EASING THE BURDEN op�mizing symptom control in pa�ents with advanced cancer Maurice van der Vorst

1 Maurice van der Vorst EASING THE BURDEN optimizing symptom control in patients with advanced cancer

2 ISBN 978-94-6421-766-7 Design and lay-out Paulien Varkevisser | fotografie & vormgeving, Nijmegen Printing Ipskamp Printing B.V., Enschede, the Netherlands © 2022, Marinus Johannes Dingeman Lambertus van der Vorst No part of this thesis may be reproduced, stored in a retrieval system of any nature, or transmitted in any form or by any means without prior written permission of the author, or when appropriate, the holder of the copyright. Omslag: Doctors in consultation around a sick person (14th century), glass, Canterbury Cathedral (Unesco World Heritage List, 1988), England, United Kingdom. (Photo by DeAgostini/Getty Images)

3 VRIJE UNIVERSITEIT EASING THE BURDEN optimizing symptom control in patients with advanced cancer ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam op gezag van de rector magnificus prof.dr. J.J.G. Geurts, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de Faculteit der Geneeskunde op vrijdag 30 september 2022 om 13.45 uur in een bijeenkomst van de universiteit, De Boelelaan 1105 door Marinus Johannes Dingeman Lambertus van der Vorst geboren te Gilze en Rijen

4 promotor: prof.dr. H.M.W. Verheul copromotor: prof.dr. J. Berkhof promotiecommissie: prof.dr. A.T.F. Beekman prof.dr. K.P. Grootens dr. E. Kuip prof.dr. A.K.L. Reyners P. van de Ven prof.dr. K.C.P. Vissers prof.dr. C. van Zuylen



7 Enkele andere overwegingen Hoe zal ik dit uitleggen, dit waarom wat wij vinden niet is wat wij zoeken? Laten we de tijd laten gaan waarheen hij wil, en zie dan hoe weiden hun vee vinden, wouden hun wild, luchten hun vogels, uitzichten onze ogen en ach, hoe eenvoud zijn raadsel vindt. Zo andersom is alles, misschien. Ik zal dit uitleggen. Rutger Kopland (1934 – 2012) Uit: Tot het ons loslaat (1997) Voor mijn liefste Hilde, Ward en Leonore

8 Table of contents

9 CHAPTER 1 General introduction and outline of the thesis Part One Cisplatin-induced acute kidney injury CHAPTER 2 Incidence and risk factors for acute kidney injury in head and neck cancer patients treated with concurrent chemoradiation with high-dose cisplatin Part Two Chemotherapy-induced nausea and vomiting CHAPTER 3 Prophylactic treatment for delayed chemotherapy-induced nausea and vomiting after non-AC based moderately emetogenic motherapy: a systematic review of randomized controlled trials CHAPTER 4 Metoclopramide, dexamethasone, or palonosetron for prevention of delayed chemotherapy-induced nausea and vomiting after moderately emetogenic chemotherapy (MEDEA): a randomized, phase III, noninferiority trial Part Three Delirium CHAPTER 5 Identification of patients with cancer with a high risk to develop delirium CHAPTER 6 Accuracy of the Delirium Observational Screening Scale (DOS) as a screening tool for delirium in patients with advanced cancer CHAPTER 7 Olanzapine vs. haloperidol for treatment of delirium in patients with advanced cancer – a phase III randomized clinical trial CHAPTER 8 Summarizing discussion and future perspectives Appendices Dutch summary (Nederlandse samenvatting) Acknowledgments (Dankwoord) About the author (Curriculum vitae) Bibliography 10 30 50 66 88 108 120 142 158 164 168 170

