Side Effects of Targeted Therapy: Introduction
Major advances have been achieved in the field of biologically based therapies for cancer in the last few years, and some of the recently approved molecular-targeted therapies are now being used in daily clinical practice. These molecular targets are also expressed in normal cells, which explains the different grades of toxicity, resulting from the disruption of normal cellular function. In general, targeted molecular therapies have good toxicity profiles, but some patients are exquisitely sensitive to these drugs and can develop particular and severe toxicities.
Side Effects of Targeted Therapy: Anti-EGFR Therapies
Skin Toxicity: the most commonly observed skin side effect with EGFR inhibitors is an acneiform eruption, also called acne-like rash or folliculitis, which occurs in 50%–100% of patients, which is more severe and diffuse with cetuximab than with small molecule TKIs. Overall, the acneiform rash is characterized by erythematous follicular papules and pustules that appear in areas rich in sebaceous glands, such as the face, forehead, upper chest, and back, and can also affect the lower parts of the back and abdomen as well as the palms and soles.
Gastrointestinal Toxicity: Postchemotherapy diarrhea is the end result of extensive crypt damage in the small bowel and colon, resulting in an excess of fluid in the bowel lumen. The exact pathophysiology of anti-EGFR agent–related diarrhea remains unclear. EGF is involved in the maintenance of mucosal integrity and is also a potent mitogen of the gastric epithelium; it stimulates mucin production and enhances prostaglandin synthesis.
Other Side Effects: Interstitial lung disease (ILD) is known to be an adverse event of some cancer chemotherapeutic agents and following local radiotherapy. ILD was diagnosed in 616 patients (2.2%), and resulted in a fatal outcome in 246 patients (0.86%), according to a report from Astra Zeneca.
Side Effects of Targeted Therapy: Anti-HER-2 Therapies
Trastuzumab: Approximately 40% of patients receiving trastuzumab experience some degree of infusion-related symptoms, such as a flu-like syndrome that includes fever and chills, mainly during the first infusion. Other common reactions include tumor site pain, shortness of breath, muscle weakness, cutaneous rash, diarrhea, and headache. Trastuzumab is administered i.v. over 90 minutes for the first infusion, and with a primary line of saline solution. If the first infusion is well tolerated, subsequent doses can be administered over 30 minutes.
Lapatinib: In phase I trials, lapatinib alone was well tolerated in heavily pretreated patients, with cutaneous rash, diarrhea, nausea/vomiting, fatigue, and anorexia being the most frequently observed grade 1 or 2 adverse events. There were no grade 4 toxicities, but grade 3 diarrhea was observed at the 900-mg twice-daily dose level. The incidence of diarrhea was linearly related to dose but not to serum concentration of the drug, suggesting that this toxicity evolves from a local effect of the drug on the gut epithelium. In the phase I study (EGF10009) that examined the safety profile of lapatinib in combination with paclitaxel, 11 (of 12) patients (92%) experienced at least one drug-related adverse event. The most frequently reported drug-related adverse events were: diarrhea (92%), vomiting (67%), rash (58%), nausea (42%), fatigue (42%), anorexia (33%), and constipation (33%) . In the phase II trial testing the combination of lapatinib plus capecitabine versus capecitabine alone in 316 patients (164 versus 152), diarrhea of any grade was higher in the combinational arm (60% versus 39%), but only two women (1%) developed grade 4 diarrhea when lapatinib was administered.
Side Effects of Targeted Therapy: Antiangiogenic Therapies
In a randomized phase II study evaluating the efficacy and safety of bevacizumab in combination with 5-FU plus leucovorin in patients with previously untreated advanced colorectal cancer, venous thromboembolism was the most significant adverse event, together with hypertension, proteinuria, and epistaxis. Forty patients, of the 67 (59%) who received bevacizumab in combination with chemotherapy, experienced bleeding episodes, in comparison with only four patients (11%) in the chemotherapy alone arm. Furthermore, 13 patients (19%) experienced thrombotic episodes, in comparison with 9% in the control arm
Side Effects of Targeted Therapy: Antiangiogenic Reference
Widakowich C et al. Review: side effects of approved molecular targeted therapies in solid cancers[J]. The oncologist, 2007, 12(12): 1443-1455.