Toxicities of Novel Anticancer Agents

Toxicities of Novel Anticancer Agents

Overview

Three major classes of novel anticancer agents

  • Molecular targeted therapy (MTT)
    • Antiangiogenic: VEGF inhibitors
    • Non-antiangiogenic: EGFR, BRAF, mTOR inhibitors
  • Immune checkpoint inhibitors
    • Anti–CTLA-4: ipilimumab
    • Anti–PD-1 and PD-L1: Nivolumab, Pembrolizumab
  • Hormonal agents

Toxicities of novel anticancer agents

  • Dependent on mechanism of action
  • Often subtle appearance
  • Prompt detection and communication still important
  • Some toxicities may serve as biomarker of response

Toxicities of Molecular Targeted Therapy

Common toxicities of molecular targeted therapy

Organ Findings
Bowel Enterocolitis, pneumatosis, perforation, anastomotic dehiscence, tumor-bowel fistula
Liver Hepatic steatosis
Lungs Pneumonitis, pulmonary hemorrhage
Pancreas Pancreatitis
Gallbladder Sludge, gallbladder wall edema, cholecystitis
Kidney Crizotinib-associated cysts, infarcts
Vessels Thromboembolism (PV thrombus, DVT, PE), hemorrhage
Sof Tissues Fluid retention – ascites, pleural effusion, anasarca

Bowel Complications

Mechanism
  • Compromised bowel wall integrity (VEGF)
  • Serosal tumor necrosis
  • Impaired healing
  • Ischemic changes
Bowel complications mechanism

Colitis

  • Diarrhea ± abdominal pain
  • Usually subtle on imaging
  • Mild wall thickening
  • Vascular engorgement
  • Mild or no fat stranding
  • Little or no ascites
  • Rx: Drug discontinuation ± steroids
Bowel complications colitisBowel complications colitis

Pneumatosis and Perforation

  • Often asymptomatic, but may present with abdominal pain, distention, obstructive symptoms
  • Median 3-4 months of starting treatment
  • Pneumatosis may involve normal bowel wall
  • Perforation often at surgical or tumor site
  • Exclude other more serious causes such as ischemic bowel
  • Usually resolve after drug discontinuation
  • May worsen or recur if the drug is continued or restarted

Anastomotic Dehiscence

  • Can occur late after surgery
  • Look for foci of gas adjacent to surgical anastomosis
  • Discontinue Rx at earliest sign
Bowel complications Patient with pneumatosis on antiangiogenic therapyBowel complications Patient with pneumatosis on antiangiogenic therapy

Patient with pneumatosis on antiangiogenic therapy

Bowel complications Resolution of pneumatosis after treatment stoppedBowel complications Resolution of pneumatosis after treatment stopped

Resolution of pneumatosis after treatment stopped

Bowel complications Anastomotic dehiscence in patient with rectal cancer on bevacizumab
Anastomotic dehiscence in patient with rectal cancer on bevacizumab

Tumor-bowel Fistula

  • Bowel fistulization conventionally due to tumor progression
  • With MTT, it can occur with treatment response
  • Changes of treatment response seen
    • Decreased tumor size and enhancement
  • Look for large serosal implants before starting Rx
Bowel complications Tumor-bowel fistulaBowel complications Tumor-bowel fistula

Patient with ovarian cancer: Tumor-bowel fistula on bevacizumab

Other Toxicities of Molecular Targeted Therapy

Pneumonitis

  • Class-specific toxicity of mTOR inhibitors
  • Basilar, peripheral, reticular or groundglass opacities
Other toxicities of molecular targeted therapy, Pneumonitis
Patient RCC on everolimus with pneumonitis and colitis

Hepatic Toxicity: Hepatic Steatosis (fatty liver)

  • Common with Bevacizumab, tyrosine kinase inhibitors
  • Can obscure metastases

Note: Steatohepatitis (Irinotecan) and veno-occlusive disease (Oxaliplatin) common with colon and pancreatic cancer patients

Occasionally focal fatty change may mimic metastases

  • MRI problem-solving tool (signal drop on out of phase images)
  • Check CEA levels, Karnofsky performance status
  • Can obtain short interval follow-up

