposure in animal models formed the rationale to study the effects of a single and multiple doses of Il-12. In chapter 3 the immunomodulatory activities of IL-12 in humans are described in detail, with emphasis on the induction of secondary cytokines and the effects on circulating leucocyte subset counts. Based on the observation that side effects decreased upon repeated injections of IL-12, we specifically studied whether or not immunomodulatory effects were downregulated in the course of multiple IL-12 injections with special attention for the role of the immunosuppressive cytokine IL-10. Chapter 4 describes a study of the effect of IL-12 on fibrinolysis and coagulation in humans. This study was performed because several bleeding episodes were reported in simultaneously performed clinical studies, whereas studies in mice and non-human primates had shown that IL-12 induced activation of coagulation and fibrinolysis. Il-12 is a strong pro-inflammatory cytokine. Studies in patients and experimental animals have demonstrated that endogenously produced IL-12 plays an important role in the toxic sequel of sepsis and endotoxemia. In these situations, excessive activation of various components of the inflammatory cascade contributes to the development of tissue injury and mortality. In chapter 5 we describe the in-vivo effects of different doses of subcutaneous Il-12 on components of the inflammatory cascade. We specifically addressed the degranulation of neutrophils and the formation of secretory phospholipase Az, a regulatory enzyme in the formation of eicosanoids. The study described in chapter 2 was one of four phase I studies, that were simultaneously performed in Europe and the US. Subsequent phase II studies in patients with advanced renal cell cancer and ovarian cancer demonstrated disappointing anti-tumor effects. The results described in chapter 3, together with other pharmacodynamic studies, indicate that the lack of efficacy was accompanied by, and probably related to, declining biological effects of IL-12 in the course of repeated administrations at doses approaching the maximum tolerated dose (MTD). Nevertheless, IL-12 remains a promising immunotherapeutic agent because recent cancer vaccination studies in animal models and humans have demonstrated its powerful adjuvant properties. Chapter 6 reviews the adjuvant properties of IL-12 and delineates how the immuneregulatory properties of IL-12 described in the previous chapters may contribute to the adjuvant effects. In addition, it is discussed how the studies presented in this paper, together with other clinical studies of systemic IL-12, indicate that IL- 12 may exert optimal adjuvant effects only at low dose levels. Finally, the future perspectives of IL-12 in the treatment of cancer are addressed

A comparison of treatment allocation and survival between younger and older patients with HER2-overexpressing de novo metastatic breast cancer

Introduction: There have been several developments in the treatment of HER2-overexpressing metastatic breast cancer. However, pivotal trials mainly included younger and healthier patients, resulting in a lack of information about the benefits and harms of treatment for most older patients. The aim of this study was to provide an overview of the differences in treatment allocation and survival outcomes over time between younger and older patients with HER2-overexpressing metastatic breast cancer. Materials and Methods: All patients from the Netherlands Cancer Registry with de novo metastatic breast cancer between 2005 and 2021 were included. Patients were divided into three age groups: &lt;65, 65–74, and ≥ 75 years. Changes in treatment allocation were graphically depicted over time. Cox proportional hazard models were used to calculate overall survival and Poisson models for relative survival. Results: Overall, 2,722 patients were included. Between 2005 and 2021, the use of targeted therapy as first-line treatment increased for all age groups (&lt;65 years from 33.8% to 90.6%, p &lt; 0.001; 65–74 years from 29.2% to 86.5%, p = 0.001; ≥75 years from 4.3% to 55.8%, p &lt; 0.001). Use of chemotherapy as first-line treatment also increased for all age groups (&lt;65 years from 73.5% to 89.8%, p &lt; 0.001; 65–74 years from 50.0% to 78.4%, p = 0.01; ≥75 years from 8.7% to 37.2%, p = 0.04). Although not statistically significant, the use of endocrine therapy, both as monotherapy and in combination with targeted therapy in the first line, decreased (&lt;65 years 19.1% to 5.5%, p &lt; 0.001; 65–74 years 25.0% to 13.5%, p = 0.03; ≥75 years 65.2% to 37.2%, p = 0.16). Changes in relative and overall survival were similar and improved in all age groups, but most in the youngest age group (relative excess risk [RER] 0.93, 95% confidence interval [CI] 0.91–0.94 per year, p &lt; 0.001), and least in patients ≥75 (RER 0.96, 95% CI 0.93–0.98 per year, p = 0.001). Discussion: The use of first-line chemotherapy and targeted therapy increased in all age groups, while the use of endocrine therapy decreased over time. Nevertheless, the uptake of chemotherapy and targeted therapies was substantially slower in the oldest age group. Overall survival and relative survival improved for all age groups, but these improvements were smaller in the older age groups.</p