CHAPTER 1 General introduction and outline of the thesis

12 General introduction Despite advances in the diagnosis and treatment of human malignancy [1-5], cancer remains among the leading causes of morbidity andmortality worldwide, with 19.3million new cancer cases and 10.0 million deaths attributed to cancer in 2020 [6, 7]. Based on population growth and aging, the global cancer burden is expected to grow to 29.5 million cases annually in 2040 [8]. In the Netherlands, the number of new cancer cases has more than doubled in the last 30 years, from 55,732 in 1989 to 115,047 in 2020 [9]. Each year, around 38,000 patients are diagnosed with metastatic cancer in the Netherlands [9]. Advanced or metastatic cancer is generally considered incurable. Most patients with cancer experience symptoms throughout the disease trajectory, the prevalence and severity of which vary according to cancer type, stage, disease-directed treatment(s), and comorbidities [10-13]. Optimal symptommanagement is associatedwith improved patient and family quality of life (QoL) [13-15], greater treatment compliance [16, 17], and improved survival [17-20]. Palliative care is an approach that improves the QoL of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification, assessment and treatment of distressing symptoms, physical, psychosocial and spiritual [21]. After cancer diagnosis, palliative care, which is also refered to as supportive care [22], is provided along with anticancer treatment to prevent or treat cancer symptoms and the adverse effects of cancer-directed treatment. At the end of active treatment, palliative care focuses on reviewing the patient’s goals of care, adjusting care strategies to reflect any changes in those goals, and cancer symptom management to enhance the quality of living and dying in the last phase of life in terminally ill patients. Palliative care / supportive care must be evidence-based; research is essential to generate scientific evidence to improve symptom control and QoL in cancer patients. [23, 24]. The observed quantity and quality of studies conducted to address the issues of patients with advanced cancer in palliative care suggest that greater efforts are needed so that effective, evidence-based interventions can be proposed to cancer patients at each stage of their illness [25]. Aims of this thesis The overall aim of this thesis is to improve the prevention and management of symptoms and treatment-related adverse effects that often occur in patients with advanced or metastatic cancer. In specific, we focus on:  Cisplatin-induced acute kidney injury  Chemotherapy-induced nausea and vomiting  Delirium

13 1 Outline of this thesis Part One: Cisplatin-induced acute kidney injury Cisplatin, or cis-diamminedichloroplatinum II [CDDP], is a potent and valuable chemotherapy agent used to treat a broad spectrum of malignancies. Cisplatin exerts anticancer activity through multiple mechanisms, but its most prominent (and best understood) mode of action involves the generation of DNA lesions through interaction with purine bases on DNA, followed by activation of several signal transduction pathways that ultimately lead to apoptosis in cancer cells [26]. Side effects, such as nausea and vomiting, myelosuppression, neurotoxicity and ototoxicity, often limit the use and effectiveness of cisplatin [27]. The major dose-limiting side effect of cisplatin, however, is nephrotoxicity [28, 29]. The most common and severe presentation of cisplatin-induced nephrotoxicity is acute kidney injury (AKI) [30, 31]. Multiple mechanisms contribute to cisplatin-induced kidney damage [32, 33]. Cisplatin accumulates in theproximal tubular cells during glomerular filtration and tubular secretion, and a cascade of intracellular injury pathways occurs (Figure 1). These pathways include caspase activation, cyclin-dependent kinases, mitogen-activated protein kinase activation, and p53 signaling. Along with additional inflammation, oxidative stress, and vascular injury, this results in apoptosis and necrosis of the renal tubules, ultimately leading to AKI and/ or tubulopathy. Figure 1. Cisplatin enters proximal tubular cells through organic cation transporters (OCTs), and when it accumulates within cells, it causes cell injury through multiple mechanisms. Apoptosis and necrosis of tubular cells result and cause clinical AKI and tubulopathy. Abbreviations: CDKs, cyclin-dependent kinases; Cis, cisplatin; MAPK, mitogen-activated protein kinase; MRP, multidrug-resisitant protein; NaDC, sodium dicarboxylate; OAT, organic anion transporter; P53, protein 53; Pgp, P glycoprotein; ROS, reactive oxygen species. From Clin J Am Soc Nephrol 2012;7:1713-21. Perazella MA. Onco-nephrology: renal toxicities of chemotherapeutic agents. Reprinted with permission.

