Side Effects of Targeted Molecular Agents Vary According to Mechanism of Action
By Sarah Bronson
The main side effects of cytotoxic chemotherapy are notorious. But the side effects of newer, targeted molecular agents are less well known, so patients receiving such drugs may not know what to expect and may require additional guidance from physicians.
Targeted molecular therapy is designed to disrupt oncogenic signaling pathways while leaving normal functions intact and has improved the treatment of many types of cancer. However, targeted agents frequently interfere with pathways necessary for the growth of normal cells as well as cancer cells, leading to “off-target” effects. Most of these toxic effects differ in character from those of conventional cytotoxic drugs.
Many widely used targeted drugs share common side effects. Among the most frequently seen side effects are fatigue and rashes, which can result from a wide range of targeted drugs. Gastrointestinal effects, especially diarrhea, and mouth sores, often in the form of stomatitis or mucositis, are also typical with many targeted drugs. Diarrhea occurs in a large proportion of patients treated with epidermal growth factor receptor (EGFR) inhibitors or agents that inhibit multiple tyrosine kinases. Mouth sores appear in a substantial proportion of patients treated with EGFR inhibitors, mammalian target of rapamycin (mTOR) inhibitors, or agents that inhibit multiple tyrosine kinases.
Although some side effects are shared by many targeted agents, each type of targeted drug is associated with specific side effects. Sunil Patel, M.D., an assistant professor in the Department of General Oncology at The University of Texas MD Anderson Cancer Center, said, “Now more than ever, the toxicity profile of a targeted drug can be predicted depending on the class of drug and its mechanism of action.”
EGFR inhibitors and dermatological effects
Most patients receiving EGFR inhibitors (including cetuximab, panitumumab, gefitinib, erlotinib, and lapatinib) will experience similar adverse effects in the skin. Red acneiform papules and pustules, sometimes with pain and itching, are typical in these patients and usually appear on the scalp, face, and upper trunk.
In patients who have rashes associated with EGFR inhibitors, the affected skin may develop secondary infections. Infections also may develop around the nails of these patients (paronychia).
Grade 1 or 2 rashes are usually treated with topical corticosteroids and topical or oral antibiotics; more severe rashes can be treated with antibiotics, systemic corticosteroids, or isotretinoin. If needed, the EGFR inhibitor dose can be modified. Adequate management of these dermatological side effects can significantly improve quality of life and treatment adherence in patients who receive these drugs.
Antiangiogenic drugs and cardiovascular effects
Another class of drugs with distinct side effects is the targeted antiangiogenic agents, such as the vascular endothelial growth factor (VEGF) inhibitors bevacizumab and aflibercept and the VEGF-targeting multiple tyrosine kinase inhibitors sunitinib, sorafenib, axitinib, cabozantinib, pazopanib, ponatinib, and vandetanib.
Antiangiogenic drugs share a potential for cardiovascular side effects, the most common of which is hypertension. In addition, bevacizumab and some of the tyrosine kinase inhibitors increase the risk of arterial thromboembolic events. Sunitinib and pazopanib can decrease the left ventricular ejection fraction, and vandetanib can significantly prolong the QTc interval.
Because some of the cardiovascular effects associated with angiogenesis inhibitors are potentially serious and even life threatening, patients who receive these drugs should be carefully selected and monitored. Preexisting cardiovascular conditions such as hypertension should be treated before patients receive antiangiogenic agents, and high-risk candidates—such as patients who have previously experienced arterial thromboembolic events—can receive prophylactic treatments such as anticoagulants.
Effects in other classes of targeted agents
Also linked to cardiotoxicity are human epidermal growth factor receptor 2 (HER2) inhibitors. In particular, the HER2 inhibitor trastuzumab carries a modest risk of decreased left ventricular ejection fraction and a small risk of heart failure.
Patients treated with mTOR inhibitors such as everolimus can develop elevations in blood sugar and, as mentioned above, often experience mouth sores as well as fatigue. Pneumonitis is another potential toxic effect of mTOR inhibitors.
Managing side effects
The toxic effects from targeted drugs are managed in the same way as those from cytotoxic drugs. Low-grade toxic effects that do not limit a patient’s daily life or threaten his or her health can be managed with basic interventions. For example, diarrhea can be treated with loperamide, deodorized tincture of opium, or octreotide. Higher-grade effects, however, can require a reduction in the targeted agent’s dose or, in some cases, a break in therapy.
In patients with preexisting comorbidities, certain toxic effects need to be anticipated. Depending on a patient’s baseline physical status and the planned treatment, specific conditions may need to be managed before treatment begins. For example, if echocardiography shows that a patient has a high risk of heart failure, then that patient needs to begin treatment with medications to optimize his or her cardiac function before starting a targeted drug that could cause cardiotoxicity.
The combined influence of comorbidities and toxic effects may influence which drugs are chosen to treat a patient’s cancer. Similarly, the toxic effects from other modalities of treatment may overlap with those of targeted therapy and should be planned for.
Because most targeted drugs have existed for only a few years, researchers lack data on the long-term toxic effects of these drugs. In general, however, the toxic effects subside when treatment with the targeted drug comes to an end. An exception is peripheral neuropathy, which is associated with the use of certain targeted drugs, such as the protease inhibitor bortezomib, as well as with several cytotoxic drugs. While most cases of drug-related neuropathy resolve or improve over time, neuropathy may linger 6–12 months after the end of treatment or become a lifelong issue. Chronic neuropathy can be managed with physical therapy, analgesic creams, non-steroidal anti-inflammatory drugs, and opioids but cannot be reversed.
Different approach, different effects
Although some side effects, such as neuropathy and fatigue, can be caused by targeted or cytotoxic drugs, the differences between the toxicity profiles of targeted drugs and cytotoxic agents can have clinical implications.
For patients who have experienced cytotoxic chemotherapy before but are new to targeted therapy, some of the differences may be unexpected. For instance, although cytotoxic agents will often decrease white blood cell counts, some targeted drugs have no effect on blood counts. For this reason, infection risk is less of a concern during treatment with some targeted drugs than with cytotoxic drugs.
In contrast, the side effects from targeted therapy should not always be expected to differ from those of chemotherapy in severity. Charles Cleeland, Ph.D., a professor in and chair of the Department of Symptom Research, said, “We’re realizing that these effects aren’t necessarily less than those of cytotoxic drugs; targeted therapy just has a different side effect profile.”
The key to navigating the breadth of targeted drugs that are becoming available, Dr. Patel said, is knowing the pathways that lead to cancer. “In the end, understanding what pathways are turned on and off in various cancer cells, regardless of the tissue of origin, will not only drive our treatment approaches but also determine many of the off-target effects we will need to manage.”
For more information, contact Dr. Charles Cleeland at 713-745-3470 or Dr. Sunil Patel at 713-563-9600.
OncoLog, July 2014, Volume 59, Issue 7