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Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer
Clinical Oncology xxx (xxxx) xxx Contents lists available at ScienceDirect
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Original Article
Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer N. Reed *, H. Glen *, G. Gerrard y, J. Good z, M. Lei x, A.R. Lyon k, M. Strachan {, J. Wadsley **, K. Newbold yy * Beatson
West of Scotland Cancer Centre, Glasgow, UK St James’s Hospital, Leeds, UK z QE Hospital, Birmingham, UK x Guy’s and St Thomas’ NHS Foundation Trust, London, UK { Royal Brompton & Harefield NHS Foundation Trust and Imperial College London, London, UK k Western General Hospital, Edinburgh, UK ** Weston Park Hospital, Sheffield, UK yy Royal Marsden NHS Foundation Trust, London, UK y
Received 9 July 2018; received in revised form 4 November 2019; accepted 7 November 2019
Abstract Aims: Lenvatinib is an oral multi-kinase inhibitor approved for the treatment of adults with progressive, locally advanced or metastatic, differentiated thyroid carcinoma refractory to radioactive iodine. Materials and methods: A literature review was undertaken to inform the development of consensus-based guidance for the routine management of adverse events associated with lenvatinib. PubMed was searched on 24 October 2017; the search terms were ‘lenvatinib’ and ‘thyroid cancer’. Results: Hypertension, diarrhoea, weight loss, skin toxicities and cardiovascular adverse events were considered. For grade 1/2 diarrhoea, initial treatment should be loperamide with a 1-week treatment interruption if diarrhoea persists and dose reduction if diarrhoea recurs on reinitiation of lenvatinib. Blood pressure should be monitored daily in patients with pre-existing hypertension, otherwise from 1 week after the initiation of lenvatinib and weekly for the first 2 months. For patients with systolic blood pressure 135 mmHg to <160 mmHg or diastolic blood pressure 85 mmHg to <100 mmHg, lenvatinib should be continued but antihypertensive therapy initiated/intensified. For patients who remain hypertensive, a treatment break can be considered with lenvatinib reinitiated at a reduced dose once the patient’s blood pressure has stabilised for at least 48 h. Weight loss of 10% of baseline body weight or the onset of anorexia should be managed with a 1-week treatment break; patients should maintain a healthy, active lifestyle. For patients with grade 2 proteinuria, lenvatinib may be continued, but an angiotensin II receptor blocker or angiotensin converting enzyme inhibitor should be commenced. For grade >3 proteinuria, lenvatinib should be interrupted until proteinuria returns to 1þ. For chronic proteinuria, lenvatinib should be stopped. Skin toxicities should be managed with moisturisers or emollients and soap substitutes. Conclusions: Prophylaxis, regular monitoring and symptomatic management with appropriate short treatment breaks and, for persistent adverse events, dose reductions, are recommended to enable patients to remain on the optimal dose regimen. Ó 2019 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.
Keywords: Diarrhoea; Hypertension; Lenvatinib; Practical management; Proteinuria
Introduction
Author for correspondence: N. Reed, Beatson West of Scotland Cancer Centre, Gartnavel General Hospital, 1053 Great Western Road, Glasgow, G12 0YN, UK. E-mail address: [email protected] (N. Reed).
Lenvatinib is an oral multi-kinase inhibitor approved for the treatment of adults with progressive, locally advanced or metastatic, differentiated thyroid carcinoma that is refractory to radioactive iodine (RIR-DTC) [1,2]. Therapeutic options for patients with RIR-DTC are currently limited to the multi-kinase inhibitors including lenvatinib and
https://doi.org/10.1016/j.clon.2019.11.010 0936-6555/Ó 2019 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.
Please cite this article as: Reed N et al., Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer, Clinical Oncology, https://doi.org/10.1016/j.clon.2019.11.010
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sorafenib. These agents exert an anti-angiogenic effect, preventing the formation of new vasculature, a process that is required for tumour growth and progression. Lenvatinib inhibits signalling via the vascular endothelial growth factor receptors (VEGFR) 1e3 as well as the fibroblast growth factor receptors [1e4], the ret proto-oncogene and the plateletderived growth factor receptor-beta. Together, inhibition of these signalling pathways disrupts tumour angiogenesis, growth and metastatic processes [2]. The efficacy of lenvatinib for the treatment of RIR-DTC was shown in the phase III SELECT trial [3]. This study, which included 392 patients who were randomly assigned to lenvatinib 24 mg per day or placebo, confirmed that lenvatinib significantly prolongs progression-free survival (PFS) by 14.7 months compared with placebo in patients with RIR-DTC regardless of age [3e5]. Moreover, prolongation of overall survival was observed for older patients treated with lenvatinib despite the design of the study, which allowed for crossover from placebo to lenvatinib after disease progression [4]. However, as for other multikinase inhibitors used in this setting, lenvatinib is associated with a number of adverse events, which require prompt and appropriate management in order to ensure patients remain on and obtain maximum benefit from treatment [6e9]. This review provides appropriate strategies for the routine management of adverse events associated with lenvatinib for RIR-DTC. The recommendations are based on a review of the literature and the expert opinion of the authors following a meeting held in October 2017.
Materials and Methods Consensus Generation A consensus meeting was convened by Eisai on 24 October 2017 to review the current recommendations for the management of adverse events associated with the use of lenvatinib for the treatment of RIR-DTC. The expert panel identified the most relevant adverse events associated with the use of lenvatinib and reviewed current management recommendations or lack thereof. The expert panel discussed and agreed recommendations for the clinical management of such adverse events, principally within the context of the UK healthcare system, but with applicability to the wider European healthcare system. An informal roundtable voting system was used to ensure consensus between the expert panel members for the recommendations proposed for the management of each adverse event. Literature Review PubMedÒ was searched on 24 October 2017 using the MESH search terms ‘lenvatinib’ and ‘thyroid cancer’ to identify the evidence base supporting the use of lenvatinib for the treatment of RIR-DTC. Special emphasis was placed on the identification of papers reporting the adverse event profile associated with lenvatinib in this setting and
approaches to the management of such adverse events. All English language publication types were accepted. In total, 122 publications were identified and reviewed for relevance to the management of adverse events associated with lenvatinib. Of these, 12 publications provided relevant information and formed the evidence base for the development of management recommendations [2e13]. Lenvatinib for the Treatment of Radioactive IodineRefractory Differentiated Thyroid Carcinoma In the phase III SELECT trial, the most commonly reported adverse events (any grade) considered to be related to treatment were hypertension (reported in 68% of patients), diarrhoea (59% of patients), fatigue (59% of patients) and decreased appetite (50% of patients) [3]. The most common grade 3 adverse events in the SELECT trial were hypertension (42%), proteinuria (10%), decreased weight (9.6%), fatigue (9.2%) and diarrhoea (8%) [3]. Consistent with this, the most commonly reported grade 3 adverse events in a real-world study of 88 patients treated with lenvatinib in France were hypertension (67%), fatigue (61%), weight loss (59%), diarrhoea (45%) and anorexia (36%) [10]. In addition to these most common grade 3 events, skin toxicities (including palmar-plantar erythema [PPE] and rash) and cardiovascular adverse events were considered of clinical relevance to the care of patients receiving lenvatinib and are also considered. General Advice when Initiating Lenvatinib Treatment with lenvatinib should be initiated in clinics with experience in managing patients with advanced thyroid cancer on tyrosine kinase inhibitor therapy. Patients should have a named person to contact during the initial days of treatment. Before initiating treatment, the overall health of the patient should be evaluated, and comorbidities identified. Pre-existing hypertension should be well controlled, and a baseline blood pressure recorded. Patients should be educated on the kind of adverse events they may experience in the initial days or weeks of treatment and provided with an action plan to manage such events, and specific guidance on who to contact and when to contact them (see Supplementary Table S1 for an example leaflet and Supplementary Figure S1 for an example patient information poster for display in a clinic). With regards to treatment planning, palliative radiotherapy does not necessitate interruption of lenvatinib treatment, although if treatment fields are large and radiotherapy-induced toxicity overlaps with lenvatinib adverse events (e.g. diarrhoea), clinical discretion should be used. Treatment should be stopped 3 days before a surgical procedure, including dental work, and wound healing should be complete before treatment is reinitiated. Diarrhoea Diarrhoea has been reported as an adverse event associated with a number of multi-kinase inhibitors, including
Please cite this article as: Reed N et al., Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer, Clinical Oncology, https://doi.org/10.1016/j.clon.2019.11.010