14 Several classification systems have been developed to streamline research and clinical practice with respect to AKI [34-36]. The 2011 Kidney Disease: Improving Global Outcomes (KDIGO) definition and staging criteria of AKI [36] are based on the Risk, Injury, Failure; Loss, End-stage renal disease (RIFLE) [34] and Acute Kidney Injury Network (AKIN) [35] classifications for AKI. According to KDIGO, AKI is diagnosed by an absolute increase in serum creatinine (SCr) at least 0.3 mg/dl (≥26.5 μmol/l ) within 48 hours (hr) or by a 50% increase in SCr from baseline within 7 days, or a urine volume of less than 0.5 ml/kg/h for at least 6 hr (Table 1). A patient’s progress can be staged over the entire time frame encompassed by an episode of AKI. An increase in SCr up to 3 times from baseline, or a SCr of more than 4.0 mg/dL (354 μmol/L), or initiation of renal replacement therapy (RRT), are all classified as stage 3. Table 1. Staging of AKI according to the Kidney Disease Improving Global Outcomes (KDIGO) definition and classification. Stage Serum Creatinine Urine output 1 1.5–1.9 times baseline OR ≥0.3 mg/dl (≥26.5 μmol/l) increase <0.5 ml/kg/h for 6-12 hr 2 2.0–2.9 times baseline <0.5 ml/kg/h for ≥12 hr 3 3.0 times baseline OR Increase in SCr to ≥4.0 mg/dl (≥353.6 μmol/l) OR Initiation of RRT OR In patients <18 years, decrease in GFR to <35 ml/min per 1.73 m2 <0.3 ml/kg/h for ≥24 hr OR Anuria for ≥12 hr Abbreviations: GFR, glomerular filtration rate; Hr, hours; RRT, renal replacement therapy; SCr, serum creatinine. In squamous cell carcinomas of the head and neck (SCCHN), the prevailing clinical presentation is a locoregionally advanced (LA) disease stage, for which patients are usually offered a multimodality approach involving chemoradiotherapy (CRT) [37, 38]. Based on four large randomized trials [39-42], conventionally fractionated external beam radiotherapy with concurrent administration of three cycles of high-dose cisplatin (100 mg/m2) given once every 3 weeks represents the current standard in definitive and adjuvant treatment of LASCCHN, as it results insignificantlybetter locoregional control and/oroverall survival relative to radiotherapy alone. Nevertheless, concerns exist about its toxicity and compliance, and AKI is considered a dose-limiting toxicity of cisplatin in this patient group [43]. Chapter 2 describes the results of a retrospective cohort study to establish the incidence and risk factors of AKI among patients diagnosed with LA-SCCHN who were treated with high-dose cisplatin-based CRT. In this chapter, we also investigate the impact of cisplatininduced AKI on long-term renal function and treatment outcomes in this patient cohort.

15 1 Part Two: Chemotherapy-induced nausea and vomiting Nausea and vomiting are serious side effects of cancer chemotherapy that can cause significant negative impacts onpatients’ QoL andon their ability to tolerateandcomplywith therapy [44-46]. Despite the substantial progress in CINV prophylactic strategies, as many as 40% of patients with cancer still experience nausea, vomiting, or both following receipt of chemotherapy [47]. CINV is caused by neurotransmitters and chemical substances stimulating the receptors in either the vomiting center or chemoreceptor trigger zone (Figure 2). Such substances include dopamine, serotonin, histamine, acetylcholine, and substance P [48-50]. Antiemetic agents are designed to target one of these relevant receptors. Phenothiazine andmetoclopramide, agentswidely inuse fromthe 1980s, inhibit the action of dopamine [51]. Figure 2. Pathophysiology of chemotherapy-induced nausea and vomiting. From N Engl J Med, Volume No. 374, Page No. 1357. Navari RM, Aapro M, Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting, Reprinted with permission.