Patient Preferences for Treatment Outcomes in Oncology with a Focus on the Older Patient:A Systematic Review

SIMPLE SUMMARY: In oncology, treatment outcomes can be competing, which means that one treatment could benefit one outcome, like survival, and negatively influence another, like independence. The choice of treatment therefore depends on the patient’s preference for outcomes, which needs to be assessed explicitly. Especially in older patients, patient preferences are important. Our systematic review summarizes all studies that assessed patient preferences for various treatment outcome categories. A total of 28 studies with 4374 patients were included, of which only six studies included mostly older patients. Although quality of life was only included in half of the studies, overall quality of life (79%) was most frequently prioritized as highest or second highest, followed by overall survival (67%), progression- and disease-free survival (56%), absence of severe or persistent treatment side effects (54%), treatment response (50%), and absence of transient short-term side effects (16%). In shared decision-making, these results can be used by healthcare professionals to better tailor the information provision and treatment recommendations to the individual patient. ABSTRACT: For physicians, it is important to know which treatment outcomes are prioritized overall by older patients with cancer, since this will help them to tailor the amount of information and treatment recommendations. Older patients might prioritize other outcomes than younger patients. Our objective is to summarize which outcomes matter most to older patients with cancer. A systematic review was conducted, in which we searched Embase and Medline on 22 December 2020. Studies were eligible if they reported some form of prioritization of outcome categories relative to each other in patients with all types of cancer and if they included at least three outcome categories. Subsequently, for each study, the highest or second-highest outcome category was identified and presented in relation to the number of studies that included that outcome category. An adapted Newcastle–Ottawa Scale was used to assess the risk of bias. In total, 4374 patients were asked for their priorities in 28 studies that were included. Only six of these studies had a population with a median age above 70. Of all the studies, 79% identified quality of life as the highest or second-highest priority, followed by overall survival (67%), progression- and disease-free survival (56%), absence of severe or persistent treatment side effects (54%), and treatment response (50%). Absence of transient short-term side effects was prioritized in 16%. The studies were heterogeneous considering age, cancer type, and treatment settings. Overall, quality of life, overall survival, progression- and disease-free survival, and severe and persistent side effects of treatment are the outcomes that receive the highest priority on a group level when patients with cancer need to make trade-offs in oncologic treatment decisions

Nationwide trends in chemotherapy use and survival of elderly patients with metastatic pancreatic cancer

Despite an aging population and underrepresentation of elderly patients in clinical trials, studies on elderly patients with metastatic pancreatic cancer are scarce. This study investigated the use of chemotherapy and survival in elderly patients with metastatic pancreatic cancer. From the Netherlands Cancer Registry, all 9407 patients diagnosed with primary metastatic pancreatic adenocarcinoma in 2005–2013 were selected to investigate chemotherapy use and overall survival (OS), using Kaplan–Meier and Cox proportional hazard regression analyses. Over time, chemotherapy use increased in all age groups (<70 years: from 26 to 43%, 70–74 years: 14 to 25%, 75–79 years: 5 to 13%, all P < 0.001, and ≥80 years: 2 to 3% P = 0.56). Median age of 2,180 patients who received chemotherapy was 63 years (range 21–86 years, 1.6% was ≥80 years). In chemotherapy-treated patients, with rising age (<70, 70–74, 75–79, ≥80 years), microscopic tumor verification occurred less frequently (91-88-87-77%, respectively, P = 0.009) and OS diminished (median 25-26-19-16 weeks, P = 0.003). After adjustment for confounding factors, worse survival of treated patients ≥75 years persisted. Despite limited chemotherapy use in elderly age, suggestive of strong selection, elderly patients (≥75 years) who received chemotherapy for metastatic pancreatic cancer exhibited a worse survival compared to younger patients receiving chemotherapy