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cabozantinib, vandetanib, sorafenib, regorafenib, axitinib and lenvatinib [8]. For patients receiving lenvatinib for RIRDTC, diarrhoea is most often seen in the initial months of treatment. In the SELECT trial, the median time to onset of diarrhoea was 12.1 weeks [6]. However, patients should be advised that diarrhoea can be a later-onset toxicity. A multivariate analysis of data from the SELECT trial found that the overall survival for patients with RIR-DTC was significantly positively associated with the presence of diarrhoea [6]. This association was not observed for PFS. Management The underlying pathogenesis of multi-kinase inhibitorassociated diarrhoea is not well understood [14] but may involve ischaemic colitis or inflammation of the upper gastrointestinal tract [15]. As such, interventions should focus on symptomatic management (Figure 1). Before starting lenvatinib, patients should be offered general dietary advice and education appropriate for minimising or managing diarrhoea, including advice on keeping a food diary to identify whether certain foods trigger diarrhoea. Mild (Common Terminology Criteria for Adverse events [CTCAE] grade 1 or 2) diarrhoea should be managed with loperamide (per manufacturer’s guidance) and oral hydration and electrolyte replacement as needed. Codeine phosphate may be considered if loperamide is ineffective or not tolerated. Patients could be provided with a prescription for loperamide and guidance for use, at the time of
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initiating lenvatinib therapy. A lenvatinib treatment interruption of 1 week should be considered if diarrhoea persists despite optimal supportive therapy. Lenvatinib should be reinitiated at the same dose once the diarrhoea has resolved to grade 1 or less. If diarrhoea continues or re-emerges within days of reinitiating lenvatinib, it should be managed with loperamide and lenvatinib treatment should be interrupted again and reinitiated once diarrhoea has returned to grade 1 but at a lower dose. The recommended dose reduction schema for lenvatinib is shown in Table 1. Using this approach, no patient should reach grade 3 diarrhoea. However, should this occur, treatment should be interrupted and lenvatinib reinitiated at a reduced dose. Active supportive measures should be provided as clinically indicated, including intravenous hydration and electrolyte replacement. Lenvatinib treatment should be stopped if the patient experiences grade >3 diarrhoea again. Hypertension The aetiology of multi-kinase inhibitor-associated hypertension is complex and involves several potential mechanisms [16]. VEGF plays a regulatory role in blood pressure homeostasis through the production of nitric oxide with nitric oxide-dependent dilation of small arterioles and venules, and turnover of the capillary and microvasculature network (capillary rarefraction). Anti-VEGF therapy reduces the density of such microvessels [17]. Vascular
Provide appropriate pa ent educa on about the risk for diarrhoea during treatment with lenva nib and ac ons to take if diarrhoea emerges Preven on/prepara on: • Consider providing a prescrip on for loperamide and an electrolyte solu on for pa ent use if diarrhoea emerges prior to the next clinic visit Resolves: No further ac on
CTCAE Grade 1 or 2: •
Loperamide 4 mg followed by 2 mg a er each episode of diarrhoea (up to 16 mg/day)
CTCAE Grade 3: • • •
Consider admission to hospital for IV fluids and electrolyte replacement Loperamide 4 mg followed by 2 mg a er each episode of diarrhoea (up to 16 mg/day) Lenva nib should be stopped and restarted at a dose reduc on when resolved
CTCAE Grade 4: Stop lenva
Con nues or recurs: Consider a 1 week treatment break and reini ate to the same lenva nib dose Recurs within days of reini a ng lenva nib: Treat with loperamide and 1 week treatment break. Reini ate to a lower lenva nib dose
Resolves: No further ac on
Con nues or recurs: Consider a 1 week treatment break and reini ate to a lower lenva nib dose
nib treatment
CTCAE, Common Terminology Criteria for Adverse Events NB: consider codeine phosphate if loperamide is ineffec ve or not tolerated
Fig 1. Management algorithm for the prevention and management of diarrhoea during treatment with lenvatinib. Please cite this article as: Reed N et al., Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer, Clinical Oncology, https://doi.org/10.1016/j.clon.2019.11.010
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Table 1 Dose modifications from the recommended lenvatinib daily dose [1] Dose level
Daily dose
Recommended daily dose
24 mg orally once daily (2 10 mg capsules plus 1 4 mg capsule) 20 mg orally once daily (2 10 mg capsules) 14 mg orally once daily (1 10 mg capsule plus 1 4 mg capsule) 10 mg orally once daily* (1 10 mg capsule)
First dose reduction Second dose reduction
Third dose reduction
* Further dose reductions may be considered on an individual patient basis.
endothelial dysfunction has been proposed as a mechanism for lenvatinib-associated hypertension [11]. In addition to peripheral vascular resistance, VEGF also regulates endothelial function within the renal glomeruli, and loss can result in reduced glomerular filtration, proteinuria, salt and water retention and hypertension. However, these observations cannot fully explain the aetiopathology of the hypertension reported during multi-kinase inhibitor therapy [12]. The management of multi-kinase inhibitor-associated hypertension can be challenging, with at least 50% of cases requiring two or more new antihypertensive drugs. The choice of antihypertensive medication depends on a number of factors, including the current understanding of the pathophysiology of multi-kinase inhibitor-associated hypertension, pre-existing cardiac diagnoses and cardiovascular risk factors, left ventricular function, renal function, proteinuria, concomitant complications and potential cardiovascular risks of these drugs. Early, acute hypertension has been reported within 24e48 h of initiating lenvatinib [5]. An analysis of data from the SELECT trial found that the emergence of hypertension during treatment with lenvatinib is associated with longer PFS [13]. Patients initiating lenvatinib should be made aware of the symptoms that might indicate the onset of acute hypertension, including severe headache, fatigue or confusion and blurred vision, and advised to contact their oncology team or general practitioner should they experience any of them. For patients with a history of hypertension, this should be well controlled with stable doses of antihypertensive therapy for at least 1 week prior to initiating lenvatinib. Monitoring Stage 1 hypertension is defined as clinic-measured blood pressure 140/90 mmHg and subsequent ambulatory blood pressure monitoring daytime average or home blood pressure monitoring average blood pressure 135/85 mmHg [18]. For patients initiating lenvatinib, blood pressure should be measured at baseline, before treatment. If elevated in the
hospital clinic, then a home blood pressure diary or a 24-h ambulatory blood pressure monitor should be offered. For patients with pre-existing hypertension, blood pressure should be monitored daily, particularly if their hypertension was uncontrolled prior to assessment. Otherwise blood pressure should be monitored from 1 week after the start of lenvatinib and subsequently weekly for the first 2 months. Home blood pressure monitoring with commercially available blood pressure monitors is an appropriate approach for the monitoring of blood pressure in the initial days of treatment. Alternatively, patients could be advised to attend their general practitioner clinic or local pharmacist for blood pressure monitoring, even in the absence of secondary symptoms indicative of emerging hypertension. An example alert letter that can be given to the patient for them to take to their general practitioner should they require community blood pressure monitoring is provided in Supplementary Table S2. According to the Summary of Product Characteristics, blood pressure should be monitored 1 week after the start of lenvatinib, then every 2 weeks for the first 2 months and monthly thereafter [1]. However, weekly monitoring for the first 2 months and every 2 weeks thereafter is regarded by the authors as acceptable for pragmatic reasons, for example, to align with scheduled clinic visits. If blood pressure is elevated on a home measurement (>135/85 mmHg), patients should start daily measurements, and if consistently elevated across 3 or more days then treatment is recommended. Patients should be educated on the correct technique for home blood pressure measurement as provided by the British Hypertension Society [19]. Management For patients presenting with systolic blood pressure 140 mmHg to <160 mmHg or diastolic blood pressure 90 mmHg to <100 mmHg in clinic, or systolic blood pressure 135 mmHg to <160 mmHg or diastolic blood pressure 85 mmHg to <100 mmHg on home diary measurements, lenvatinib therapy should be continued but antihypertensive therapy initiated or intensified (Table 2). For patients who remain hypertensive (systolic blood pressure 180 mmHg or diastolic blood pressure 110 mmHg) despite optimal antihypertensive therapy, a lenvatinib treatment break should be considered, with the aim of reinitiating lenvatinib at a reduced dose once the patient’s blood pressure has stabilised (systolic blood pressure 160 mmHg, diastolic blood pressure 95 mmHg) on antihypertensive therapy for at least 48 h. Reversible causes of hypertension and exacerbating factors should be reviewed. Cessation of non-steroidal antiinflammatory drugs, reduction of steroid doses and counselling regarding salt and fluid and excessive alcohol intake are important. Secondary causes including obstructive sleep apnoea, renovascular disease and hyperaldosteronism should also be considered. Stress may be contributory and challenging to manage e referral for clinical psychological review and stress management may be appropriate in selected cases.