16 The development of first-generation serotonergic receptor antagonists (5-HT3 RA) in the 1990s effectively suppressed acute CINV (0-24 hr after chemotherapy) [52], particularly whenused in tandemwithdexamethasone [53, 54]. This combinationhas been regarded as the standard prophylaxis ever since; however, delayed CINV (24-120 hr after chemotherapy still remains difficult to control [46, 55]. Newer antiemetic agents, that is, neurokinin-1 receptor antagonist (NK1 RA) [56, 57] and the second-generation 5-HT3 RA palonosetron [58, 59], were both introduced in the 2000s and have been proven to be equally effective for both acute and delayed CINV. Drug and guideline development have focused on the degree of emetogenicity of a chemotherapy regimen: highly emetogenic chemotherapy drugs (CINV in at least 90% of patients after chemotherapy); moderately emetogenic (MEC) drugs (30-90%); low emetogenic (10-30%); andminimal emetogenicity (<10%) [60]. Most research has focused on preventing episodes of vomiting. Less is known about reducing nausea independent of vomiting [61], and many of the antiemetic agents currently available do little to relieve chemotherapy-induced nausea [62]. Practice guidelines from the Multinational Association of Supportive Care in Cancer (MASCC)/European Society of Medical Oncology (MASCC/ESMO) [63] and the American Society of Clinical Oncology (ASCO) [64] are available to help determine optimal prophylaxis and treatment of CINV. Table 2 summarizes specific recommendations from these guidelines for MEC regimens. For patients receivingMEC (e.g. doxorubicin, irinotecan, oxaliplatinand cyclophosphamide, the MASCC/ESMO and ASCO guidelines recommend a 2-drug combination of a 5-HT3 RA with dexamethasone for the prophylaxis of acute CINV. They have recommended dexamethasone on days 2 and 3 following chemotherapy for MEC agents that are known to cause delayed CINV, such as cyclophosphamide, doxorubicin, and oxaliplatin. Dexamethasone-sparing or dose-modification approaches may be applicable when a patient’s exposure to corticosteroids must be limited. Recent studies involving 5-HT3 and/ or NK1 RA combinations support the use of dexamethasone-sparing approaches (i.e. dexamethasone coadministration on day 1 only) [65-70]. However, several questions remain unanswered regarding the exact therapeutic impact of the dexamethasone-sparing strategy on the management of CINV. Specifically, how effective is this strategy compared with a multiple-day dexamethasone regimen against delayed CINV. It is also not sufficiently clear whether the effect is different when control of nausea is assessed, and what evidence exists for the efficacy of a dexamethasone-sparing strategy in combination with other active agents.

17 1 Table 2. CINV prophylaxis recommendations for MEC regimens. MEC regimen type Recommendations ASCO (2017) MASCC/ESMO (2016) Carboplatin AUC ≥4 (mg/mL)/min Acute Delayed Carboplatin AUC <4 (mg/mL)/min or non-carboplati Acute Delayed 5-HT3 RA + NK1 RA + DEX AQE: high ASR: strong No prophylaxis QE: high ASR: strong 5-HT3 RA + DEX AQE: high ASR: strong No prophylaxis; DEX for agents known to cause delayed CINV AQE: low ASR: moderate 5-HT3 RA + NK1 RA + DEX MLCO: moderate; MLCS: moderate ELE: II; EGR: B No prophylaxis; APR if APR used in acute MLCO: moderate; MLCS: moderate ELE: III; EGR: B 5-HT3 RA + DEX MLCO: moderate; MLCS: moderate ELE: II; EGR: B No prophylaxis (a); DEX (b) for agents known to cause delayed CINV (a) MLCO: no confidence possible; MLCS: high ELE: IV; EGR: D (b) MLCO: low; MLCS: moderate ELE III; EGR: C Abbreviations: APR, aprepitant; AQE, ASCO quality of evidence; ASCO, American Society of Clinical Oncology; ASR, ASCO strenght of recommendation; AUC, area under the curve; DEX, dexamethasone; ELE ESMO level of evidence; EGR, ESMO grade of recommendation; MASCC/ESMO, Multinational Association of Supportive Care in Cancer/European Society of Medical Oncology; MEC, moderately emetogenic chemotherapy; MLCO, MASCC level of confidence; MLCS, MASCC level of consensus; NK1 RA, neurokinin-1 receptor antagonist; 5-HT3 RA, serotonergic receptor antagonist.

