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Myositis - A common but underreported adverse effect of osimertinib: Case series and review of the literature.
Parafianowicz, P, Krishan, R, Beutler, BD, Islam, RX, Singh, T
Cancer treatment and research communications. 2020;:100254
Abstract
BACKGROUND Lung cancer is the second most common cancer in both men and women and the leading cause of cancer death worldwide. The development of novel tyrosine kinase inhibitors (TKIs) represented a paradigm shift in the management of lung cancer and has resulted in markedly prolonged survival. Osimertinib is a TKI that was fast-tracked by the United States Food and Drug Administration in 2015 and subsequently approved for the treatment of metastatic epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer. However, despite the generally favorable outcomes associated with osimertinib, rapid development and deployment of any new drug increases the risk of unforeseen adverse effects. Post-marketing surveillance studies therefore play an important role in further elucidating the risks and benefits of novel anti-neoplastic agents. MATERIAL AND METHODS We describe four patients with non-small cell lung cancer who developed myositis after beginning treatment with osimertinib. In addition, we review the literature on osimertinib-associated myositis. Using PubMed, the following terms were searched and relevant citations assessed: creatine phosphokinase, myositis, osimertinib, rhabdomyolysis, osimertinib, and Tagrisso. CASE PRESENTATION Thirty-eight patients were treated with osimertinib in our community clinic. Four with non-small cell lung cancer developed myositis after beginning treatment. The onset of symptoms and/or elevation of creatine phosphokinase occurred between two weeks and eleven months after osimertinib was initiated. Alternative causes for myositis were not identified. In two patients, myositis resolved within one month of withdrawing treatment. Two other patients continued osimertinib treatment with close monitoring. CONCLUSION Myositis is a serious and potentially underreported adverse effect of osimertinib. Previous studies suggest that osimertinib-associated myositis is rare, occurring in less than 1% of patients. However, myositis occurred in over 10% of patients treated with osimertinib in our clinic population. We suggest regular monitoring for myositis among patients being treated with osimertinib and dose-reduction or cessation of treatment if clinically indicated.
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Lenvatinib complementary with radioiodine therapy for patients with advanced differentiated thyroid carcinoma: case reports and literature review.
Sheu, NW, Jiang, HJ, Wu, CW, Chiang, FY, Chiou, HC, Hsiao, PJ
World journal of surgical oncology. 2019;(1):84
Abstract
BACKGROUND The prognosis for patients with advanced differentiated thyroid carcinoma (ADTC) with disseminated distant metastases is very poor. Tyrosine kinase inhibitors targeting tumor angiogenesis have been shown to improve progression-free survival in patients with advanced thyroid carcinoma and progressive radioiodine-refractory thyroid carcinoma. Tyrosine kinase inhibitor has been reported as a successful neoadjuvant for total thyroidectomy to reduce tumor burden. However, the special indications for prompt treatment with lenvatinib as a rescue therapy to reduce tumor burden and prolong a durable response to radioiodine therapy have not been explored. CASE PRESENTATION Here, we present two ADTC cases with distant metastases who were effectively treated by total thyroidectomy combined with lenvatinib to prolong a durable response to radioiodine therapy. Case 1 was a 66-year-old male diagnosed with ADTC and disseminated brain, lung, and bone metastases. Lenvatinib was initiated via compassionate access because of rapidly progressive tumor growth even after second doses of radioiodine therapy and external beam radiation therapy for his brain metastases. The result was a durable response to lenvatinib, slowing progressive tumor growth for 3 years and allowing a third course of radioiodine therapy to treat the bone metastases. Case 2 was a 45-year-old male diagnosed with ADTC and diffuse disseminated lung metastases. Respiratory failure ensued after total thyroidectomy, requiring mandatory support by respirator. Lenvatinib was started as a rescue therapy to reduce tumor burden rapidly. The patient was successfully weaned off the respirator only 1 week after using lenvatinib. The patient was then maintained on a low dose of lenvatinib, allowing three subsequent courses of radioiodine therapy. Currently, his lung metastasis remains well controlled with decreased lung infiltrating nodules and the patient can tolerate exercise well. CONCLUSION Our case experience indicated that lenvatinib has significant value as salvage therapy, reducing tumor burden, producing a durable response and maintaining quality of life. For ADTC patients with progressive life-threatening metastases, our experience suggests that lenvatinib treatment can be used as an urgent rescue therapy as well as a complement to radioiodine therapy to improve tumor eradication.
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Complete response of advanced hepatocellular carcinoma to sorafenib: another case and a comprehensive review.