Please cite this article as: Reed N et al., Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer, Clinical Oncology, https://doi.org/10.1016/j.clon.2019.11.010
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Table 2 Antihypertensive management for patients experiencing hypertension during treatment with lenvatinib Antihypertensive class
Drug
Dose
ACE inhibitor
Enalapril Ramipril Amlodipine Losartan Valsartan Irbesartan Hydrochlorthiazide Spironolactone Nebivolol Carvedilol Long-acting nitrates Isosorbide dinitrate Isosorbide mononitrate
Initial: 5 mg/day then 10 mg/day to a maximum of 40 mg/day Initial: 2.5 mg/day then 5 mg/day to a maximum of 10 mg/day 2.5e10 mg/day 50e100 mg/day 80e230 mg/day 150e300 mg/day 12.5e25 mg twice daily 12.5e100 mg/day 2.5e5 mg/day 3.125e25 mg twice daily 40e60 mg/day
CCB ARB
Diuretics BBA Nitrate derivatives
ACE, angiotensin converting enzyme; CCB, calcium channel blockers; ARB, angiotensin II receptor blocker; BBA, ß-adrenoceptor antagonist.
Initial antihypertensive treatment should be with an angiotensin converting enzyme (ACE) inhibitor (e.g. ramipril [initial dose 2.5 mg/day], enalapril [initial dose 5 mg/ day] or lisinopril [initial dose 5 mg/day]). These agents are also effective for the treatment of heart failure and proteinuria, both of which may be associated with multi-kinase inhibitor therapy, whereas other antihypertensive agents are not. Indeed, recent data in renal cancer suggest improved outcomes for patients with renal cancer treated with ACE inhibitors compared with those who received other antihypertensive agents [20,21]. Treatment should be escalated within 3 days if hypertension persists with increased doses of ACE inhibitor followed by the addition of a second agent. The choice will depend on fluid retention, cardiovascular risk factors, left ventricular function, coronary disease, arrhythmias and renal dysfunction or proteinuria. Options include thiazide diuretics, spironolactone, nebivolol, carvedilol or amlodipine, with referral to a cardiologist if hypertension remains uncontrolled. Once a patient is stable with regards to their hypertension, routine monitoring and management can be referred back to their general practitioner. Patients with multi-kinase inhibitor-associated hypertension should be reviewed clinically for symptoms or signs of left ventricular dysfunction and heart failure. Left ventricular systolic dysfunction (LVSD) is present in 5e10% of patients taking VEGF-based multi-kinase inhibitors. This may be due to hypertensive heart failure, but LVSD can occur without hypertension. All hypertensive patients should have their serum natriuretic peptide (brain natriuretic peptide or N-terminal-pro-brain natriuretic peptide) levels checked and, if elevated, or if the patient is symptomatic, then an echocardiogram is appropriate to assess for evidence of left ventricular dysfunction. This is also important to guide antihypertensive medication choices, as amlodipine is generally avoided in patients with left ventricular ejection fraction <50%. For patients with both proteinuria and hypertension, antihypertensive therapy should be initiated as described and the patient should be re-evaluated for proteinuria once
the hypertension is well controlled. Should proteinuria persist in the case of well-controlled hypertension, a lenvatinib dose reduction may be considered. Care should be taken to identify and avoid hypotension when interrupting lenvatinib treatment for patients receiving multiple antihypertensive agents. For such patients, antihypertensives should be withdrawn gradually in reverse order and blood pressure monitored every 2e3 days. Weight Loss and Decreased Appetite In the phase III SELECT trial, grade 3 weight loss was reported among 9.6% of patients treated with lenvatinib [3]. Moreover, cancer-associated cachexia (marked weight loss that cannot be reversed by normal nutritional support) is estimated to affect up to 80% of patients with cancer and may be the cause of death in 20% [22]. Consequently, patients and physicians should be alert for weight loss and decreased appetite so that appropriate interventions and supportive strategies can be introduced prior to the patient progressing to a cachectic state [23]. Before starting treatment, patients should be educated about the importance of maintaining a healthy diet and body weight. Such education could include advice about the impact of excessive weight loss on other potential adverse events such as fatigue. Patients should be encouraged to maintain a healthy, active lifestyle and should aim to maintain their fitness levels during lenvatinib treatment. Management Weight loss of 10% of baseline body weight or the onset of anorexia should be managed with a short treatment break (about 1 week), after which lenvatinib should be reinitiated at the same dose. If weight loss or anorexia recur, a further treatment break should be considered until appetite improves and weight loss stops with reinitiation of lenvatinib at a lower dose. Referral to a dietitian or specialist nurse for dietary advice and support may be beneficial where available and patients should be encouraged to eat little and often. High-calorie foods (milk shakes, ice cream,
Please cite this article as: Reed N et al., Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer, Clinical Oncology, https://doi.org/10.1016/j.clon.2019.11.010
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frozen yoghurts) recommended.
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and
nutrition
bars
can
also
be
effect of drugs targeting the VEGF system [28,29]. In the SELECT trial, 10% of patients experienced grade 3 proteinuria and the median time to onset was 6.1 weeks [3,6].
Fatigue Fatigue is common among patients with cancer and can have multiple causes, including emotional distress and sleep disturbance, disease-related morbidities such as weight loss, and anaemia, and may also be a treatmentrelated effect [24]. In the SELECT trial, the median time to the first onset of fatigue was 3 weeks [6], with 9.2% of patients reporting grade 3 fatigue [3]. Management As an initial step, any potential link to a rise in thyroidstimulating hormone, weight loss/anorexia or disease progression should be considered. Patients should be encouraged to maintain a healthy, active lifestyle and should aim to maintain their fitness levels during lenvatinib treatment. Aerobic and non-aerobic exercise have been shown to reduce cancer-related fatigue and patients should be encouraged to undertake exercise that suits their lifestyle and personal preference [25,26]. Skin Toxicities Skin toxicities, including PPE and rash, although considerably less common in the SELECT trial than other events such as diarrhoea, have the potential to significantly impact the patient’s quality of life [27]. Rash of any grade was reported by 16.1% of patients treated with lenvatinib in the SELECT trial, with 0.4% of patients reporting CTCAE grade 3 rash. PPE syndrome (PPES) was reported by 31.8% of patients, with grade 3 PPES reported by 3.4%. The median time to the first onset of rash was 7.3 weeks and of PPES, 5.9 weeks [6]. Management Patients should be provided with general skin care advice, including the use of moisturisers or emollients and soap substitutes such as Dermol 500 (Supplementary Table S3). For more severe skin toxicities, topical steroids such as 1% hydrocortisone are recommended, although consideration should be given to potential side-effects of these treatments (Table 3). Oral antibiotics such as doxycycline or minocycline may also be considered. Steroid creams containing an antimicrobial can be used for scrotal rash. Ureabased creams are useful for patients with hyperkeratosis and creams containing antipruritic agents may be helpful for patients experiencing itch. Referral for podiatry evaluation should be considered for patients with existing calluses. Proteinuria The incidence of proteinuria of any grade during VEGFRetyrosine kinase inhibitor therapy has been reported to be 18.7%, with 2.4% of patients reporting grade 3 proteinuria (>3.5 g/24 h) and is thought to represent a class
Monitoring and Management Dipstick testing is an appropriate strategy for routine monitoring of patients for proteinuria. Initially, patients should be assessed every 14 days then, if proteinuria is not evident, monitoring can be reduced to every 28 days. A protein/creatinine ratio (PCR) should be measured in all patients with grade 2 þ proteinuria. A PCR can be measured on an early morning specimen of urine collected in a universal container and is a very reliable measure of urine protein loss. Although a 24-h urine collection is considered the ‘gold standard’ method of assessing the degree of proteinuria, it is inconvenient for patients and may be misleading if the collection is incomplete. If a PCR is not available, an albumin/creatinine ratio (ACR) is an acceptable alternative. A PCR >300 mg/mmol (ACR >250 mg/mmol) is broadly consistent with grade 3 proteinuria. A PCR of 100e300 mg/mmol (ACR 70e250 mg/mmol) is consistent with grade 2 proteinuria (1.0e3.5 g/24 h). Proteinuria is often very sensitive to high blood pressure and aggressive blood pressure reduction can reduce proteinuria. Angiotensin receptor blockers (e.g. candesartan or losartan) or ACE inhibitors are particularly effective at treating proteinuria. For patients with grade 2 proteinuria, lenvatinib may be continued, but an angiotensin II receptor blocker (ARB) or an ACE inhibitor should be started (if the patient is not already on this therapy). The blood pressure target should be < 135/85 mmHg and if necessary additional antihypertensive agents should be started, as per the above guidelines on hypertension. For patients with grade 3 proteinuria, lenvatinib treatment should be interrupted until proteinuria returns to grade 1þ (PCR <100 mg/mmol or ACR <70 mg/mmol). An ARB or an ACE inhibitor should be started (if not already). Blood pressure may need to be lowered below 120/70 mmHg to maintain an acceptable level of proteinuria. For patients with chronic, resistant grade 3 proteinuria, lenvatinib treatment should be stopped. Referral to a nephrologist should be considered. Cardiovascular Effects Patients should be monitored for clinical symptoms or signs of cardiac decompensation [1]. Patients considered to be at risk for cardiovascular events are those with a preexisting history of coronary artery disease (myocardial infarction, angina), heart failure, hypertensive heart disease with left ventricular hypertrophy, atrial fibrillation and rarer diseases, including inherited cardiomyopathies and congenital long QT syndrome. Patients should be advised to avoid where possible other medication known to prolong the QT interval (including class Ia and III anti-arrhythmics). These higher risk patients should undergo echocardiography and cardiac troponin and natriuretic peptide measurement at baseline and should be monitored via echocardiograms at each treatment with lenvatinib. This
