How to Manage Side Effects of Colorectal Cancer Therapies

Rona Yaeger, MD Memorial Sloan Kettering Cancer Center | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

Key Points

• Fluorouracil (5-FU) backbone–related side effects are observed across treatment settings, and reducing the bolus component is a common modification in the adjuvant setting.

• The FDA updated the label for 5-FU and capecitabine to include testing for dihydropyrimidine dehydrogenase (DPD) deficiency, which can increase the risk of serious side effects.

• In the metastatic setting, combination regimens may have overlapping side effects, and determining which agent drives toxicities is crucial for appropriate dose modifications.

Managing Side Effects of Colorectal Cancer Therapies 

As part of a three-episode series on colorectal cancer on the Oncology Brothers podcast, cohosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, met with Rona Yaeger, MD, a medical oncologist from Memorial Sloan Kettering Cancer Center, to discuss managing side effects of colorectal cancer therapies used in early-stage or metastatic treatment settings. The doctors covered the toxicity profiles of fluorouracil (5-FU), capecitabine, oxaliplatin, irinotecan, bevacizumab, encorafenib, cetuximab, panitumumab, regorafenib, and fruquintinib.

5-FU and Capecitabine

5-FU and capecitabine are fluoropyrimidine chemotherapy agents that form the backbone of treatment for many cancers, including colorectal cancer. 5-FU is typically combined with leucovorin and additional chemotherapy agents, such as oxaliplatin (FOLFOX), irinotecan (FOLFIRI), or both (FOLFOXIRI). 5-FU is associated with hematologic, gastrointestinal (GI), dermatologic, and cardiac toxicities. Special care should be taken in patients with cardiac comorbidities, and those who experience chest pain should immediately contact their physician. Generally, weekly dosing may help reduce coronary vasospasm or angina events.

Capecitabine is an oral prodrug of 5-FU that is typically combined with oxaliplatin (CAPOX). Capecitabine shares a similar side effect profile as intravenous 5-FU, but generally has lower rates of cytopenias and mouth sores and higher rates of hand-foot syndrome. Hand-foot syndrome can be dose-limiting, though diclofenac gel may help manage it. 

Historically, 5-FU has been administered as a bolus dose followed by a continuous infusion. Both the bolus component and leucovorin are often omitted in the metastatic setting to reduce toxicity. In the adjuvant setting, Dr. Yaeger attempts 5-FU bolus and leucovorin, but has a low threshold for dropping them. Her center has shifted toward capecitabine–based regimens in the adjuvant setting based on the IDEA study. 

Notably, the FDA recently updated the label for 5-FU and capecitabine to recommend testing patients for DPYD mutations that cause DPD deficiency before starting treatment. Patients with DPD deficiency have an increased risk of serious, potentially fatal side effects from these treatments.

Oxaliplatin and Irinotecan

Oxaliplatin is a platinum-based chemotherapy agent used across treatment settings, typically in combination with a 5-FU backbone. Oxaliplatin is associated with neurologic, GI, hematologic, and hepatic toxicities, as well as infusion-related reactions. The most notable dose-limiting toxicity is neuropathy, which is cumulative over time. Oxaliplatin should be stopped early in response to neuropathy, as it can escalate for a period after stopping treatment. Otherwise, medications like gabapentin may help control pain, depending on symptom characteristics, said Dr. Yaeger.

Irinotecan is a topoisomerase I inhibitor chemotherapy agent used alongside a 5-FU backbone in the metastatic treatment setting. Irinotecan is associated with GI events, hematologic toxicity, hepatic toxicity, and infusion reactions. Cholinergic diarrhea can occur during infusion or within 24 hours of infusion. Diarrhea presenting more than 24 hours after infusion can be a dose-limiting toxicity. Atropine and loperamide are recommended for prophylaxis of cholinergic diarrhea and late diarrhea, respectively. When discussing 5-FU–based regimens with patients, Dr. Yaeger often contrasts the neuropathy with oxaliplatin neuropathy versus the alopecia with irinotecan. 