Other toxicities of molecular targeted therapy, Hepatic toxicity, Hepatic steatosis (fatty liver)
Fatty liver almost completely obscuring a metastasis

Other toxicities of molecular targeted therapy, Hepatic toxicity, Hepatic steatosis (fatty liver) Other toxicities of molecular targeted therapy, Hepatic toxicity, Hepatic steatosis (fatty liver)
Focal fatty change mimicking metastases

Pancreatitis

  • Uncommon, underdiagnosed
  • Usually mild
  • May be asymptomatic
  • Focal (often tail) or diffuse
  • Resolves after stopping treatment
  • Often recurs if drug restarted
  • Correlate with lipase, amylase levels
Other toxicities of molecular targeted therapy, Pancreatitis
Pancreatitis on sunitinib
 

Vascular Complications

  • Arterial thrombi
  • Venous thrombosis (DVT, portal vein thrombus)
  • PE (can be asymptomatic)
  • Hemorrhage
Other-toxicities molecular targeted therapy, Vascular Complications, Renal Infarct
Renal infarct
Other-toxicities molecular targeted therapy, Vascular Complications, Pulmonary EmbolismPulmonary embolism

Fluid Retention

  • Thought to be due to capillary leak syndrome
  • Ascites, effusion, anasarca
  • Dose-dependent
  • More common and severe in older patients
  • Treatment supportive but may require treatment discontinuation
Other toxicities of molecular targeted therapy, Fluid Retention

Fluid retention in patient with imatinib

Immune-related Adverse Events

  • Immune-related adverse events (irAEs) are immunologic “flare” phenomenon
  • Clinically any grade irAEs in 72%; high-grade in 24%
  • On imaging: 31% with ipilimumab, 14% with nivolumab
  • Colitis (12-19%), pneumonitis (5%), sarcoid-like reaction (5%) 
  • Treatment steroids

Common toxicities of immune checkpoint inhibitors

Organ Findings
Bowel

Enterocolitis

Liver

Hepatitis, cholangitis

Lungs

Pneumonitis

Lymph Nodes

Sarcoid-like reaction

Pancreas

Pancreatitis

Endocrine

Hypophysitis, thyroiditis, adrenalitis

Immune-mediated Colitis

  • Most common irAE
  • 2-3 months after starting treatment
  • Often subtle on imaging
  • Fluid-filled bowel
  • Mild bowel wall thickening
  • Fat stranding

Patterns of Colitis:

Diffuse Colitis

  • Fluid-filled colon, vascular engorgement
  • Wall thickening or stranding not usual
  • Usually treated with steroids

Segmental Colitis

  • Often associated with diverticulosis
  • Wall thickening, stranding common
  • May require steroids and antibiotics

Immune-related adverse events, Immune-mediated colitis

Immune-related adverse events, Diffuse colitis
Diffuse colitis

Immune-related adverse events, Segmental colitis
Segmental Colitis

Immune-mediated Pneumonitis

  • 2-6 months of therapy
  • Higher risk with combination therapy > PD-1 > PD-L11,2
  • Lower lobe predominant
  • Bilateral more common
  • Usually peripheral
  • Groundglass or reticular opacities
  • May mimic lobar pneumonia
  • Eventually may develop cryptogenic organizing pneumonia-like picture
Immune-related adverse events, Immune-mediated pneumonitisImmune-related adverse events, Immune-mediated pneumonitis
Two different patients with immune-mediated pneumonitis

Sarcoid-like Reaction

  • Best-known with ipilimumab
  • Mediastinal lymphadenopathy, pulmonary nodules, splenic involvement
  • Can involved other nodal sites
Immune-related adverse events, Sarcoid-like reaction
Thoracic lumphadenopathy, pulmonary nodules and splenic uptake at 3 months that resolved spontaneously

Immune-mediated Hepatitis

  • Non-specific imaging findings
  • Normal CT and US if mild
  • CT: Hepatomegaly, periportal edema, diffuse low attenuation of liver, periportal lymphadenopathy
  • US: Prominent periportal echogenicity, gallbladder wall edema

Immune-mediated Cholangitis

  • Uncommon
  • Elevated LFTs
  • Imaging features
    • Biliary wall thickening and narrowing
    • Biliary dilation
    • Ill-defined peribiliary enhancement
  • Rule out other autoimmune disorders including PSC or IgG4-related disease