Please cite this article as: Reed N et al., Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer, Clinical Oncology, https://doi.org/10.1016/j.clon.2019.11.010
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Table 3 Management of skin toxicities during treatment with lenvatinib (with kind permission from the Beatson West of Scotland Cancer Centre, Glasgow, UK) Common terminology criteria for adverse events grade
Definition
Action
1
Minimal skin changes or dermatitis without pain Skin changes (e.g. peeling, blisters, bleeding, oedema or hyperkeratosis) with pain, limiting function but not selfcare
General skin care advice Continue lenvatinib therapy at full dose General skin care advice Commence prescribed application of 10% urea-based creams and topical steroids if indicated Consider oral antibiotics such as doxycycline or minocycline Consider withholding treatment until resolved to grade 1. If first episode, recommence at lenvatinib original dose. If grade 2 toxicity recurs, consider dose reduction General skin care advice Commence prescribed application of 10% urea-based creams and topical steroids if indicated Withhold treatment until resolved to grade 1. Recommence at lower lenvatinib dose
2
3
Severe skin changes (e.g. peeling, blisters, bleeding, oedema or hyperkeratosis) with pain and limiting activities of daily living including self-care
Table 4 Recommended baseline assessments and monitoring during lenvatinib therapy Timing
Assessment
Baseline (pretreatment)
Weeks 1e8
Advice
Offer advice on: The risk for diarrhoea during treatment and actions to take if diarrhoea emerges The importance of maintaining a healthy diet and body weight Fatigue and the importance of maintaining a healthy lifestyle General skin care and initial management of skin toxicities Daily home blood pressure monitoring for patients with pre-existing hypertension* Weekly home blood pressure monitoring for patients without pre-existing hypertension for the first 8 weeks of treatment* Regular dipstick test for proteinuria (every 14 days initially, then monthly if no evidence of proteinuria seen) Blood pressure Weight Dipstick test for proteinuria Electrocardiograph, troponin and natriurietic peptide for patients with pre-existing cardiac issues Consider cardiology review and echocardiography for patients with pre-existing heart failure
* Patients should be advised to attend their general practitioner clinic or local pharmacist for blood pressure monitoring if home blood pressure monitoring is not appropriate.
should be continued for as long as the patient is receiving lenvatinib. If pre-existing heart failure or LVSD exists at baseline then a specialist cardiology review is recommended, with discussion regarding the alternative cancer treatment options and risk:benefit balance. It is reasonable to start lenvatinib in patients with pre-existing heart failure provided they are clinically stable and close monitoring is advised, e.g. clinical review, echocardiogram and cardiac biomarkers 2e4 weeks after starting and then every 3 months in high risk patients. This surveillance strategy in patients at highest risk is now provided by specialist cardio-oncology services, which are increasingly available in tertiary hospitals in the UK [30].
Summary Lenvatinib has been shown to significantly prolong PFS for patients with RIR-DTC [3]. Patients should be educated about the benefits of lenvatinib therapy and also what adverse effects they can expect during the initial weeks of treatment. An example patient information sheet is provided in Supplementary Table S1 to support initial discussions and for patients to refer to at home. Careful management of emergent adverse events for patients initiated on lenvatinib is essential to enable patients to remain on the optimal dose regimen with minimal impact on their quality of life. A summary of recommended baseline assessments and recommended monitoring in the first
Please cite this article as: Reed N et al., Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer, Clinical Oncology, https://doi.org/10.1016/j.clon.2019.11.010
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4 weeks of lenvatinib therapy is provided in Table 4. Prophylaxis, regular monitoring and symptomatic management with appropriate short treatment breaks and, for persistent adverse events, dose reductions, are recommended for the routine management of patients receiving lenvatinib.
Conflicts of Interest N. Reed and H. Glenn have participated in advisory boards and have received speaker fees from Eisai; G. Gerrard has received honoraria from Eisai and Genzyme; J. Good, M. Lei and M. Strachan have received honoraria from Eisai; A.R. Lyon has received research contracts from Pfizer and Servier, has acted as a consultant for Eisai, Pfizer, Servier, Novartis, BMS and Clinigen, and has participated in advisory boards and received speaker fees from Pfizer, Servier, Novartis, Clinigen, Takenda, Janssen-Cilag, Eli-Lilly, Ferring and Boehringher-Inglehaim; J. Wadsley has received research funding from AstraZeneca, Sanofi-Genzyme and honoraria from Eisai, AstraZeneca, Sanofi-Genzyme, Ipsen, Novartis, Bayer, Baxalta, Lilly and Celgene; K. Newbold has held consultancy roles and has been a member of speaker bureaus for Eisai and Sanofi-Genzyme.
Acknowledgements This work was supported by an unrestricted educational grant from Eisai Ltd, which included honoraria paid to each participant to support their attendance at the consensus meeting and the editorial support provided by Dr Tracey Lonergan (Nyxeon, Healthcare Communications Consultancy). Eisai Ltd did not contribute to or influence the conceptual development of the manuscript and all decisions regarding content were the responsibility of the authors.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.clon.2019.11.010.
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[5] Suyama K, Fujiwara S, Takeshita T, et al. Clinical features of lenvatinib treatment in elderly patients with advanced thyroid cancer. Mol Clin Oncol 2017;7:24e26. [6] Haddad RI, Schlumberger M, Wirth LJ, et al. Incidence and timing of common adverse events in lenvatinib-treated patients from the SELECT trial and their association with survival outcomes. Endocrine 2017;56:121e128. [7] Krajewska J, Kukulska A, Jarzab B. Drug safety evaluation of lenvatinib for thyroid cancer. Expert Opin Drug Saf 2015;14: 1935e1943. [8] Li J, Gu J. Risk of gastrointestinal events with newly approved (after 2011) vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: a meta-analysis of randomized controlled trials. Eur J Clin Pharmacol 2017;73: 1209e1217. [9] Zhu C, Ma X, Hu Y, et al. Safety and efficacy profile of lenvatinib in cancer therapy: a systematic review and meta-analysis. Oncotarget 2016;7:44545e44557. [10] Berdelou A, Borget I, Godbert Y, et al. Lenvatinib for the treatment of radio-iodine refractory thyroid cancer in real-life practice. Thyroid 2018 [Epub ahead of print]. [11] Sueta D, Suyama K, Sueta A, et al. Lenvatinib, an oral multikinase inhibitor, -associated hypertension: potential role of vascular endothelial dysfunction. Atherosclerosis 2017;260: 116e120. [12] Ancker OV, Wehland M, Bauer J, Infanger M, Grimm D. The adverse effect of hypertension in the treatment of thyroid cancer with multi-kinase inhibitors. Int J Mol Sci 2017;18:625. [13] Wirth LJ, Tahara M, Robinson B, et al. Treatment-emergent hypertension and efficacy in the phase 3 study of (E7080) lenvatinib in differentiated cancer of the thyroid (SELECT). Ann Oncol 2015;25(Suppl 4):iv353eiv354. [14] Bowen JM. Mechanisms of TKI-induced diarrhea in cancer patients. Curr Opin Support Palliat Care 2013;7:162e167. [15] Boers-Sonderen MJ, Mulder SF, Nagteqaal ID, et al. Endoscopy in patients with diarrhea during treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors: is the cause in the mucosa? Acta Oncol 2016;55:444e448. [16] Pandey AK, Singhi EK, Arroyo JP, et al. Mechanisms of VEGF (vascular endothelial growth factor) inhibitor-associated hypertension and vascular disease. Hypertension 2018;71. e1e8. [17] Steeghs N, Gelderblom H, Roodt JO, et al. Hypertension and rarefaction during treatment with telatinib, a small molecule angiogenesis inhibitor. Clin Cancer Res 2008;14:3470e3476. [18] NICE. Hypertension in adults: diagnosis and management. Clin Guidel [CG127] November 2016. Available at: https:// www.nice.org.uk/guidance/cg127/chapter/1Guidance#measuring-blood-pressure. [Accessed April 2019]. [19] Williams B, Poulter NR, Brown MJ, et al. British Hypertension Society guidelines for hypertension management 2004 (BHSIV): summary. BMJ 2004;328:634e640. [20] McKay RR, Rodriguez GE, Lin X, et al. Angiotensin system inhibitors and survival outcomes in patients with metastatic renal cell carcinoma. Clin Cancer Res 2015;21:2471e2479. [21] Penttila P, Rautiola J, Poussa T, Peltola K, Bono P. Angiotensin inhibitors as treatment of sunitinib/pazopanib-induced hypertension in metastatic renal cell carcinoma. Clin Genitourin Cancer 2016;15:384e390. [22] Ryan AM, Power DG, Daly L, Cushen SJ, Ni Bhuachalla E, Prado CM. Cancer-associated malnutrition, cachexia and sarcopenia: the skeleton in the hospital closet 40 years later. Proc Nutr Soc 2016;75:199e211. [23] Lucia S, Esposito M, Rossi Fanelli F, Muscaritoli M. Cancer cachexia: from molecular mechanisms to patient’s care. Crit Rev Oncol 2012;17:315e321.