18 Chapter 3 describes the results of a systematic review of randomized controlled trials (RCT’s) with antiemetics for the prevention of delayed CINV in cancer patients treated with MEC. In Chapter 4, a multicenter, randomized, phase III, non-inferiority study to assess the efficacy and tolerability of dexamethasone-sparing strategies for the prevention of delayed CINV, and specifically nausea, after MEC is described. Part Three: Delirium Delirium is a severe neuropsychiatric syndrome characterized by the acute onset of deficits in attention and other aspects of cognition. Patients often have altered arousal, from reduced responsiveness at a near-coma level to hypervigilance and severe agitation. They may also experience highly distressing symptoms of psychosis, including delusions and hallucinations, and altered mood. Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) diagnostic criteria for delirium [71] are as follows: disturbance of consciousness (ie, reduced clarity of awareness of the environment) occurs, with reduced ability to focus, sustain, or shift attention. The features of delirium tend to fluctuate in presence and severity. Delirium is associated with considerable distress in patients and caregivers [72, 73]. The incidence of delirium in advanced cancer patients has been reported as varying greatly [74, 75]. During hospitalization, 16.5% [76] to 18% [77] of patients with cancer or a haematological malignancy admitted to oncology or internal medicine units developed delirium. Up to 88% of patients develop delirium in the last hours to weeks of life [78]. This variation depends on the study population, the delirium definition and method of assessment used and staff training, as well as delirium subtype (hyperactive, hypoactive, or mixed) and methods used for subtype classification. The risk of delirium is determined by predisposing risk factors (i.e. the background characteristics of patients) and precipitating risk factors (i.e. acute insults, injury or drugs) (Figure 3). Typically, more than one precipitating factor is present in patients [79, 80]. Studies in oncology settings have not documented specific socio-demographic and disease-related predictive factors for delirium. As a consequence, the number of patients with delirium in these studies has often been insufficient to precisely determine associated risk factors. An accurate and timely predictionmodel for deliriumwould facilitate early implementation of prevention measures based on individual risk profiles. However, existing delirium prediction models use different methods of delirium identification and different risk factors for model calibration, and do not have adequate predictive capabilities [81-82]. In chapter 5, we evaluate the incidence of delirium and its risk factors in hospitalized patients with advanced cancer in a retrospective cohort study. In this chapter, a prediction algorithm that we have developed to help identify patients at high risk of delirium is described.

19 1 From Nat Rev Dis Primers 2020;6:90. Wilson JE, Mart MF, Cunningham C, Shehabi Y, Girard TD, MacLullich AMJ, Slooter AJC, Wesley Ely E. Delirium. Reprinted with permission. Figure 3. Risk factors for delirium. Risk factors relate to premorbid or predisposing factors and to precipitating factors.

20 Abbreviations: 5-HT, 5-hydroxytryptamine; ACh, acetylcholine; BF, basal forebrain; His, histamine; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; NA, noradrenaline; NO, nitric oxide; PPT, pedunculopontine tegmentum; RAS, reticular activating system; TMN, tuberomammillary nucleus. From Nat Rev Dis Primers 2020;6:90. Wilson JE, Mart MF, Cunningham C, Shehabi Y, Girard TD, MacLullich AMJ, Slooter AJC, Wesley Ely E. Delirium. Reprinted with permission. Figure 4. Major mechanisms in delirium pathophysiology. All of these mechanisms contribute to the most obvious proximate cause of delirium: acute neuronal dysfunction and network disintegration.

