Muratori, L.

Scagliotti, G. V.

Sperone, P.

English

Institutional Research Information System University of Turin

SupplementLong-term disease control and high clinicalbenefit in a patient with advanced thyroidcancer treated with lenvatinibLeonardo Muratori*,1, Paola Sperone1 & Giorgio Vittorio Scagliotti11Medical Oncology, Department of Oncology, University of Turin, Azienda Ospedaliera Universitaria San Luigi Gonzaga, RegioneGonzole 10, Orbassano 10043, Turin, Italy*Author for correspondence: Tel.: +39 393 7010166; muratorileonardo@gmail.comWe report a case of a 37-year-old man with metastatic differentiated thyroid carcinoma, previously sub-mitted to total thyroidectomy, radio-iodine therapy and lung metastasectomy, who underwent systemictreatment with lenvatinib for tumor recurrence in the lung, mediastinal lymph nodes, left gluteus andleft orbit. Lenvatinib induced rapid and durable disease regression; the drug effect has continued after>1 year, as well as a very considerable clinical benefit. The results achieved by lenvatinib in treatmentof metastatic differentiated thyroid carcinoma are clear and irrefutable. Real-life data, obtained by casereports and retrospective studies, are equally important to increase the knowledge about this drug andimprove the clinical management.First draft submitted: 19 February 2019; Accepted for publication: 18 July 2019; Published online:6 August 2019Keywords: case report • lenvatinib • thyroid cancerDifferentiated thyroid carcinoma (DTC) is the most common malignant tumor of the thyroid gland. Althoughthe incidence of this cancer has been increasing over the last few decades, mortality is constantly decreasing, owingmainly to improvements in early diagnosis and local treatment [1]. In fact, low-stage disease, which is amenableto surgical resection, has excellent prognosis [2]. Post-surgical radioiodine (131I) therapy is not generally indicatedin T1 and T2 stages even though it could be considered in case of presence of other risk factors (more aggressivehistological types, positive lymph nodes, history of exposure to radiation) [3]. 131I therapy is generally recommendedfor adjuvant treatment for T3 and T4 patients, with the aim of reducing the risk of disease relapse [4]. Distantmetastatic spread occurs in aminority of cases (approximately 10%), with lung and bones being themost commonlyinvolved sites. Thyroid cancer that relapses during or after adjuvant 131I therapy carries a poor prognosis becauseof refractoriness to conventional anticancer treatments. Historically, surgical resection of metastases and externalbeam radiotherapy, when feasible, has represented suitable treatment options. Increased knowledge in the molecularbiology of thyroid cancer has clarified the complex signaling networks that sustain this cancer phenotype. Theseinvolve angiogenesis, BRAF, NRAS, HRAS, RET/DTC, FGFR and PDGFR signaling. As a consequence, a strongrationale supported the clinical evaluation of multitargeted tyrosine kinase inhibitors (TKIs). One of these agents,sorafenib, was investigated in a randomized Phase III trial that included 417 patients, where it resulted superiorto placebo in terms of progression-free survival (PFS; 10.8 vs 5.4 months) [5]. More recently, lenvatinib, an oralmultitargeted TKI that inhibits VEGFR1–3, PDGFR-α, FGFR1–4, RET and KIT – all targets implicated insignaling networks that promote angiogenesis [6] – was approved on the basis of a Phase III trial enrolling 360patients with iodine-refractory thyroid cancer, who were randomized to lenvatinib 24 mg/day or placebo. PFS wassignificantly higher in lenvatinib group (median PFS: 18.2 vs 3.6 months, hazard ratio: 0.21; 99% CI: 0.14–0.31;p < 0.001), although no advantage in overall survival was observed [7]. Based on these results, lenvatinib wasapproved for the treatment of patients with radioiodine-refractory metastatic DTC (MDTC). Here, we reportthe case of a young patient with MDTC treated with lenvatinib after total thyroidectomy, 131I therapy and lungmetastasectomy. The patient achieved a long-term response on all sites of metastasis and a very important clinicalFuture Oncol. (2019) 15(24s), 3–6 ISSN 1479-6694 310.2217/fon-2019-0092 C© 2019 Leonardo MuratoriFor reprint orders, please contact: reprints@futuremedicine.comSupplement Muratori, Sperone & Scagliottibenefit with complete resolution of all symptoms. The collection of clinical cases concerning this uncommonneoplasm could help the clinicians in the management of daily practice.Presentation of caseA 37-year-old man underwent total thyroidectomy in October 2013 because of the incidental finding of a thyroidlesion. Histological examination showed a papillary carcinoma, staged T3Nx, according to the seventh edition ofTumor, Node, Metastasis staging. No distant metastases were detected by total body CT scan. Because of the highstage, the patients received an adjuvant therapy with 131I (0.7 μg/kg/day in 3 days). The post-131I CT-scan showedno residual disease and the follow-up was unremarkable until September 2015 when a routine blood test revealed anincrease in the levels of high-sensitivity human thyroglobulin. The 18-fluorodeoxyglucose (18-FDG) PET CT scanshowed significant radiotracer uptake in the right lung. In November 2015, the patient underwent resection of thelung lesions, with histopathological examination confirming metastatic thyroid cancer, with oxyphil cells and lowdifferentiated features. Based on no other clear evidence of distant metastases after surgical resection, the patientresumed regular clinical follow-up. In May 2016, multiple bilateral lung lesions