Please cite this article as: Reed N et al., Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer, Clinical Oncology, https://doi.org/10.1016/j.clon.2019.11.010
N. Reed et al. / Clinical Oncology xxx (xxxx) xxx [24] Gerber LH. Cancer-related fatigue: persistent, pervasive, and problematic. Phys Med Rehabil Clin N Am 2017;28:65e88. [25] Hilfiker R, Meichtry A, Eicher M, et al. Exercise and other nonpharmaceutical interventions for cancer-related fatigue in patients during or after cancer treatment: a systematic review incorporating an indirect-comparisons meta-analysis. Br J Sports Med 2018;52:651e658. [26] Mustian KM, Alfano CM, Heckler C, et al. Comparison of pharmaceutical, psychological, and exercise treatments for cancer-related fatigue: a meta-analysis. JAMA Oncol 2017;3: 961e968. [27] Nikolau V, Syrigos K, Saif MW. Incidence and implications of chemotherapy related hand-foot syndrome. Expert Opin Drug Saf 2016;15:1625e1633.
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[28] Launay-Vacher V, Deray G. Hypertension and proteinuria: a class-effect of antiangiogenic therapies. Anticancer Drugs 2009;20:81e82. [29] Zhang ZF, Wang T, Liu LH, Guo HQ. Risks of proteinuria associated with vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: a systematic review and meta-analysis. PLoS ONE 2014;9:e90135. [30] Bennett J, Lyon AR, Plummer C, Rosen SD, Shiu KK. Cardiooncology: a new sub-specialty. Br J Cardiol 2018. Available at: https://doi.org/10.5837/bjc.2018.001 https://bjcardio.co.uk/ 2018/01/cardio-oncology-a-new-sub-specialty/. [Accessed May 2018].
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Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Original Article
Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer N. Reed *, H. Glen *, G. Gerrard y, J. Good z, M. Lei x, A.R. Lyon k, M. Strachan {, J. Wadsley **, K. Newbold yy * Beatson
West of Scotland Cancer Centre, Glasgow, UK St James’s Hospital, Leeds, UK z QE Hospital, Birmingham, UK x Guy’s and St Thomas’ NHS Foundation Trust, London, UK { Royal Brompton & Harefield NHS Foundation Trust and Imperial College London, London, UK k Western General Hospital, Edinburgh, UK ** Weston Park Hospital, Sheffield, UK yy Royal Marsden NHS Foundation Trust, London, UK y
Received 9 July 2018; received in revised form 4 November 2019; accepted 7 November 2019
Abstract Aims: Lenvatinib is an oral multi-kinase inhibitor approved for the treatment of adults with progressive, locally advanced or metastatic, differentiated thyroid carcinoma refractory to radioactive iodine. Materials and methods: A literature review was undertaken to inform the development of consensus-based guidance for the routine management of adverse events associated with lenvatinib. PubMed was searched on 24 October 2017; the search terms were ‘lenvatinib’ and ‘thyroid cancer’. Results: Hypertension, diarrhoea, weight loss, skin toxicities and cardiovascular adverse events were considered. For grade 1/2 diarrhoea, initial treatment should be loperamide with a 1-week treatment interruption if diarrhoea persists and dose reduction if diarrhoea recurs on reinitiation of lenvatinib. Blood pressure should be monitored daily in patients with pre-existing hypertension, otherwise from 1 week after the initiation of lenvatinib and weekly for the first 2 months. For patients with systolic blood pressure 135 mmHg to <160 mmHg or diastolic blood pressure 85 mmHg to <100 mmHg, lenvatinib should be continued but antihypertensive therapy initiated/intensified. For patients who remain hypertensive, a treatment break can be considered with lenvatinib reinitiated at a reduced dose once the patient’s blood pressure has stabilised for at least 48 h. Weight loss of 10% of baseline body weight or the onset of anorexia should be managed with a 1-week treatment break; patients should maintain a healthy, active lifestyle. For patients with grade 2 proteinuria, lenvatinib may be continued, but an angiotensin II receptor blocker or angiotensin converting enzyme inhibitor should be commenced. For grade >3 proteinuria, lenvatinib should be interrupted until proteinuria returns to 1þ. For chronic proteinuria, lenvatinib should be stopped. Skin toxicities should be managed with moisturisers or emollients and soap substitutes. Conclusions: Prophylaxis, regular monitoring and symptomatic management with appropriate short treatment breaks and, for persistent adverse events, dose reductions, are recommended to enable patients to remain on the optimal dose regimen. Ó 2019 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.
Keywords: Diarrhoea; Hypertension; Lenvatinib; Practical management; Proteinuria
Introduction
Author for correspondence: N. Reed, Beatson West of Scotland Cancer Centre, Gartnavel General Hospital, 1053 Great Western Road, Glasgow, G12 0YN, UK. E-mail address: [email protected] (N. Reed).
Lenvatinib is an oral multi-kinase inhibitor approved for the treatment of adults with progressive, locally advanced or metastatic, differentiated thyroid carcinoma that is refractory to radioactive iodine (RIR-DTC) [1,2]. Therapeutic options for patients with RIR-DTC are currently limited to the multi-kinase inhibitors including lenvatinib and
https://doi.org/10.1016/j.clon.2019.11.010 0936-6555/Ó 2019 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.
Please cite this article as: Reed N et al., Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer, Clinical Oncology, https://doi.org/10.1016/j.clon.2019.11.010
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sorafenib. These agents exert an anti-angiogenic effect, preventing the formation of new vasculature, a process that is required for tumour growth and progression. Lenvatinib inhibits signalling via the vascular endothelial growth factor receptors (VEGFR) 1e3 as well as the fibroblast growth factor receptors [1e4], the ret proto-oncogene and the plateletderived growth factor receptor-beta. Together, inhibition of these signalling pathways disrupts tumour angiogenesis, growth and metastatic processes [2]. The efficacy of lenvatinib for the treatment of RIR-DTC was shown in the phase III SELECT trial [3]. This study, which included 392 patients who were randomly assigned to lenvatinib 24 mg per day or placebo, confirmed that lenvatinib significantly prolongs progression-free survival (PFS) by 14.7 months compared with placebo in patients with RIR-DTC regardless of age [3e5]. Moreover, prolongation of overall survival was observed for older patients treated with lenvatinib despite the design of the study, which allowed for crossover from placebo to lenvatinib after disease progression [4]. However, as for other multikinase inhibitors used in this setting, lenvatinib is associated with a number of adverse events, which require prompt and appropriate management in order to ensure patients remain on and obtain maximum benefit from treatment [6e9]. This review provides appropriate strategies for the routine management of adverse events associated with lenvatinib for RIR-DTC. The recommendations are based on a review of the literature and the expert opinion of the authors following a meeting held in October 2017.