21 1 Inclinical settings, physicians andnurse specialists continue tounderdiagnosedelirium[83]. Assessmenttoolsforclinicianswithoutpsychiatrictrainingtoidentifyandrecognizedelirium. are helpful. Although there are a plethora of validated delirium screening tools, it is unclear which tool best suits particular populations [84]. The ideal screening tool should have a high level of sensitivity, be brief and easy to use with minimal training [85]. The nurse-based Delirium Observation Screening (DOS) Scale is a brief screening tool based on observation [86]. The DOS has been validated in several patient populations, but no published studies focused on an inpatient population with advanced cancer. In chapter 6 we compare the accuracy of the DOS as a screening tool for delirium in patients with advanced cancer with the clinician-based Delirium Rating Scale-revised-98 (DRS-R98) tool [87] in a prospective study. Delirium treatment in patients with advanced cancer is complex, as it involves addressing multiple domains [88]. Although it is now recognised that there are multiple factors implicated in the aetiology of delirium [89, 90], there are likely several neurobiological processes that contribute to delirium pathogenesis, including neuroinflammation, brain vascular dysfunction, altered brainmetabolism, neurotransmitter imbalance and impaired neuronal network connectivity (Figure 4). The cerebral imbalance resulting in a relative excess of dopaminergic and deficiency of cholinergic transmission has been one of the main proposed mechanisms in the neuropathogenesis of delirium [91]. It has also provided a target mechanism or basis for much of the strategic approach in the pharmacological management of delirium with antipsychotics used historically in delirium treatment [92]. Typical antipsychotic drugs (e.g. haloperidol) act on the dopaminergic system, blocking the dopamine type 2 (D2) receptors [93]. Owing to this D2 blockade, they also induce a number of side effects, among which extrapyramidal symptoms are the most prominent. Atypical antipsychotics (e.g. olanzapine) have lower affinity and occupancy for the dopaminergic receptors and a high degree of occupancy of the serotoninergic receptors 5-HT2A [94]. Compared to typical antipsychotics, atypicals are supposed to induce fewer extrapyramidal side effects. [95]. In Chapter 7, the results of a multicenter, randomized, phase III study to compare the efficacy and tolerability of olanzapine with haloperidol for the treatment of delirium in a population of hospitalized patients with advanced cancer are described. Summarizing discussion and future perspectives In chapter 8 the main findings in this thesis are summarized and discussed. Finally, recommendations for future research are presented. A Dutch summary of this thesis is given in the Appendices, that also hold a list of publications, acknowledgements, and a curriculum vitae of the PhD candidate.

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28 Part One Cisplatin-induced acute kidney injury


CHAPTER 2 Incidence and risk factors for acute kidney injury in head and neck cancer patients treated with concurrent chemoradiation with high-dose cisplatin

Maurice JDL van der Vorst, Elisabeth CW Neefjes, Elisa C Toffoli, Jolanda EW Oosterling-Jansen, Marije R Vergeer, C René Leemans, Menno P Kooistra, Jens Voortman, Henk MW Verheul BMC Cancer 2019;19:1066

32 PART ONE | CISPLATIN-INDUCED ACUTE KIDNEY INJURY Abstract Background: Three-weekly high-dose cisplatin (100 mg/m2) is considered the standard systemic regimen given concurrently with postoperative or definitive radiotherapy in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Concurrent chemoradiation (CRT) with high-dose cisplatin is associated with significant acute and late toxicities, including acute kidney injury (AKI). The aims of this study were to investigate the incidence of AKI in patients with LA-SCCHN during and after treatment with high-dose cisplatinbased CRT, to identify risk factors for cisplatin-induced AKI, and to describe the impact of AKI on long-term renal function and treatment outcomes. Methods: This is a retrospective cohort study with measurements of renal function before CRT, weekly during CRT, every one or two days during hospitalizations, and three and twelve months after CRT in patients with LA-SCCHN. AKI was defined as increase in serum creatinine (sCr) of ≥1.5 times baseline or by ≥0.3 mg/dL (≥26.5 µmol/L) using the Kidney Disease Improving Global Outcomes (KDIGO) classification. Logistic regression models were estimated to analyze renal function over time and to identify predictors for AKI. Results: One hundred twenty-four patients completed all measurements. AKI was reported in 85 patients (69%) with 112 episodes of AKI. Sixty of 85 patients experienced one AKI episode; 20 patients experienced ≥ 2 AKI episodes. Ninetythree (83%) AKI episodes were stage 1, 13 (12%) were stage 2, and 6 (5%) AKI episodes were stage 3. Median follow-up time was 29 months (Interquartile Range, IQR 22-33). Hypertension (Odds Ratio, OR 2.7, 95% Confidence Interval, CI 1.1-6.6; p= 0.03), and chemotherapy-induced nausea and vomiting (CINV; OR 4.3, 95% CI 1.6-11.3; p= 0.003) were associated with AKI. In patients with AKI, renal function was significantly more impaired at three and twelve months post-treatment compared to patients without AKI. AKI did not have a negative impact on treatment outcomes. Conclusion: AKI occurred in 69% of patients with LA-SCCHN undergoing CRT with high-dose cisplatin. Long-term renal function was significantly more impaired in patients with AKI. Hypertension and CINV are significant risk factors. Optimizing prevention strategies for CINV are urgently needed. Key words: locally advanced squamous cell carcinoma of the head and neck, high-dose cisplatin, chemoradiation, acute kidney injury, risk factors

