Complications of Targeted Drug Therapies for Solid Malignancies: Manifestations and Mechanisms

Abramson, Richard G.; Abramson, Vandana G.; Chan, Emily; Horn, Leora; Keedy, Vicki L.; Pao, William; Sosman, Jeffrey A.

doi:10.2214/ajr.12.9049

Cited by 28 publications

(22 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mechanism underlying TT toxicity is complex and not entirely understood [4]. While fatigue/asthenia, rash, and diarrhea are common to both sunitinib and mTOR inhibitors, other AEs are class-specific [1,2].…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenomic Markers of Targeted Therapy Toxicity in Patients with Metastatic Renal Cell Carcinoma

Velasco

Gray

Hamieh

et al. 2016

European Urology Focus

View full text Add to dashboard Cite

Background Targeted therapy (TT) in metastatic renal cell carcinoma (mRCC) may be associated with a high rate of toxicity that undermines treatment efficacy and patient quality of life. Polymorphisms in genes involved in the pharmacokinetic pathways of TTs may predict toxicity. Objective To investigate whether selected single-nucleotide polymorphisms (SNPs) in three core genes involved in the metabolism and transport of sunitinib and the mTOR inhibitors everolimus and temsirolimus are associated with adverse events (AEs). Design, setting, and participants Germline DNA was extracted from blood or normal kidney tissue from mRCC patients of Caucasian ethnicity in two cohorts treated with either sunitinib (n = 159) or mTOR inhibitors (n = 62). Six SNPs in three candidate genes (CYP3A4: rs2242480, rs4646437, and rs2246709; CYP3A5: rs15524; and ABCB1: rs2032582 and rs1045642) were analyzed. Outcome measurements and statistical analysis Primary endpoints were grade ≥3 AEs for all patients; grade ≥3 hypertension in the sunitinib cohort, and any grade pneumonitis in the mTOR inhibitors cohort. A logistic regression model was used to assess the association between SNPs and AEs, with adjustment for relevant clinical factors. Results and limitations In total, 221 samples were successfully genotyped for the selected SNPs. In the sunitinib cohort, the CYP3A4 rs464637 AG variant was associated with a lower risk of high-grade AEs (odds ratio 0.27, 95% confidence interval 0.08–0.88; p = 0.03), but no SNPs were associated with hypertension. In the mTOR inhibitor cohort, none of the selected SNPs was associated with any toxicity. Conclusions We observed an association between CYP3A4 polymorphisms and toxicity outcomes in mRCC patients treated with sunitinib, but not with everolimus or temsirolimus. Our findings are exploratory in nature, and further validation in independent and larger cohorts is needed. Patient summary We found that variants of CYP3A4, a gene involved in drug metabolism, are associated with sunitinib toxicity. This information may help in better selection of patients for targeted therapies in metastatic renal cell carcinoma.

show abstract

Section: Introductionmentioning

confidence: 99%

Pharmacogenomic Markers of Targeted Therapy Toxicity in Patients with Metastatic Renal Cell Carcinoma

Velasco

Gray

Hamieh

et al. 2016

European Urology Focus

View full text Add to dashboard Cite

show abstract

“…Several side effects have been described including dermatological, cardiovascular, respiratory, gastrointestinal, hematological, and renal compromise, with different grades of severity [2]. However, the most common side effects consist of reversible skin rashes (in 40% of patients), diarrhea (43%), hand-foot syndrome (30%), and hypertension (17%).…”

Section: Discussionmentioning

confidence: 99%

Sorafenib-Induced Acute Pancreatitis in a Patient with Differentiated Thyroid Cancer

2018

View full text Add to dashboard Cite

Background: Sorafenib is a tyrosine kinase inhibitor approved for the treatment of metastatic renal cell carcinoma, hepatocellular carcinoma, and recently for radioactive iodine (RAI)-refractory metastatic differentiated thyroid carcinoma (DTC). Several side effects have been described including alterations in amylase and lipase levels. Nonetheless, only a few cases of pancreatitis during renal carcinoma and hepatocellular carcinoma treatment have been described. Objective: To describe the first case report of sorafenib-induced acute pancreatitis during the treatment of thyroid carcinoma. Methods and Results: In a 60-year-old Latin woman with RAI-refractory papillary thyroid carcinoma, T4bN1bM1, sorafenib was indicated due to locally recurrent, metastatic, and progressive lung involvement without iodine uptake. Therapy was initiated (200 mg) every 8 h. Three days after starting the medication, abdominal pain, nausea, and emesis appeared. A blood test revealed elevated amylase (343 U/L RV: 28–100) and lipase (1,969 U/L RV: 23–300) levels, but no other findings, confirming acute mild pancreatitis. Hypertriglyceridemia, hypercalcemia, and alcohol and biliary etiologies were ruled out and sorafenib-acute pancreatitis was concluded. Two weeks later, sorafenib was resumed without recurrence. To date, this is the tenth sorafenib-related pancreatitis report and the first in a patient with RAI-refractory metastatic DTC. Conclusions: Sorafenib-acute pancreatitis may develop in patients with RAI-refractory thyroid cancer. This adverse event seems to be independent of the treatment duration and administered dose. Resuming the medication with an adjusted dose after pancreatitis resolution may be safe.

show abstract

“…By virtue of their complexity, monoclonal antibodies are more expensive to create and are generally more specific, whereas small molecule inhibitors are cheaper to manufacture but often cause more toxic effects. In part, small molecule inhibitors cause a greater number of toxic effects because they usually target a family of enzymes called kinases, which share important molecular similarities with one another (2)(3)(4)8).…”

Section: Classification Of Adverse Effects Associated With Targeted Cmentioning

confidence: 99%

Molecular and Clinical Approach to Intra-abdominal Adverse Effects of Targeted Cancer Therapies

et al. 2017

View full text Add to dashboard Cite

Targeted cancer therapies encompass an exponentially growing number of agents that involve a myriad of molecular pathways. To excel within this rapidly changing field of clinical oncology, radiologists must eschew traditional organ system-based approaches of cataloging adverse effects in favor of a conceptual framework that incorporates molecular mechanisms and associated clinical outcomes. Understanding molecular mechanisms that underlie imaging manifestations of adverse effects and known associations with treatment response allows radiologists to more effectively recognize adverse effects and differentiate them from tumor progression. Radiologists can therefore more effectively guide oncologists in the management of adverse effects and treatment decisions regarding continuation or cessation of drug therapy. Adverse effects from targeted cancer therapies can be classified into four categories: (a) category 1, on-target adverse effects associated with treatment response; (b) category 2, on-target adverse effects without associated treatment response; (c) category 3, off-target adverse effects; and (d) category 4, tumor necrosis-related adverse effects. This review focuses on adverse effects primarily within the abdomen and pelvis classified according to established or hypothesized molecular mechanisms and illustrated with images of classic examples and several potential emerging toxic effects. RSNA, 2017.

show abstract

Complications of Targeted Drug Therapies for Solid Malignancies: Manifestations and Mechanisms

Cited by 28 publications

References 43 publications

Pharmacogenomic Markers of Targeted Therapy Toxicity in Patients with Metastatic Renal Cell Carcinoma

Pharmacogenomic Markers of Targeted Therapy Toxicity in Patients with Metastatic Renal Cell Carcinoma

Sorafenib-Induced Acute Pancreatitis in a Patient with Differentiated Thyroid Cancer

Molecular and Clinical Approach to Intra-abdominal Adverse Effects of Targeted Cancer Therapies

Contact Info

Product

Resources

About