were detected by a routine totalbody CT scan. Considering the small size of the new nodules and the absence of symptoms, the treating physicianopted for a wait-and-see approach. Repeat CT scans revealed no signs of progression until March 2017, when,in spite of stable numerical and dimensional disease in the lung, a new 16-mm nodule was detected in the rightkidney. Concomitantly, the patient presented with pain in left gluteus muscle, diplopia and vision impairment ofthe left eye. A CT scan of the head showed thickening of medial rectus muscle, with deviation and compression ofhomolateral optical nerve. An 18-FDG PET-CT scan revealed pathological uptake in left orbit, in the mediastinallymph nodes and in the left gluteus, confirming the clinical suspicion of disease progression. A multidisciplinaryevaluation was performed, and it was decided to treat the patient with radiotherapy to the right retrobulbar space.This consisted of 44 Gy administered in 22 fractions, from June to July 2017, with a partial benefit on visualsymptoms. In August 2017, systemic therapy with lenvatinib was started. The patient received the recommendeddose of 24 mg daily and underwent clinical and laboratory evaluation initially every 2 weeks for 2 months, andsubsequently every month. Arterial blood pressure, physical examination, serum chemistry and hematology wereevaluated at each visit. Serum thyroid hormone concentration, ECG and echocardiogram were repeated every 3months. The first CT scan performed in October 2017, showed partial response of disease in all sites of metastases.However, the full dose of lenvatinib was not well tolerated, in particular, in terms of recurrent grade 3 hypertension,according to the common terminology criteria for adverse events version 4.03. According to the insert package,the drug was reduced to 20 mg daily with no subsequent recurrence of clinically relevant hypertension. Cardiacand thyroid functions remained within in the normal range. Patient symptoms, including visual disturbances thathad remained after radiotherapy, resolved completely within the first 6 months of treatment with lenvatinib. The3-monthly follow-up CT scans showed no signs of disease progression. The following CT scans, performed every3 months, showed no signs of disease progression, and even a progressive reduction of all sites of metastases. Thelast CT scan, performed in early May 2019, confirmed this trend, showing an additional response of all sites ofmetastases. At more than 22 months from the start of systemic therapy, the patient is asymptomatic and with nomajor treatment-related side effects.Discussion & conclusionMultitargeted TKIs represent a relevant therapeutic option for patients with iodine-resistant metastatic DTC, acondition that had very limited therapeutic options before the advent of these drugs [5–7]. By targeting multiplepathways that underlie this cancer phenotype, lenvatinib has confirmed a remarkable effect on PFS, comparedwith placebo, in a large randomized clinical trial [7]. Off-target activity, which represents the downside of thesedrugs, has resulted in a spectrum of side effects that should account for when deciding when and how to use thisdrug in the clinical practice. Indeed, based on the results of the pivotal trial, about six out of ten patients areexpected to show disease response and median duration of response is 30 months, which translates in very longdrug exposure in the majority of treated patients [8]. The case that we discuss here is interesting for a number ofpractical reasons. First, the drug induced rapid disease regression, as revealed by improvement in related diseasesymptoms (gluteal pain) and radiological evidence. One of the first aims of the treatment of metastatic disease issymptom palliation and, in this case, further improvement occurred in the initial months of treatment, leading tocomplete and long-lasting resolution of patient initial complaints. Second, the patient has been on treatment formore than 1 year now and, except for the initial 2 months, he now undergoes monthly visits to check tolerance4 Future Oncol. (2019) 15(24s) future science groupLong-term disease control with lenvatinib Supplementand toxicity. Indeed, management of toxicities is an important issue, treatment is to be continued until diseaseprogression and the quality of life is an essential end point to consider. Multitargeted TKIs are generally associatedwith several adverse effects, including hypertension, oral mucositis, fatigue, increased risk of thromboembolism,hepatotoxicity, skin changes, nausea, diarrhea, anorexia and thyroid function alteration [9]. For this reason, anadequate follow-up of these patients in order to introduce the opportune countermeasures when necessary isfundamental. These potential side effects may negatively impact the quality of life, resulting frequently in dosereduction or treatment discontinuation. In the case, we described here, only a dose reduction from 24 to 20 mg/daywas necessary when grade 3 hypertension occurred, with no further recurrence of this side effect. The clinical benefitwas particularly interesting, especially concerning the ocular symptoms. The patient developed a metastasis in theorbital cavity, which affected his sight, producing diplopia and reduction of visual acuity. As described above, thislesion was treated with radiotherapy according to standard of care. Residual sight impairment resolved completelyduring systemic therapy with lenvatinib. Concomitantly, pain reported at the start of lenvatinib therapy and thatrequired analgesic disappeared after approximately 1 month of