33 2 CISPLATIN-INDUCED ACUTE KIDNEY INJURY | PART ONE Background Three-weekly high-dose cisplatin (100 mg/m2) is considered the standard systemic regimen given concurrently with postoperative or definitive radiotherapy in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) [1-3]. The additional absolute benefit in overall survival of adding cisplatin chemotherapy has been best estimated as 6.5% at five years when compared with radiotherapy alone [4]. However, concurrent highdose cisplatin is associated with significant acute and late toxicities [5,6]. Acute kidney injury (AKI) is a common and serious side effect of high-dose cisplatin-based concurrent chemoradiation (CRT). AKI is a predictor of immediate and long-term adverse outcomes. Even a minor acute reduction in kidney function has an adverse prognosis [7]. The incidence of cisplatin-induced AKI has been reported before [5, 8-10]. However, development of AKI during high-dose cisplatin-based CRT is underreported, using the Kidney Disease Improving Global Outcomes (KDIGO) criteria [11], which are the most recent and preferred criteria for diagnosis and staging of AKI. Also, little is known about the impact of AKI on long-term renal function and treatment outcomes in patients with LA-SCCHN. Early detection of AKI enables early intervention, which might lessen treatment burden and improves efficacy and cost-effectiveness of care [12]. Therefore, it is clinically relevant to identify potentially modifiable risk factors for cisplatin-induced AKI in this patient group. The purpose of this study is to answer the following questions: (1) what is the incidence of AKI during treatmentwithhigh-dose cisplatin-basedCRT for LA-SCCHN, according toKDIGO criteria, (2) which predictors for development of cisplatin-induced AKI can be identified, and (3) what are the long-termconsequences of cisplatin-inducedAKI in this patient group? Methods Study design From January 2017 to July 2017, patient data were collected retrospectively by two investigators (M.V. and E.N.) from electronic medical records (EMRs) between January 2011 (introduction of EMRs in our center) and January 2014. Patient population Patients, both female and male, 18 years or older, with histologically proven, resectable high-risk or not-resectable LA-SCCHN, who were treated with three-weekly high-dose (100 mg/m2) cisplatin-based CRT from January 2011 to January 2014 at the Amsterdam University Medical Center, VU University, were included in this study. Exclusion criteria were a history of AKI or a creatinine clearance of ≤60 mL/min/1.73 m2 (estimated by the Cockcroft-Gault equation) before start of CRT. Other exclusion criteria were diagnosis of nasopharyngeal carcinoma, previous treatment with radiotherapy and/or chemotherapy, and treatment with biologicals. This retrospective study was not subject to the Dutch Medical Research Involving Human Subjects (WMO) act as was determined by theMedical Ethics Committee of the Amsterdam UMC, Vrije Universiteit Amsterdam.