Immune-related adverse events, Immune-mediated hepatitis
Patient treated with ipilimumab with immune-mediated hepatitis

Immune-related adverse events, Immune-mediated cholangitis
Ill-defined peribiliary enhancement from immune-mediated cholangitis

Immune-mediated Pancreatitis

  • Subtle finding
  • Often focal
  • Asymptomatic or abdominal pain
  • Correlate with lipase, amylase levels
Immune-related adverse events, Immune-mediated pancreatitis

Diffuse peripancreatic stranding from immune-mediated pancreatitis in patient being treated with pembrolizumab

Endocrine irAE

  • Hypophysitis
  • Thyroiditis
  • Adrenalitis
  • More common with combination therapies
Immune-related adverse events, Endocrine irAE

Bulky heterogeneous thyroid in a patient on nivolumab with hoarseness of voice

Toxicities of Hormonal Therapy

Vascular Thromboembolism

  • Progestins associated with arterial and venous thromboembolism, osteoporosis
Vascular Thromboembolism

Pneumatosis, AVN

  • Corticosteroids associated with pneumatosis and osteonecrosis

Pneumatosis, AVN

Pneumatosis, AVN

Endometrial Changes

  • Selective estrogen receptor modulators (tamoxifen) may cause endometrial polyp, hyperplasia, carcinoma, uterine sarcoma
Endometrial changes

Endometrial hyperplasia in a patient with breast cancer treated with tamoxifen

Practical Approach

Drug Class-based Approach

Antiangiogenic agents Bowel complications
Hepatic steatosis
Pancreatitis
Vascular complications, fluid retention
mTOR inhibitors Pneumonitis
Enteritis
Immune checkpoint inhibitors Colitis
Pneumonitis
Sarcoid-like reaction
Hepatitis, cholangitis
Pancreatitis
Endocrine events
Hormonal therapy Vascular Thromboembolism
Pneumatosis
Avascular necrosis
Endometrial changes

Toxicity Checklist-based Approach

Brain, Head and neck Hypophysitis
Thyroiditis
Chest Lungs: Pneumonitis
Mediastinum: Sarcoid-like reaction
Vascular: Hemorrhage, pulmonary embolism, fluid retention (pleural effusion, subcutaneous edema)
Abdomen and Pelvis Bowel: Enterocolitis, pneumatosis, perforation, tumor-bowel fistula
Liver: Steatosis, hepatitis
Pancreatitis, cholecystitis
Vascular: Arterial or venous thromboemboli, infarcts, hemorrhage, fluid retention (ascites, subcutaneous edema)

References

  • Alessandrino et al. Frequency and imaging features of abdominal immune-related adverse events in metastatic lung cancer patients treated with PD-1 inhibitor. Abdom Radiol (NY). 2019 May;44(5):1917-1927.
  • Dabydeen et al. Pneumonitis associated with mTOR inhibitors therapy in patients with metastatic renal cell carcinoma: incidence, radiographic findings and correlation with clinical outcome. Eur J Cancer. 2012 Jul;48(10):1519-24.
  • Kim et al. Ipilimumab-associated colitis: CT findings. AJR 2013 May;200(5):W468-74.
  • Nishino et al. Anti-PD-1 Inhibitor-Related Pneumonitis in Non-Small Cell Lung Cancer. Cancer Immunol Res. 2016 Apr;4(4):289-93.
  • Parithivel et al. Everolimus- and temsirolimus-associated enteritis: report of three cases. J Clin Oncol. 2011 May 10;29(14):e404-6.
  • Shinagare et al. Pneumatosis intestinalis and bowel perforation associated with molecular targeted therapy: an emerging problem and the role of radiologists in its management. AJR 2012 Dec;199(6):1259-65.
  • Tirumani et al. Tumor-bowel fistula: what radiologists should know. Abdom Imaging. 2013 Oct;38(5):1014-23.
  • Tirumani et al. Radiographic Profiling of Immune-Related Adverse Events in Advanced Melanoma Patients Treated with Ipilimumab. Cancer Immunol Res. 2015 Oct;3(10):1185-92.