Materials and Methods Consensus Generation A consensus meeting was convened by Eisai on 24 October 2017 to review the current recommendations for the management of adverse events associated with the use of lenvatinib for the treatment of RIR-DTC. The expert panel identified the most relevant adverse events associated with the use of lenvatinib and reviewed current management recommendations or lack thereof. The expert panel discussed and agreed recommendations for the clinical management of such adverse events, principally within the context of the UK healthcare system, but with applicability to the wider European healthcare system. An informal roundtable voting system was used to ensure consensus between the expert panel members for the recommendations proposed for the management of each adverse event. Literature Review PubMedÒ was searched on 24 October 2017 using the MESH search terms ‘lenvatinib’ and ‘thyroid cancer’ to identify the evidence base supporting the use of lenvatinib for the treatment of RIR-DTC. Special emphasis was placed on the identification of papers reporting the adverse event profile associated with lenvatinib in this setting and
approaches to the management of such adverse events. All English language publication types were accepted. In total, 122 publications were identified and reviewed for relevance to the management of adverse events associated with lenvatinib. Of these, 12 publications provided relevant information and formed the evidence base for the development of management recommendations [2e13]. Lenvatinib for the Treatment of Radioactive IodineRefractory Differentiated Thyroid Carcinoma In the phase III SELECT trial, the most commonly reported adverse events (any grade) considered to be related to treatment were hypertension (reported in 68% of patients), diarrhoea (59% of patients), fatigue (59% of patients) and decreased appetite (50% of patients) [3]. The most common grade 3 adverse events in the SELECT trial were hypertension (42%), proteinuria (10%), decreased weight (9.6%), fatigue (9.2%) and diarrhoea (8%) [3]. Consistent with this, the most commonly reported grade 3 adverse events in a real-world study of 88 patients treated with lenvatinib in France were hypertension (67%), fatigue (61%), weight loss (59%), diarrhoea (45%) and anorexia (36%) [10]. In addition to these most common grade 3 events, skin toxicities (including palmar-plantar erythema [PPE] and rash) and cardiovascular adverse events were considered of clinical relevance to the care of patients receiving lenvatinib and are also considered. General Advice when Initiating Lenvatinib Treatment with lenvatinib should be initiated in clinics with experience in managing patients with advanced thyroid cancer on tyrosine kinase inhibitor therapy. Patients should have a named person to contact during the initial days of treatment. Before initiating treatment, the overall health of the patient should be evaluated, and comorbidities identified. Pre-existing hypertension should be well controlled, and a baseline blood pressure recorded. Patients should be educated on the kind of adverse events they may experience in the initial days or weeks of treatment and provided with an action plan to manage such events, and specific guidance on who to contact and when to contact them (see Supplementary Table S1 for an example leaflet and Supplementary Figure S1 for an example patient information poster for display in a clinic). With regards to treatment planning, palliative radiotherapy does not necessitate interruption of lenvatinib treatment, although if treatment fields are large and radiotherapy-induced toxicity overlaps with lenvatinib adverse events (e.g. diarrhoea), clinical discretion should be used. Treatment should be stopped 3 days before a surgical procedure, including dental work, and wound healing should be complete before treatment is reinitiated. Diarrhoea Diarrhoea has been reported as an adverse event associated with a number of multi-kinase inhibitors, including
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N. Reed et al. / Clinical Oncology xxx (xxxx) xxx
cabozantinib, vandetanib, sorafenib, regorafenib, axitinib and lenvatinib [8]. For patients receiving lenvatinib for RIRDTC, diarrhoea is most often seen in the initial months of treatment. In the SELECT trial, the median time to onset of diarrhoea was 12.1 weeks [6]. However, patients should be advised that diarrhoea can be a later-onset toxicity. A multivariate analysis of data from the SELECT trial found that the overall survival for patients with RIR-DTC was significantly positively associated with the presence of diarrhoea [6]. This association was not observed for PFS. Management The underlying pathogenesis of multi-kinase inhibitorassociated diarrhoea is not well understood [14] but may involve ischaemic colitis or inflammation of the upper gastrointestinal tract [15]. As such, interventions should focus on symptomatic management (Figure 1). Before starting lenvatinib, patients should be offered general dietary advice and education appropriate for minimising or managing diarrhoea, including advice on keeping a food diary to identify whether certain foods trigger diarrhoea. Mild (Common Terminology Criteria for Adverse events [CTCAE] grade 1 or 2) diarrhoea should be managed with loperamide (per manufacturer’s guidance) and oral hydration and electrolyte replacement as needed. Codeine phosphate may be considered if loperamide is ineffective or not tolerated. Patients could be provided with a prescription for loperamide and guidance for use, at the time of
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initiating lenvatinib therapy. A lenvatinib treatment interruption of 1 week should be considered if diarrhoea persists despite optimal supportive therapy. Lenvatinib should be reinitiated at the same dose once the diarrhoea has resolved to grade 1 or less. If diarrhoea continues or re-emerges within days of reinitiating lenvatinib, it should be managed with loperamide and lenvatinib treatment should be interrupted again and reinitiated once diarrhoea has returned to grade 1 but at a lower dose. The recommended dose reduction schema for lenvatinib is shown in Table 1. Using this approach, no patient should reach grade 3 diarrhoea. However, should this occur, treatment should be interrupted and lenvatinib reinitiated at a reduced dose. Active supportive measures should be provided as clinically indicated, including intravenous hydration and electrolyte replacement. Lenvatinib treatment should be stopped if the patient experiences grade >3 diarrhoea again. Hypertension The aetiology of multi-kinase inhibitor-associated hypertension is complex and involves several potential mechanisms [16]. VEGF plays a regulatory role in blood pressure homeostasis through the production of nitric oxide with nitric oxide-dependent dilation of small arterioles and venules, and turnover of the capillary and microvasculature network (capillary rarefraction). Anti-VEGF therapy reduces the density of such microvessels [17]. Vascular
Provide appropriate pa ent educa on about the risk for diarrhoea during treatment with lenva nib and ac ons to take if diarrhoea emerges Preven on/prepara on: • Consider providing a prescrip on for loperamide and an electrolyte solu on for pa ent use if diarrhoea emerges prior to the next clinic visit Resolves: No further ac on
CTCAE Grade 1 or 2: •
Loperamide 4 mg followed by 2 mg a er each episode of diarrhoea (up to 16 mg/day)
CTCAE Grade 3: • • •
Consider admission to hospital for IV fluids and electrolyte replacement Loperamide 4 mg followed by 2 mg a er each episode of diarrhoea (up to 16 mg/day) Lenva nib should be stopped and restarted at a dose reduc on when resolved
CTCAE Grade 4: Stop lenva
Con nues or recurs: Consider a 1 week treatment break and reini ate to the same lenva nib dose Recurs within days of reini a ng lenva nib: Treat with loperamide and 1 week treatment break. Reini ate to a lower lenva nib dose
Resolves: No further ac on
Con nues or recurs: Consider a 1 week treatment break and reini ate to a lower lenva nib dose
nib treatment
CTCAE, Common Terminology Criteria for Adverse Events NB: consider codeine phosphate if loperamide is ineffec ve or not tolerated
Fig 1. Management algorithm for the prevention and management of diarrhoea during treatment with lenvatinib. Please cite this article as: Reed N et al., Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer, Clinical Oncology, https://doi.org/10.1016/j.clon.2019.11.010
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N. Reed et al. / Clinical Oncology xxx (xxxx) xxx
Table 1 Dose modifications from the recommended lenvatinib daily dose [1] Dose level
Daily dose
Recommended daily dose
24 mg orally once daily (2 10 mg capsules plus 1 4 mg capsule) 20 mg orally once daily (2 10 mg capsules) 14 mg orally once daily (1 10 mg capsule plus 1 4 mg capsule) 10 mg orally once daily* (1 10 mg capsule)
First dose reduction Second dose reduction
Third dose reduction
* Further dose reductions may be considered on an individual patient basis.