Kim, TS, Kim, JH, Kim, BH, Lee, YS, Yoo, YJ, Kang, SH, Suh, SJ, Jung, YK, Seo, YS, Yim, HJ, et al
Clinical and molecular hepatology. 2017;(4):340-346
Abstract
Since sorafenib was introduced in 2007 for treating advanced hepatocellular carcinoma (HCC), 15 patients have achieved a complete response (CR) in advanced HCC. However, only four of these reports can be regarded as real CRs involving adequate assessments including imaging, serum tumor markers, and histologic examinations of completely resected specimens. A 54-year-old man with hepatitis C virus (HCV)-related liver cirrhosis (LC) presented to our unit. A CT scan demonstrated a 3.8-cm arterial hypervascular/portal-washout mass in the right lobe and invasion in the right portal vein. Twelve weeks after beginning sorafenib therapy, the AFP level was normalized and a CT scan showed a prominent decrease in the hepatic mass and a significant decrease in the volume of portal vein thrombosis (PVT). The patient received a right liver hemihepatectomy after 12 months. No viable tumor cells were found in the resected specimen, and there was no thrombotic obstruction of the portal vein. Twelve months later the patient showed no clinical evidence of HCC recurrence. This is the first case of CR in HCC treatment following sorafenib with histologically confirmed HCV-related HCC without LC evidence, HCC with PVT, and a follow-up of longer than 12 months. This case seems to be an extremely unusual clinical outcome in advanced HCC.
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Complete and Sustained Off-Therapy Response to Sorafenib in Advanced Hepatocellular Carcinoma.
Maida, M, Macaluso, FS, Valenza, F, Virdone, R
Journal of gastrointestinal and liver diseases : JGLD. 2016;(2):253-5
Abstract
UNLABELLED A 75-year-old Caucasian woman with alcohol-related cirrhosis was admitted to our Unit in October 2012 for the diagnostic evaluation of a focal liver lesion detected by regular surveillance ultrasound. The subsequent dynamic CT and MR led to a diagnosis of infiltrative hepatocellular carcinoma (HCC) of 5 cm in the hepatic segment IV with neoplastic infiltration of the left branch of the portal vein, in absence of extrahepatic metastases. Therapy with sorafenib 400 mg bid was started and the subsequent dynamic CT performed at the 10th month of therapy showed a complete response according to RECIST criteria and mRECIST, while seriated dosages of α-fetoprotein levels showed a progressive reduction up to normalization. After 18 months of therapy, Sorafenib was discontinued due to a grade 3 adverse event. Nonetheless, all subsequent radiological controls, performed over the following two years confirmed a complete off-therapy response despite withdrawal of Sorafenib. After three years the patient is asymptomatic, with a preserved liver function and undetectable solid tumor lesions at dynamic CT. This case represents one of the few examples of complete response to anti-angiogenic drugs and, to our knowledge, the only case of sustained response, even after the discontinuation of Sorafenib, described so far in the literature. KEY WORDS hepatocellular carcinoma - HCC - BCLC - sorafenib - complete response. ABBREVIATIONS AFP: alpha-fetoprotein; AE: adverse event; BCLC Barcelona Clinic Liver Cancer; CT: computed tomography; HCC: hepatocellular carcinoma; mRECIST modified response evaluation criteria in solid tumors; PS: Performance status; RCTs: randomized controlled trials.
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Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F.
Shaw, AT, Friboulet, L, Leshchiner, I, Gainor, JF, Bergqvist, S, Brooun, A, Burke, BJ, Deng, YL, Liu, W, Dardaei, L, et al
The New England journal of medicine. 2016;(1):54-61
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Abstract
In a patient who had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer, resistance to crizotinib developed because of a mutation in the ALK kinase domain. This mutation is predicted to result in a substitution of cysteine by tyrosine at amino acid residue 1156 (C1156Y). Her tumor did not respond to a second-generation ALK inhibitor, but it did respond to lorlatinib (PF-06463922), a third-generation inhibitor. When her tumor relapsed, sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation. The L1198F substitution confers resistance to lorlatinib through steric interference with drug binding. However, L1198F paradoxically enhances binding to crizotinib, negating the effect of C1156Y and resensitizing resistant cancers to crizotinib. The patient received crizotinib again, and her cancer-related symptoms and liver failure resolved. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT01970865.).
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Identification of a novel HER3 activating mutation homologous to EGFR-L858R in lung cancer.
Umelo, I, Noeparast, A, Chen, G, Renard, M, Geers, C, Vansteenkiste, J, Giron, P, De Wever, O, Teugels, E, De Grève, J
Oncotarget. 2016;(3):3068-83
Abstract
Somatic mutations found within the tyrosine kinase domain (TKD) of the human epidermal growth factor (HER) family of receptors have been implicated in the development and progression of non-small cell lung cancer (NSCLC). However, no conclusive reports have described pathogenic mutations in kinase-impaired HER3. Here, we report a case of an advanced chemotherapy-resistant NSCLC, harboring a novel HER3(V855A) somatic mutation homologous to the EGFR(L858R)activating mutation. Co-expression of HER3(V855A) and wild-type HER2 enhances ligand-induced transformation of murine and human cell lines, while HER-targeted inhibitors potently suppress mutant HER3 activity. Consistent with these observations, in silico computational modeling predicts that mutant V855A alters the kinase domain and c-terminal end of the HER3 protein. Taken together, these findings provide a basis for the clinical exploration of targeted therapies in HER3 mutant NSCLC and by extrapolation, in other cancers that more frequently carry somatic HER3 mutations.