Loss of skeletal muscle density during neoadjuvant chemotherapy in older women with advanced stage ovarian cancer is associated with postoperative complications

Objective: To assess the association between loss of lumbar skeletal muscle mass and density during neoadjuvant chemotherapy (NACT) and postoperative complications after interval cytoreductive surgery (CRS) in older patients with ovarian cancer. Materials and methods: This multicenter, retrospective cohort study included patients aged 70 years and older with primary advanced stage ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV), treated with NACT and interval CRS. Skeletal muscle mass and density were retrospectively assessed using Skeletal Muscle Index (SMI) and Muscle Attenuation (MA) on routinely made Computed Tomography scans before and after NACT. Loss of skeletal muscle mass or density was defined as >2% decrease per 100 days in SMI or MA during NACT. Results: In total, 111 patients were included. Loss of skeletal muscle density during NACT was associated with developing any postoperative complication ≤30 days after interval CRS both in univariable (Odds Ratio (OR) 3.69; 95% Confidence Interval (CI) 1.57–8.68) and in multivariable analysis adjusted for functional impairment and WHO performance status (OR 3.62; 95%CI 1.27–10.25). Loss of skeletal muscle density was also associated with infectious complications (OR 3.67; 95%CI 1.42–9.52) and unintended discontinuation of adjuvant chemotherapy (OR 5.07; 95%CI 1.41–18.19). Unlike loss of skeletal muscle density, loss of skeletal muscle mass showed no association with postoperative outcomes. Conclusion: In older patients with ovarian cancer, loss of skeletal muscle density during NACT is associated with worse postoperative outcomes. These results could add to perioperative risk assessment, guiding the decision to undergo surgery or the need for perioperative interventions

First-line palliative HER2-targeted therapy in HER2-positive metastatic breast cancer is less effective after previous adjuvant trastuzumab-based therapy

Background. Survival of patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC) has improved dramatically since trastuzumab has become available, although the disease eventually progresses in most patients. This study investigates the outcome (overall survival [OS] and time to next treatment [TNT]) in MBC patients pretreated with trastuzumab in the adjuvant setting (TP-group) compared with trastuzumab-näive patients (TN-group) in order to investigate the possibility of trastuzumab resistance. Patients and Methods. Patients treated with first-line HER2-targeted- containing chemotherapy were eligible for the study. A power analysis was performed to estimate the minimum size of the TP-group. OS and TNT were estimated using Kaplan-Meier curves andmultivariable Cox proportional hazards models. Results. Between January 1, 2000, and June 1, 2014, 469 patients were included, of whom 82 were in the TP-group and 387 were in the TN-group. Median OS and TNT were significantly worse in the TP-group compared with the TN-group (17 vs. 30 months, adjusted hazard ratio [HR] 1.84 [1.15-2.96], p5.01 and 7 vs. 13 months, adjusted HR 1.65 [1.06-2.58], p5.03) after adjustment for age, year of diagnosis, diseasefree interval, hormone receptor status, metastatic site, and cytotoxic regimens. Conclusion. First-line trastuzumab-containing treatment regimens are less effective in patients with failure of adjuvant trastuzumab compared with trastuzumab-näive patients and might be due to trastuzumab resistance. The impact of trastuzumab resistance on the response on dual HER2 blockade with trastuzumab and pertuzumab and how resistance mechanisms can be used in the optimization of HER2-targeted treatment lines need further investigation.</p

A Prospective Comparison of Younger and Older Patients' Preferences for Adjuvant Chemotherapy and Hormonal Therapy in Early Breast Cancer