endothelial dysfunction has been proposed as a mechanism for lenvatinib-associated hypertension [11]. In addition to peripheral vascular resistance, VEGF also regulates endothelial function within the renal glomeruli, and loss can result in reduced glomerular filtration, proteinuria, salt and water retention and hypertension. However, these observations cannot fully explain the aetiopathology of the hypertension reported during multi-kinase inhibitor therapy [12]. The management of multi-kinase inhibitor-associated hypertension can be challenging, with at least 50% of cases requiring two or more new antihypertensive drugs. The choice of antihypertensive medication depends on a number of factors, including the current understanding of the pathophysiology of multi-kinase inhibitor-associated hypertension, pre-existing cardiac diagnoses and cardiovascular risk factors, left ventricular function, renal function, proteinuria, concomitant complications and potential cardiovascular risks of these drugs. Early, acute hypertension has been reported within 24e48 h of initiating lenvatinib [5]. An analysis of data from the SELECT trial found that the emergence of hypertension during treatment with lenvatinib is associated with longer PFS [13]. Patients initiating lenvatinib should be made aware of the symptoms that might indicate the onset of acute hypertension, including severe headache, fatigue or confusion and blurred vision, and advised to contact their oncology team or general practitioner should they experience any of them. For patients with a history of hypertension, this should be well controlled with stable doses of antihypertensive therapy for at least 1 week prior to initiating lenvatinib. Monitoring Stage 1 hypertension is defined as clinic-measured blood pressure 140/90 mmHg and subsequent ambulatory blood pressure monitoring daytime average or home blood pressure monitoring average blood pressure 135/85 mmHg [18]. For patients initiating lenvatinib, blood pressure should be measured at baseline, before treatment. If elevated in the
hospital clinic, then a home blood pressure diary or a 24-h ambulatory blood pressure monitor should be offered. For patients with pre-existing hypertension, blood pressure should be monitored daily, particularly if their hypertension was uncontrolled prior to assessment. Otherwise blood pressure should be monitored from 1 week after the start of lenvatinib and subsequently weekly for the first 2 months. Home blood pressure monitoring with commercially available blood pressure monitors is an appropriate approach for the monitoring of blood pressure in the initial days of treatment. Alternatively, patients could be advised to attend their general practitioner clinic or local pharmacist for blood pressure monitoring, even in the absence of secondary symptoms indicative of emerging hypertension. An example alert letter that can be given to the patient for them to take to their general practitioner should they require community blood pressure monitoring is provided in Supplementary Table S2. According to the Summary of Product Characteristics, blood pressure should be monitored 1 week after the start of lenvatinib, then every 2 weeks for the first 2 months and monthly thereafter [1]. However, weekly monitoring for the first 2 months and every 2 weeks thereafter is regarded by the authors as acceptable for pragmatic reasons, for example, to align with scheduled clinic visits. If blood pressure is elevated on a home measurement (>135/85 mmHg), patients should start daily measurements, and if consistently elevated across 3 or more days then treatment is recommended. Patients should be educated on the correct technique for home blood pressure measurement as provided by the British Hypertension Society [19]. Management For patients presenting with systolic blood pressure 140 mmHg to <160 mmHg or diastolic blood pressure 90 mmHg to <100 mmHg in clinic, or systolic blood pressure 135 mmHg to <160 mmHg or diastolic blood pressure 85 mmHg to <100 mmHg on home diary measurements, lenvatinib therapy should be continued but antihypertensive therapy initiated or intensified (Table 2). For patients who remain hypertensive (systolic blood pressure 180 mmHg or diastolic blood pressure 110 mmHg) despite optimal antihypertensive therapy, a lenvatinib treatment break should be considered, with the aim of reinitiating lenvatinib at a reduced dose once the patient’s blood pressure has stabilised (systolic blood pressure 160 mmHg, diastolic blood pressure 95 mmHg) on antihypertensive therapy for at least 48 h. Reversible causes of hypertension and exacerbating factors should be reviewed. Cessation of non-steroidal antiinflammatory drugs, reduction of steroid doses and counselling regarding salt and fluid and excessive alcohol intake are important. Secondary causes including obstructive sleep apnoea, renovascular disease and hyperaldosteronism should also be considered. Stress may be contributory and challenging to manage e referral for clinical psychological review and stress management may be appropriate in selected cases.
Please cite this article as: Reed N et al., Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer, Clinical Oncology, https://doi.org/10.1016/j.clon.2019.11.010
N. Reed et al. / Clinical Oncology xxx (xxxx) xxx
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Table 2 Antihypertensive management for patients experiencing hypertension during treatment with lenvatinib Antihypertensive class
Drug
Dose
ACE inhibitor
Enalapril Ramipril Amlodipine Losartan Valsartan Irbesartan Hydrochlorthiazide Spironolactone Nebivolol Carvedilol Long-acting nitrates Isosorbide dinitrate Isosorbide mononitrate
Initial: 5 mg/day then 10 mg/day to a maximum of 40 mg/day Initial: 2.5 mg/day then 5 mg/day to a maximum of 10 mg/day 2.5e10 mg/day 50e100 mg/day 80e230 mg/day 150e300 mg/day 12.5e25 mg twice daily 12.5e100 mg/day 2.5e5 mg/day 3.125e25 mg twice daily 40e60 mg/day
CCB ARB
Diuretics BBA Nitrate derivatives
ACE, angiotensin converting enzyme; CCB, calcium channel blockers; ARB, angiotensin II receptor blocker; BBA, ß-adrenoceptor antagonist.
Initial antihypertensive treatment should be with an angiotensin converting enzyme (ACE) inhibitor (e.g. ramipril [initial dose 2.5 mg/day], enalapril [initial dose 5 mg/ day] or lisinopril [initial dose 5 mg/day]). These agents are also effective for the treatment of heart failure and proteinuria, both of which may be associated with multi-kinase inhibitor therapy, whereas other antihypertensive agents are not. Indeed, recent data in renal cancer suggest improved outcomes for patients with renal cancer treated with ACE inhibitors compared with those who received other antihypertensive agents [20,21]. Treatment should be escalated within 3 days if hypertension persists with increased doses of ACE inhibitor followed by the addition of a second agent. The choice will depend on fluid retention, cardiovascular risk factors, left ventricular function, coronary disease, arrhythmias and renal dysfunction or proteinuria. Options include thiazide diuretics, spironolactone, nebivolol, carvedilol or amlodipine, with referral to a cardiologist if hypertension remains uncontrolled. Once a patient is stable with regards to their hypertension, routine monitoring and management can be referred back to their general practitioner. Patients with multi-kinase inhibitor-associated hypertension should be reviewed clinically for symptoms or signs of left ventricular dysfunction and heart failure. Left ventricular systolic dysfunction (LVSD) is present in 5e10% of patients taking VEGF-based multi-kinase inhibitors. This may be due to hypertensive heart failure, but LVSD can occur without hypertension. All hypertensive patients should have their serum natriuretic peptide (brain natriuretic peptide or N-terminal-pro-brain natriuretic peptide) levels checked and, if elevated, or if the patient is symptomatic, then an echocardiogram is appropriate to assess for evidence of left ventricular dysfunction. This is also important to guide antihypertensive medication choices, as amlodipine is generally avoided in patients with left ventricular ejection fraction <50%. For patients with both proteinuria and hypertension, antihypertensive therapy should be initiated as described and the patient should be re-evaluated for proteinuria once
the hypertension is well controlled. Should proteinuria persist in the case of well-controlled hypertension, a lenvatinib dose reduction may be considered. Care should be taken to identify and avoid hypotension when interrupting lenvatinib treatment for patients receiving multiple antihypertensive agents. For such patients, antihypertensives should be withdrawn gradually in reverse order and blood pressure monitored every 2e3 days. Weight Loss and Decreased Appetite In the phase III SELECT trial, grade 3 weight loss was reported among 9.6% of patients treated with lenvatinib [3]. Moreover, cancer-associated cachexia (marked weight loss that cannot be reversed by normal nutritional support) is estimated to affect up to 80% of patients with cancer and may be the cause of death in 20% [22]. Consequently, patients and physicians should be alert for weight loss and decreased appetite so that appropriate interventions and supportive strategies can be introduced prior to the patient progressing to a cachectic state [23]. Before starting treatment, patients should be educated about the importance of maintaining a healthy diet and body weight. Such education could include advice about the impact of excessive weight loss on other potential adverse events such as fatigue. Patients should be encouraged to maintain a healthy, active lifestyle and should aim to maintain their fitness levels during lenvatinib treatment. Management Weight loss of 10% of baseline body weight or the onset of anorexia should be managed with a short treatment break (about 1 week), after which lenvatinib should be reinitiated at the same dose. If weight loss or anorexia recur, a further treatment break should be considered until appetite improves and weight loss stops with reinitiation of lenvatinib at a lower dose. Referral to a dietitian or specialist nurse for dietary advice and support may be beneficial where available and patients should be encouraged to eat little and often. High-calorie foods (milk shakes, ice cream,
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frozen yoghurts) recommended.
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and
nutrition
bars
can
also
be
effect of drugs targeting the VEGF system [28,29]. In the SELECT trial, 10% of patients experienced grade 3 proteinuria and the median time to onset was 6.1 weeks [3,6].
