Modern approaches may play a role in systemic therapy after metastatic resection in colorectal cancer, a notoriously difficult disease to cure with just doublet chemotherapy, according to experts at the recent 2022 Great Debates & Updates in Gastrointestinal Malignancies. Resection for metastatic colorectal cancer has improved the long-term survival of patients, but recurrence is quite high in 50-75 percent of patients. Data to support chemotherapy as a possible option is lacking and the evidence for chemotherapy to treat colorectal metastases shows no improvement in overall survival.
In 2007, the EORTC Intergroup randomized Phase III study 40983 (EPOC) evaluated the benefit of perioperative fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) chemotherapy for patients with potentially resectable colorectal cancer liver metastases (J Clin Oncol 2007; doi: 10.1200/jco.2007.25.18_suppl.lba5). The results showed a benefit of progression-free survival (PFS) in all resected patients, but no improvement in overall survival (OS).
Standard Observation
Namrata Vijayvergia, MD, Assistant Chief of Gastrointestinal Medical Oncology at Fox Chase Cancer Center, highlighted more recent trials to support the case for standard observation.
The Phase III CALGB/SWOG 80405 trial compared the addition of bevacizumab or cetuximab to infusional FOLFOX4 or fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment of advanced colorectal cancer (J Clin Oncol 2014; doi: 10.1200/jco.2014.32.18_suppl.lba3). The results by sidedness show higher OS for left-sided versus right-sided patients, Vijayvergia noted.
Similarly, the randomized FIRE-3 trial showed FOLFIRI plus cetuximab resulted in a significantly higher overall response rate (ORR) and longer OS compared to FOLFIRI plus bevacizumab among patients with left-sided tumors (Br J Cancer 2021; https://doi.org/10.1038/s41416-020-01140-9).
In 2022, the Phase III PARADIGM trial found panitumumab led to superior OS versus bevacizumab in combination with standard doublet first-line chemotherapy for patients with RAS wild-type metastatic colorectal cancer and left-sided primary tumors, establishing this as a standard first-line combination regimen for this population (J Clin Oncol 2022; doi: 10.1200/JCO.2022.40.17_suppl.LBA1).
"The OS benefit story repeats itself," Vijayvergia said. "Anti-EGFR is superior to bevacizumab, leading to a 20-30 percent improvement in survival." She noted that the risk of rash and diarrhea has to be balanced against improved OS and ORR.
Other combinations under investigation include 5-FU with FOLFIRI and the new EPOC trial designed to integrate surgery and chemotherapy in potentially resectable colorectal cancer liver metastases.
Vijayvergia noted that "ctDNA has become an important tool to tailor treatment, but we need more studies on how to use modern approaches to help us assess treatment. Using ctDNA to guide treatment needs further evaluation and is not ready for prime time.
"Testing lags behind significantly. Bevacizumab is the easier choice as it can be started without any delay, but why settle for less? Anti-EGFR therapy may be the most cost-effective. The slight initial worsening of quality of life (QOL) can be offset by improved OS and preserved QOL in the long term. I'm a strong believer of frontline anti-EGFR therapy for left-sided colorectal cancer," she concluded.
Modern Approaches
Cathy Eng, MD, Professor of Medicine at Vanderbilt University Medical Center, promoted the benefits of modern approaches, tools, and strategies for patients with colorectal cancer metastases, such as using liquid biopsy as a guide to confirm tumors. Small studies confirm the use of ctDNA to help define which patients may recur. Without ctDNA, other potential strategies include a hepatic arterial infusion pump, which leads to a similar recurrence with systemic therapy, she said.
There may also be a role for bone marrow transplant. "This is emerging as a real therapeutic tool. Doublet chemotherapy has not moved the needle for OS," she said.
In a counter argument to Vijayvergia, Eng provided some salient points about the results of the FIRE-3 and CALGB 80405 trials. For FIRE-3, she said "PFS was not significant, OS was a secondary endpoint, and the study was not powered to compare cetuximab versus bevacizumab for left-sided RAS wild-type tumors."
A post-hoc analysis about sidedness showed "about one-third of patients in both arms did not receive oxaliplatin in the second-line setting, and only 47 percent in the cetuximab group received bevacizumab in the second line. Forty-one percent in the bevacizumab group received anti-EGFR therapy and did not continue bevacizumab, which is the standard of care in the U.S."
For CALGB 80405, she noted there was no significant difference in PFS or OS, and the study also was not powered to compare cetuximab versus bevacizumab for left-sided RAS wild-type tumors. She also noted several drawbacks to anti-EGFR therapy.
"QOL issues include electrolyte disturbances and multiple dermatologic complaints, including paronychia infection, rash, and infection. Early development of acquired KRAS mutations will require longitudinal ctDNA for RAS status...[which] is not readily available for treatment planning," she said.
Eng concluded: "Neither FIRE-3 nor CALGB 80405 was powered specifically to evaluate the role of left-sided RAS tumors and the indication of anti-EGFR versus anti-VEGF therapy. In the Phase III PARADIGM trial, it is unclear what maintenance regimen was provided. Is the depth of response impactful enough to impact OS but not PFS? Final publication is pending. OS is dependent on all subsequent lines of therapy."
Her final statement: "Not all patients with left-sided RAS wild-type metastatic colorectal cancer should receive anti-EGFR therapy as first-line chemotherapy."
Moderator David Ilson, MD, PhD, Medical Oncologist at Memorial Sloan Kettering Cancer Center, commented: "We want to embrace more modern approaches. ctDNA is strongly prognostic, but whether it is predictive of therapy is another thing. Strategies need to be refined and have a better impact on patients rather than applied broadly."
Mark L. Fuerst is a contributing writer.