AbstractBackgroundIt is unknown what minimal benefit in disease-free survival older patients with breast cancer require from adjuvant systemic therapy, and if this differs from that required by younger patients. We prospectively examined patients' preferences for adjuvant chemotherapy (aCT) and adjuvant hormonal therapy (aHT), factors related to minimally-required benefit, and patients' self-reported motivations.Patients and MethodsFifty-two younger (40-64 years) and 29 older (≥ 65 years) women with a first primary, invasive tumor were interviewed post-surgery, prior to receiving aCT/aHT recommendation.ResultsThe proportions of younger versus older participants who would accept, refuse, or were undecided about therapy were 92% versus 62%, 4% versus 24%, and 4% versus 14% for aCT, and 92% versus 59%, 8% versus 17%, and 0% versus 24% for aHT. The proportion of older participants who would refuse rather than accept aCT was larger than that of younger participants (P = .005). No significant difference was found for aHT (P = .12). Younger and older participants' minimally-required benefit, in terms of additional 10-year disease-free survival, to accept aCT (median, 5% vs. 4%; P = .13) or aHT (median, 10% vs. 8%; P = .15) did not differ. Being single/divorced/widowed (odds ratio [OR], 0.16; P = .005), presence of geriatric condition (inability to perform daily activities, incontinence, severe sensory impairment, depression, polypharmacy, difficulties with walking; OR, 0.27; P = .047), and having a preference to make the treatment decision either alone or after considering the clinician's opinion (active role; OR, 0.15; P = .012) were independently related to requiring larger benefits from aCT. The most frequent motivations for/against therapy included the wish to survive/avoid recurrence, clinician's recommendation, side effects, and treatment duration (only aHT).ConclusionWhereas older participants were less willing to accept aCT than younger participants, no significant difference was found for aHT. However, a majority of older participants would still accept both therapies. Adjuvant systemic therapy should be discussed with eligible patients regardless of age

Treatment strategies and survival outcomes in older women with breast cancer: a comparative study between the FOCUS cohort and Nottingham cohort

Objective: Clinical trials investigating breast cancer treatment often exclude or misrepresent older adults. This study compares treatment patterns and survival of older women diagnosed with breast cancer between a Dutch and a British observational cohort.Materials and Methods: Women aged 70 years and older diagnosed with breast cancer after 1990 with a T0-T2 tumor stage and no evidence of metastatic disease were included from a population-based cohort in the Netherlands and a British hospital-based cohort in Nottingham. Main outcomes were proportions of local and systemic treatment, ten-year overall survival and ten-year relative survival for each cohort.Results: 1439 patients from Nottingham and 2180 patients from the Netherlands were included. Median follow-up was 12.4 years (IQR 11.0–14.0) in the FOCUS cohort and 6.4 years (IQR 6.2–6.8) in the Nottingham cohort. British patients were more likely to receive primary endocrine therapy (50.0% vs 7.5%, P

Older patients' experiences with and attitudes towards an oncogeriatric pathway: A qualitative study

INTRODUCTION: To tailor treatment for older patients with cancer, an oncogeriatric care pathway has been developed in the Leiden University Medical Center. In this care pathway a geriatric assessment is performed and preferences concerning cancer treatment options are discussed. This study aimed to explore patient experiences with and attitudes towards this pathway.MATERIALS AND METHODS: A qualitative study was performed using an exploratory descriptive approach. Individual face-to-face semi-structured interviews were conducted with older patients (≥70 years) who had followed the oncogeriatric care pathway in the six months prior to the interview. The interviews were audio-recorded and transcribed verbatim. The transcripts were analyzed inductively using thematic analysis.RESULTS: After interviews with 14 patients with a median age of 80 years, three main themes were identified. (1) Patients' positive experiences with the oncogeriatric pathway: Patients appreciated the attitudes of the healthcare professionals and felt heard and understood. (2) Unmet information needs about the oncogeriatric care pathway: Patients experienced a lack of information about the aim and process. (3) Incomplete information for decision-making: Most patients were satisfied with decision-making process. However, treatment decisions had often been made before oncogeriatric consultation. No explicit naming and explaining of different available treatment options had been provided, nor had risk of physical or cognitive decline during and after treatment been addressed.DISCUSSION: Older patients had predominately positive attitudes towards the oncogeriatric care pathway. Most patients were satisfied with the treatment decision. Providing information on the aim and process of the care pathway, available treatment options, and treatment-related risks of cognitive and physical decline may further improve the oncogeriatric care pathway and the decision-making process.</p