Fatigue Fatigue is common among patients with cancer and can have multiple causes, including emotional distress and sleep disturbance, disease-related morbidities such as weight loss, and anaemia, and may also be a treatmentrelated effect [24]. In the SELECT trial, the median time to the first onset of fatigue was 3 weeks [6], with 9.2% of patients reporting grade 3 fatigue [3]. Management As an initial step, any potential link to a rise in thyroidstimulating hormone, weight loss/anorexia or disease progression should be considered. Patients should be encouraged to maintain a healthy, active lifestyle and should aim to maintain their fitness levels during lenvatinib treatment. Aerobic and non-aerobic exercise have been shown to reduce cancer-related fatigue and patients should be encouraged to undertake exercise that suits their lifestyle and personal preference [25,26]. Skin Toxicities Skin toxicities, including PPE and rash, although considerably less common in the SELECT trial than other events such as diarrhoea, have the potential to significantly impact the patient’s quality of life [27]. Rash of any grade was reported by 16.1% of patients treated with lenvatinib in the SELECT trial, with 0.4% of patients reporting CTCAE grade 3 rash. PPE syndrome (PPES) was reported by 31.8% of patients, with grade 3 PPES reported by 3.4%. The median time to the first onset of rash was 7.3 weeks and of PPES, 5.9 weeks [6]. Management Patients should be provided with general skin care advice, including the use of moisturisers or emollients and soap substitutes such as Dermol 500 (Supplementary Table S3). For more severe skin toxicities, topical steroids such as 1% hydrocortisone are recommended, although consideration should be given to potential side-effects of these treatments (Table 3). Oral antibiotics such as doxycycline or minocycline may also be considered. Steroid creams containing an antimicrobial can be used for scrotal rash. Ureabased creams are useful for patients with hyperkeratosis and creams containing antipruritic agents may be helpful for patients experiencing itch. Referral for podiatry evaluation should be considered for patients with existing calluses. Proteinuria The incidence of proteinuria of any grade during VEGFRetyrosine kinase inhibitor therapy has been reported to be 18.7%, with 2.4% of patients reporting grade 3 proteinuria (>3.5 g/24 h) and is thought to represent a class
Monitoring and Management Dipstick testing is an appropriate strategy for routine monitoring of patients for proteinuria. Initially, patients should be assessed every 14 days then, if proteinuria is not evident, monitoring can be reduced to every 28 days. A protein/creatinine ratio (PCR) should be measured in all patients with grade 2 þ proteinuria. A PCR can be measured on an early morning specimen of urine collected in a universal container and is a very reliable measure of urine protein loss. Although a 24-h urine collection is considered the ‘gold standard’ method of assessing the degree of proteinuria, it is inconvenient for patients and may be misleading if the collection is incomplete. If a PCR is not available, an albumin/creatinine ratio (ACR) is an acceptable alternative. A PCR >300 mg/mmol (ACR >250 mg/mmol) is broadly consistent with grade 3 proteinuria. A PCR of 100e300 mg/mmol (ACR 70e250 mg/mmol) is consistent with grade 2 proteinuria (1.0e3.5 g/24 h). Proteinuria is often very sensitive to high blood pressure and aggressive blood pressure reduction can reduce proteinuria. Angiotensin receptor blockers (e.g. candesartan or losartan) or ACE inhibitors are particularly effective at treating proteinuria. For patients with grade 2 proteinuria, lenvatinib may be continued, but an angiotensin II receptor blocker (ARB) or an ACE inhibitor should be started (if the patient is not already on this therapy). The blood pressure target should be < 135/85 mmHg and if necessary additional antihypertensive agents should be started, as per the above guidelines on hypertension. For patients with grade 3 proteinuria, lenvatinib treatment should be interrupted until proteinuria returns to grade 1þ (PCR <100 mg/mmol or ACR <70 mg/mmol). An ARB or an ACE inhibitor should be started (if not already). Blood pressure may need to be lowered below 120/70 mmHg to maintain an acceptable level of proteinuria. For patients with chronic, resistant grade 3 proteinuria, lenvatinib treatment should be stopped. Referral to a nephrologist should be considered. Cardiovascular Effects Patients should be monitored for clinical symptoms or signs of cardiac decompensation [1]. Patients considered to be at risk for cardiovascular events are those with a preexisting history of coronary artery disease (myocardial infarction, angina), heart failure, hypertensive heart disease with left ventricular hypertrophy, atrial fibrillation and rarer diseases, including inherited cardiomyopathies and congenital long QT syndrome. Patients should be advised to avoid where possible other medication known to prolong the QT interval (including class Ia and III anti-arrhythmics). These higher risk patients should undergo echocardiography and cardiac troponin and natriuretic peptide measurement at baseline and should be monitored via echocardiograms at each treatment with lenvatinib. This
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Table 3 Management of skin toxicities during treatment with lenvatinib (with kind permission from the Beatson West of Scotland Cancer Centre, Glasgow, UK) Common terminology criteria for adverse events grade
Definition
Action
1
Minimal skin changes or dermatitis without pain Skin changes (e.g. peeling, blisters, bleeding, oedema or hyperkeratosis) with pain, limiting function but not selfcare
General skin care advice Continue lenvatinib therapy at full dose General skin care advice Commence prescribed application of 10% urea-based creams and topical steroids if indicated Consider oral antibiotics such as doxycycline or minocycline Consider withholding treatment until resolved to grade 1. If first episode, recommence at lenvatinib original dose. If grade 2 toxicity recurs, consider dose reduction General skin care advice Commence prescribed application of 10% urea-based creams and topical steroids if indicated Withhold treatment until resolved to grade 1. Recommence at lower lenvatinib dose
2
3
Severe skin changes (e.g. peeling, blisters, bleeding, oedema or hyperkeratosis) with pain and limiting activities of daily living including self-care
Table 4 Recommended baseline assessments and monitoring during lenvatinib therapy Timing
Assessment
Baseline (pretreatment)
Weeks 1e8
Advice
Offer advice on: The risk for diarrhoea during treatment and actions to take if diarrhoea emerges The importance of maintaining a healthy diet and body weight Fatigue and the importance of maintaining a healthy lifestyle General skin care and initial management of skin toxicities Daily home blood pressure monitoring for patients with pre-existing hypertension* Weekly home blood pressure monitoring for patients without pre-existing hypertension for the first 8 weeks of treatment* Regular dipstick test for proteinuria (every 14 days initially, then monthly if no evidence of proteinuria seen) Blood pressure Weight Dipstick test for proteinuria Electrocardiograph, troponin and natriurietic peptide for patients with pre-existing cardiac issues Consider cardiology review and echocardiography for patients with pre-existing heart failure
* Patients should be advised to attend their general practitioner clinic or local pharmacist for blood pressure monitoring if home blood pressure monitoring is not appropriate.
should be continued for as long as the patient is receiving lenvatinib. If pre-existing heart failure or LVSD exists at baseline then a specialist cardiology review is recommended, with discussion regarding the alternative cancer treatment options and risk:benefit balance. It is reasonable to start lenvatinib in patients with pre-existing heart failure provided they are clinically stable and close monitoring is advised, e.g. clinical review, echocardiogram and cardiac biomarkers 2e4 weeks after starting and then every 3 months in high risk patients. This surveillance strategy in patients at highest risk is now provided by specialist cardio-oncology services, which are increasingly available in tertiary hospitals in the UK [30].
Summary Lenvatinib has been shown to significantly prolong PFS for patients with RIR-DTC [3]. Patients should be educated about the benefits of lenvatinib therapy and also what adverse effects they can expect during the initial weeks of treatment. An example patient information sheet is provided in Supplementary Table S1 to support initial discussions and for patients to refer to at home. Careful management of emergent adverse events for patients initiated on lenvatinib is essential to enable patients to remain on the optimal dose regimen with minimal impact on their quality of life. A summary of recommended baseline assessments and recommended monitoring in the first
Please cite this article as: Reed N et al., Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer, Clinical Oncology, https://doi.org/10.1016/j.clon.2019.11.010
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N. Reed et al. / Clinical Oncology xxx (xxxx) xxx
4 weeks of lenvatinib therapy is provided in Table 4. Prophylaxis, regular monitoring and symptomatic management with appropriate short treatment breaks and, for persistent adverse events, dose reductions, are recommended for the routine management of patients receiving lenvatinib.
Conflicts of Interest N. Reed and H. Glenn have participated in advisory boards and have received speaker fees from Eisai; G. Gerrard has received honoraria from Eisai and Genzyme; J. Good, M. Lei and M. Strachan have received honoraria from Eisai; A.R. Lyon has received research contracts from Pfizer and Servier, has acted as a consultant for Eisai, Pfizer, Servier, Novartis, BMS and Clinigen, and has participated in advisory boards and received speaker fees from Pfizer, Servier, Novartis, Clinigen, Takenda, Janssen-Cilag, Eli-Lilly, Ferring and Boehringher-Inglehaim; J. Wadsley has received research funding from AstraZeneca, Sanofi-Genzyme and honoraria from Eisai, AstraZeneca, Sanofi-Genzyme, Ipsen, Novartis, Bayer, Baxalta, Lilly and Celgene; K. Newbold has held consultancy roles and has been a member of speaker bureaus for Eisai and Sanofi-Genzyme.
Acknowledgements This work was supported by an unrestricted educational grant from Eisai Ltd, which included honoraria paid to each participant to support their attendance at the consensus meeting and the editorial support provided by Dr Tracey Lonergan (Nyxeon, Healthcare Communications Consultancy). Eisai Ltd did not contribute to or influence the conceptual development of the manuscript and all decisions regarding content were the responsibility of the authors.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.clon.2019.11.010.
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Please cite this article as: Reed N et al., Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer, Clinical Oncology, https://doi.org/10.1016/j.clon.2019.11.010