Bevacizumab

Bevacizumab is an anti-VEGF antibody used in combination with 5-FU–based regimens in metastatic colorectal cancer. Bevacizumab is associated with GI, cardiac, endocrine, genitourinary, and hematologic toxicities, including bleeding and clotting. Because of bleeding effects, bevacizumab must be held ahead of any planned procedures. If patients develop clots, Dr. Yaeger recommends pausing bevacizumab and giving 3 to 6 months of anticoagulation. If patients remain stable, bevacizumab may be resumed. Bevacizumab is also associated with fistula formation, and Dr. Yaeger avoids using it in patients with a history or risk factors of fistulas.

Cetuximab and Panitumumab

Treatment of metastatic colorectal cancer is largely driven by biomarker and mutational status. Cetuximab and panitumumab are anti-EGFR agents used alongside 5-FU–based regimens in the metastatic setting for patients with wild-type RAS disease. Cetuximab is also approved in combination with encorafenib and 5-FU–based chemotherapy for metastatic colorectal cancer with BRAF V600E mutation. Cetuximab is associated with dermatologic toxicities, fatigue, diarrhea, infusion reactions, and electrolyte imbalances. 

The risk of infusion reactions is highest in the first cycle, and patients should be pretreated prophylactically. If patients experience mild reactions, the infusion rate can be slowed for the next infusion, and gradually increased in subsequent infusions as tolerated. If patients do well, they can stop premedication. Rash is a common toxicity with EGFR inhibitors, and Dr. Yaeger advises patients to moisturize and limit sun exposure. Prophylactic antibiotics and topical steroids may also help control rash. 

Panitumumab is associated with dermatologic and GI side effects, as well as fatigue, peripheral edema, and electrolyte imbalances. Panitumumab has a lower risk of infusion reactions compared with cetuximab, and typically does not require prophylactic premedication. If patients with BRAF V600E mutations on cetuximab and encorafenib experience severe infusion reactions, the cetuximab can be switched to panitumumab, said Dr. Yaeger. Encorafenib can also be continued alone if patients do not tolerate an EGFR inhibitor.

Encorafenib

Encorafenib, a BRAF V600E inhibitor, was recently approved in combination with cetuximab and 5-FU–based chemotherapy as first-line treatment for metastatic colorectal cancer with BRAF V600E mutation based on the BREAKWATER trial. Encorafenib is associated with GI, dermatologic, cardiac, ocular, and hepatic toxicities, as well as fatigue, peripheral edema, and arthralgia or myalgia. Encorafenib is associated with cutaneous squamous cell carcinomas, although at a lower rate than other BRAF inhibitors. Patients should be monitored for lesions and referred to dermatology specialists for excisions.

Rash with encorafenib is typically milder compared with the anti-EGFR inhibitors. In combination, their mechanisms oppose each other and reduce the severity of rash. However, both agents increase photosensitivity, so patients on combination therapy should limit sun exposure, Dr. Yaeger said. 

The doctors highlighted that many agents in the BREAKWATER regimen have overlapping side effect profiles. Cytopenias, for example, may be more likely a result of 5-FU–based chemotherapy versus encorafenib, and Dr. Yaeger typically starts with 5-FU modifications before changing encorafenib.

Regorafenib and Fruquintinib

Regorafenib and fruquintinib are tyrosine kinase inhibitors used for metastatic colorectal cancer in the third line and beyond. Regorafenib is associated with dermatologic, hepatic, cardiovascular, and GI side effects, as well as fatigue or asthenia and increased risk of infection. Fruquintinib is associated with cardiovascular, dermatologic, renal, GI, and hepatic side effects, as well as fatigue, dysphonia or hoarseness, and hypothyroidism. 

For regorafenib, the ReDOS study described a step-up dosing strategy that improved toxicity, and many patients may not need to go all the way to the maximum dose. For fruquintinib, a patient’s thyroid-stimulating hormone levels should be monitored regularly.