34 PART ONE | CISPLATIN-INDUCED ACUTE KIDNEY INJURY Chemotherapy Cisplatin (100 mg/m2 ) was administered intravenously on day 1 of a three-weekly cycle for a total of three courses, with pre-hydration containing 2000 mg magnesium sulfate and 20 milliequivalents per Liter (mEq/L) of potassium chloride in 1000 mL of 0.9% normal saline over a 2-hours period, and post-hydration containing 2000 mg magnesium sulfate and 20 mEq/L of potassium chloride in 4000 mL of 0.9% normal saline over a 20-hours period. Prophylactic antiemetic therapy to prevent chemotherapy-induced nausea and vomiting (CINV) was prescribed according to international guidelines [13,14], containing a threedrug regimen, which included dexamethasone, the serotonin receptor antagonist (5HT3 RA) ondansetron, and the neurokinin-1 receptor antagonist (NK1 RA) aprepitant intravenously before administration of cisplatin (day 1), followed by aprepitant on days 2 and 3, and dexamethasone on days 2 to 4 taken orally. The use of rescue antiemetics was allowed and reported in the EMR. Measurements Demographic and tumor characteristics, tumor and nodal stage (seventh edition of the American Joint Committee on Cancer (AJCC) TNM classification of malignant tumors), medical history, weight and height, age-adjusted Charlson Comorbidity Index (CCI) [15], and Eastern Cooperative Oncology Group (ECOG) performance status score were derived from the EMRs of the included patients. Information on the use of potentially nephrotoxic co-medications was obtained by medical prescription history from the week before start of treatment until the last day of chemoradiation. The drugs documented included all categories of diuretics, angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers, non-steroidal anti-inflammatory drugs (NSAIDs), proton-pump inhibitors, lithium, haloperidol, and intravenous contrast media. Data on early termination of cisplatin or dose reductions, radiotherapy delay or truncations, occurrence of CINV, the use of rescue antiemetics, and the number and length of emergency hospitalizations were also obtained, including the reason for treatment modifications and emergency admissions. Serumcreatinine (sCr) valueswere derived fromthe clinical laboratory database at baseline (day before start CRT), weekly during CRT, at least every other day during (emergency) hospitalizations, and three and twelve months after completion of CRT. The criteria for AKI based on the KDIGO criteria were applied [11]. AKI (stage 1) was defined by sCr rise of greater than or equal to 26.5 µmol/l within 48 hours, or sCr increase greater than or equal to 1.5-fold from the baseline reference value. Stage 2 AKI was defined as a greater than or equal to 2.0- to 2.9 fold increase from baseline reference sCr. Stage 3 AKI was defined as a greater than or equal to threefold increase from baseline reference sCr, or increase of 354 µmol/l, or commenced on renal-replacement therapy irrespective of stage of AKI. The reference sCr is defined as the lowest creatinine value recorded within 3 months of the event, or from repeat sCr within 24 hours, or estimated from the nadir sCr value if a patient recovers from AKI. The urine output criterion was not used in this study. Disease free survival (DFS) and disease-specific mortality (DSM) were assessed from the last day of radiotherapy until disease recurrence or death, respectively.

35 2 CISPLATIN-INDUCED ACUTE KIDNEY INJURY | PART ONE Statistics Descriptive analyses were used to describe patient and treatment characteristics and the incidence of AKI. To indicate predictors for cisplatin-induced AKI, univariate analysis was used to analyze the association between AKI and age (<60 years vs, ≥60 years), sex, ECOG performance status score before start of treatment (<2 vs. ≥2), presence of hypertension (defined as systolic pressure >140 millimeters of mercury (mmHg) or diastolic pressure >90 mmHg) before start of treatment (yes vs. no), presence of diabetes mellitus (yes vs. no), presence of cognitive impairment (yes vs. no), number of nephrotoxic co-medications taken in the week before start of CRT (<2 vs. ≥2), number of pack-years (<10 years or ≥10 years), excessive alcohol consumption (<14 units per week or ≥14 units per week), primary LA-SCCHN tumor site (oropharyngeal vs. non-oropharyngeal), and occurrence of clinically relevant CINV (defined as administration of rescue antiemetics and/or hospital admission to provide targeted care for CINV) during treatment. Variables in the univariate logistic regression analysis with an association p< 0.20 were included as independent variables into the multivariate logistic regression model. In the multivariate analysis model, p values <0.05 were considered statistically significant. The paired samples t test was used to compare mean sCr values at baseline, and at three and twelve months post-treatment, in both patients with AKI during treatment, and those without (non-AKI patients). The independent samples t test was used to compare the means of sCr values between AKI and non-AKI patients at baseline, and at three and twelve months post-treatment. Kaplan-Meier and log-rank methods were used to compare the curves of DFS and DSM between AKI and non-AKI patients. Analyses were performed with IBM SPSS statistics version 22 (Chicago, IL, United States). Results A total of 124 patients were included in this study. The median age was 60 years (range, 30 to 74 years), 78% of patients were male, and 94% had ECOG performance status 0 to 1 (Table 1). Twenty percent of patients had hypertension, age-adjusted CCI score was 0 to 1 in 74% of patients. Most patients (74%) had a smoking history of ≥10 pack-years, and 20% indicated excessive use of alcohol. Median number of potentially nephrotoxic comedications was 2 (range, 0 to 3).