Toxicities of Novel Anticancer Agents

Authors: Atul Shinagare, Richard Thomas ,Katherine Krajewski

Date: January 11, 2021

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

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

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

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

Patient with pneumatosis on antiangiogenic therapy

Resolution of pneumatosis after treatment stopped


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

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
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


Fatty liver almost completely obscuring a metastasis


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
Pancreatitis on sunitinib
 

Vascular Complications

  • Arterial thrombi
  • Venous thrombosis (DVT, portal vein thrombus)
  • PE (can be asymptomatic)
  • Hemorrhage

Renal infarct		 Pulmonary 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

Fluid retention in patient with imatinib
  • 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


Diffuse 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
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
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


Patient treated with ipilimumab with immune-mediated hepatitis


Ill-defined peribiliary enhancement from immune-mediated cholangitis

Immune-mediated Pancreatitis

  • Subtle finding
  • Often focal
  • Asymptomatic or abdominal pain
  • Correlate with lipase, amylase levels

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

Endocrine irAE

  • Hypophysitis
  • Thyroiditis
  • Adrenalitis
  • More common with combination therapies

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

Vascular Thromboembolism

  • Progestins associated with arterial and venous thromboembolism, osteoporosis

Pneumatosis, AVN

  • Corticosteroids associated with pneumatosis and osteonecrosis

Endometrial Changes

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

Endometrial hyperplasia in a patient with breast cancer treated with tamoxifen

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)
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