treatment, with consequent withdrawal of painmedications. One final point emerges from this clinical case, which – due to the efficacy of lenvatinib – shouldnot be considered ‘anecdotal’ but yet a frequent occurrence. Our patient underwent surgical treatment of the firstmetastatic occurrence and local therapy to a critical orbital lesion. These two options, although not devoid ofpotential complications, have always been considered the standard of care in the absence of active systemic drugs.Nowadays, with the availability of drugs yielding high response rate and long-lasting disease control, the questionis – what is the role of local therapy in the management of metastatic DTC? In our opinion, it could be reasonableto treat this disease upfront with lenvatinib or with similar drugs that will show comparable or increased efficacy inthe future, reserving surgery or radiation therapy either for resistant disease or for particular situations (medullarycompression and oligometastatic progression). However, it should be noted that even this approach, although itcould be reducing the local treatment related comorbidities, is not without limitations. For example, the upfrontstrategy requires a lifelong therapy, which could be impaired the patients’ quality of life. Furthermore, in caseof TKI-refractory disease, the upfront approach would leave very few treatment options. Then, even though thesystemic therapy in DTC is generally effective and well tolerated, the treatment strategy should be planned by amultidisciplinary team, on a case-by-case basis.In conclusion, the results achieved by lenvatinib in treatment of MDTC are clear and irrefutable. Real-life data,obtained by case reports and retrospective studies, are equally important to increase the knowledge about this drugand improve the clinical management. The optimal approach to thyroid cancer remains multidisciplinary, involvingsurgeons, radiation therapists, endocrinologists and oncologists, but due to the availability active systemic drugs,such as lenvatinib, current treatment paths should be redesigned.Summary points• Differentiated thyroid carcinoma (DTC) is the most common thyroid cancer.• Metastatic disease is rare, but not occasional.• Metastatic disease has few treatment options.• Lenvatinib showed great efficacy in metastatic DTC.• A 37-year-old man with DTC was described.• Lenvatinib therapy was performed.• The patient was responding to lenvatinib for 22 months.• The patient noticed a very important quality of life improvement.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or finan-cial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria,stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Editorial assistance was provided by A Shah and L Giacomelli, PhD (Polistudium srl, Milan, Italy), on behalf of Content Ed Net.This assistance was supported by Eisai.future science group www.futuremedicine.com 5Supplement Muratori, Sperone & ScagliottiInformed consentPatient gave written informed consent to describe his case.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license,visit http://creativecommons.org/licenses/by-nc-nd/4.0/ReferencesPapers of special note have been highlighted as: • of interest; •• of considerable interest1. La Vecchia C, Malvezzi M, Bosetti C et al. Thyroid cancer mortality and incidence: a global overview. Int. J. Cancer 136(9), 2187–2195(2015).2. Miccoli P, Sohail B. Surgical management of papillary thyroid carcinoma: an overview. Updates Surg. 69(2), 145–150 (2017).3. Lamartina L, Durante C, Filetti S et al. Low-risk differentiated thyroid cancer and radioiodine remnant ablation: a systematic review ofthe literature. J. Clin. Endocrinol. Metab. 100(5), 1748–1761 (2015).4. Verburg FA, Ma¨der U, Reiners C et al. Long-term survival in differentiated thyroid cancer is worse after low-activity initial post-surgical131I therapy in both high-and low-risk patients. J. Clin. Endocrinol. Metab. 99(12), 4487–4496 (2014).5. Brose MS, Nutting CM, Jarzab B et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroidcancer: a randomized, double-blind, Phase III trial. Lancet 384(9940), 319–328 (2014).6. Yamamoto Y, Matsui J, Matsushima T et al. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumoractivity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc. Cell. 6, 18 (2014).7. Schlumberger M, Tahara M, Wirth LJ et al. Lenvatinib versus placebo in radioiodinerefractory thyroid cancer. N. Engl. J. Med. 372(7),621–630 (2015).• This is the article that every clinician should know, in which the activity of lenvatinib in DTC was demonstrated in a Phase IIIrandomized trial, challenging the clinical practice.8. Cabanillas ME, Schlumberger M, Jarzab B et al. A Phase II trial of lenvatinib (E7080) in advanced progressive, radio-iodine refractory,differentiated thyroid cancer: a clinical outcome and biomarker assessment. Cancer 121(16), 2749–2756 (2015).9. Klastersky JA. Adverse events of targeted therapies. Curr. Opin. Oncol. 26(4), 395–402 (2014).•• This is an interesting article that made the point about the most common target therapies related toxicities and theirmanagement in clinical practice.6 Future Oncol. (2019) 15(24s) future science group

Long-term disease control and high clinical benefit in a patient with advanced thyroid cancer treated with lenvatinib

https://iris.unito.it/bitstream/2318/1711951/1/fon-2019-0092.pdf

Long-term disease control and high clinical benefit in a patient with advanced thyroid cancer treated with lenvatinib

Abstract

Similar works

Full text

Available Versions

Institutional Research Information System University of Turin