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MEK inhibitors: a new class of chemotherapeutic agents with ocular toxicity.
Duncan, KE, Chang, LY, Patronas, M
Eye (London, England). 2015;(8):1003-12
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Abstract
A new class of chemotherapeutic agents, MEK inhibitors, has recently been developed and is proving to be an effective treatment for a number of cancers. A pattern of ocular adverse events has followed these drugs through clinical trials and their association with retinopathy is only just beginning to be recognized. We present two cases of MEK inhibitor-associated retinopathy followed by a review of the current literature on ocular toxicity associated with MEK inhibitors. Patients undergoing treatment with MEK inhibitors appear to have high rates of multifocal serous retinal detachments as well as retinal vein occlusions. We present the first report of cystoid macular edema associated with MEK inhibitor use. The mechanism of these adverse events is still unclear though they seem to be related to oxidative stress and blood retinal barrier breakdown. Management of the ocular toxicity can range from observation to topical treatments or intravitreal injections. Fortunately most ocular adverse events appear to be self-limited and do not require discontinuing the MEK inhibitor. Discontinuation or decreased dosing of MEK inhibitors may be reserved for cases of severe sight-threatening ocular toxicity.
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Case analysis of complete remission of advanced hepatocellular carcinoma achieved with sorafenib.
Liu, D, Liu, A, Peng, J, Hu, Y, Feng, X
European journal of medical research. 2015;(1):12
Abstract
BACKGROUND To evaluate the feasibility and security of complete remission (CR) of advanced hepatocellular carcinoma (HCC) achieved with sorafenib treatment, and investigate the previously described predictive factors in CR. METHODS The case of a patient who achieved CR of advanced HCC with sorafenib treatment was analyzed. The case analysis was performed by a literature review of relevant reports retrieved from the PubMed database. RESULTS A 58-year-old male patient achieved CR of advanced HCC after 23 weeks of oral treatment with sorafenib alone for 41 months and maintained CR for more than 35 months. Eleven reports worldwide have documented a total of twelve patients who achieved CR of advanced HCC, including six with nonsurgical oral sorafenib treatment, four with surgical resection in the descent stage following oral sorafenib treatment and two with oral sorafenib treatment for postoperative metastasis. CONCLUSIONS For unresectable advanced HCC, sorafenib can significantly improve progression-free survival and overall survival, achieving CR in some cases. In addition, surgical resection of advanced HCC in the descent stage is possible following oral sorafenib treatment. For patients with postoperative distant metastasis of HCC, sorafenib treatment also provides clinical benefits and can even achieve CR. Besides, long-term sorafenib administration is safe, and patients should continually receive sorafenib to avoid recurrence after complete remission of cancer. Furthermore, early HFSR, rapid decline of AFP levels and rapid tumor shrinking observed by imaging are known parameters describing sorafenib's effects. Finally, it is important to assess the gene locus of sorafenib sensitivity in HCC patients in future research.
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Complete response to sorafenib in a patient with recurrent hepatocellular carcinoma.
Huan, HB, Lau, WY, Xia, F, Ma, KS, Bie, P
World journal of gastroenterology. 2014;(39):14505-9
Abstract
Partial hepatectomy is still the treatment of choice aiming at a cure for patients with hepatocellular carcinoma (HCC), provided that the patient can tolerate the treatment. For patients with multiple recurrent HCC after partial hepatectomy which cannot be treated by re-hepatectomy or local ablative therapy, the prognosis is extremely poor. Sorafenib is a molecular-targeted agent which has been demonstrated in two global phase III randomized controlled trials to show survival benefit for advanced HCC. Here, we present a 56-year-old patient with HCC who showed complete clinical response after sorafenib was used for tumor recurrence which developed 3 mo after partial hepatectomy. There was no evidence of progression of disease for 60 mo till now after continuous treatment with sorafenib.
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Fatal case of sorafenib-associated idiosyncratic hepatotoxicity in the adjuvant treatment of a patient with renal cell carcinoma.
Fairfax, BP, Pratap, S, Roberts, IS, Collier, J, Kaplan, R, Meade, AM, Ritchie, AW, Eisen, T, Macaulay, VM, Protheroe, A
BMC cancer. 2012;:590
Abstract
BACKGROUND Sorafenib is an orally available kinase inhibitor with activity at Raf, PDGFβ and VEGF receptors that is licensed for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). Current evidence-based post-nephrectomy management of individuals with localized RCC consists of surveillance-based follow up. The SORCE trial is designed to investigate whether treatment with adjuvant sorafenib can reduce recurrence rates in this cohort. CASE PRESENTATION Here we report an idiosyncratic reaction to sorafenib resulting in fatal hepatotoxicity and associated renal failure in a 62 year-old man treated with sorafenib within the SORCE trial. CONCLUSION This is the first reported case of sorafenib exposure associated fatal toxicity in the adjuvant setting and highlights the unpredictable adverse effects of novel adjuvant therapies.