Treatment of Metastatic Colorectal Cancer: ASCO Guideline

Author(s): Van K. Morris, MD¹;Erin B. Kennedy, MHSc²;Nancy N. Baxter, MD, PhD³;Al B. Benson III, MD⁴;Andrea Cercek, MD⁵;May Cho, MD⁶;Kristen K. Ciombor, MD, MSCI⁷;Chiara Cremolini, MD, PhD⁸;Anjee Davis, MPPA⁹;Dustin A. Deming, MD¹⁰;Marwan G. Fakih, MD¹¹;Sepideh Gholami, MD¹²;Theodore S. Hong, MD¹³;Ishmael Jaiyesimi, DO¹⁴;Kelsey Klute, MD¹⁵;Christopher Lieu, MD¹⁶;Hanna Sanoff, MD, MPH¹⁷;John H. Strickler, MD¹⁸;Sarah White, MD¹⁹;Jason A. Willis, MD, PhD¹;and Cathy Eng, MD⁷

Source: DOI: 10.1200/JCO.22.01690 Journal of Clinical Oncology 41, no. 3 (January 20, 2023) 678-700.

Dr. Anjan Patel's Thoughts

Guideline of the month — ASCO guidance on mCRC. Many interesting points made.

PURPOSE

To develop recommendations for treatment of patients with metastatic colorectal cancer (mCRC).

METHODS

ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice.

RESULTS

Five systematic reviews and 10 randomized controlled trials met the systematic review inclusion criteria.

RECOMMENDATIONS

Doublet chemotherapy should be offered, or triplet therapy may be offered to patients with previously untreated, initially unresectable mCRC, on the basis of included studies of chemotherapy in combination with anti–vascular endothelial growth factor antibodies. In the first-line setting, pembrolizumab is recommended for patients with mCRC and microsatellite instability-high or deficient mismatch repair tumors; chemotherapy and anti–epidermal growth factor receptor therapy is recommended for microsatellite stable or proficient mismatch repair left-sided treatment-naive RAS wild-type mCRC; chemotherapy and anti–vascular endothelial growth factor therapy is recommended for microsatellite stable or proficient mismatch repair RAS wild-type right-sided mCRC. Encorafenib plus cetuximab is recommended for patients with previously treated BRAF V600E–mutant mCRC that has progressed after at least one previous line of therapy. Cytoreductive surgery plus systemic chemotherapy may be recommended for selected patients with colorectal peritoneal metastases; however, the addition of hyperthermic intraperitoneal chemotherapy is not recommended. Stereotactic body radiation therapy may be recommended following systemic therapy for patients with oligometastases of the liver who are not considered candidates for resection. Selective internal radiation therapy is not routinely recommended for patients with unilobar or bilobar metastases of the liver. Perioperative chemotherapy or surgery alone should be offered to patients with mCRC who are candidates for potentially curative resection of liver metastases. Multidisciplinary team management and shared decision making are recommended. Qualifying statements with further details related to implementation of guideline recommendations are also included.

Author Affiliations

¹University of Texas MD Anderson Cancer Center, Houston, TX; ²American Society of Clinical Oncology, Alexandria, VA; ³Melbourne School of Population and Public Health, Melbourne, Australia; ⁴Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; ⁵Memorial Sloan Kettering Cancer Center, New York, NY; ⁶UCI Health, Irvine, CA; ⁷Vanderbilt Ingram Cancer Center, Nashville, TN; ⁸University of Pisa, Pisa, Italy; ⁹Fight Colorectal Cancer, Springfield, MO; ¹⁰University of Wisconsin Carbone Cancer Center, Madison, WI; ¹¹City of Hope Helford Clinical Research Hospital, Duarte, CA; ¹²UC Davis Health, Davis, CA; ¹³Massachusetts General Hospital, Boston, MA; ¹⁴Beaumont Hospital, Royal Oak, MI; ¹⁵University of Nebraska, Omaha, NE; ¹⁶CU Medicine, Denver, CO; ¹⁷University of North Carolina, Chapel Hill, NC; ¹⁸University Medical Center, Durham, NC; ¹⁹Medical College of Wisconsin, Milwaukee, WI

Trastuzumab Rezetecan in Human Epidermal Growth Factor Receptor 2–Expressing Advanced Gastric Cancer or Gastroesophageal Junction Adenocarcinoma and Colorectal Cancer: A Multicenter, Open-Label, Phase I Trial

Encouraging phase I signal for this HER2-targeted Antibody-drug conjugate (ADC) in heavily pretreated GI cancers, 45% overall response rate (ORR) and 16.3mo median overall survival (OS) in HER2-positive gastric compares favorably with T-DXd benchmarks, and the 40.5% objective response rate (ORR) with 22.7mo OS in HER2-positive colorectal cancer (CRC) is notable. The 2% ILD rate looks meaningfully better than T-DXd’s reported range, which could be a real differentiator. Hematologic toxicity is substantial but manageable. Small China-only phase I, but worth watching closely as this advances.

Postoperative Hepatic Arterial Infusion With Oxaliplatin After Surgery of Four or More Colorectal Liver Metastases: A Randomized Phase II Trial

For high-risk patients with four or more colorectal liver metastases, adjuvant hepatic arterial infusion oxaliplatin roughly doubled hepatic recurrence-free survival versus standard IV chemotherapy (25 vs. 12 months), with recurrence-free survival (RFS) benefit as well. Overall survival (OS) didn't reach significance but the absolute difference and 5-year OS of 62% versus 47% suggest a real effect worth confirming in phase III. Toxicity was higher in the hepatic arterial infusion (HAI) arm but manageable with no treatment-related deaths. Generalizability remains the challenge, these needs specialized centers with HAI expertise, but worth keeping in mind for your highest-risk resected liver met patients.

Randomized Phase II/III Trial Comparing Hepatectomy, Followed by mFOLFOX6 With Hepatectomy Alone for Liver Metastasis From Colorectal Cancer: Long-Term Results of JCOG0603

The mature overall survival (OS) data from this Japanese randomized trial answer the question the initial publication left open, and the answer is no, adjuvant mFOLFOX6 after hepatectomy for resectable colorectal liver metastases does not improve overall survival (HR 1.07, P=.74), despite the previously reported DFS benefit. Five-year OS was numerically worse in the chemotherapy arm (73% vs 80%), though not significantly so. The disease-free survival (DFS) benefit was likely confounded by oxaliplatin-induced hepatic changes obscuring imaging and imbalances in post-recurrence therapy. Selection of patients and those with curable vs incurable intent surgery may have led to some bias in my opinion.

Tumor Debulking in Combination With Chemotherapy in Multiorgan Metastatic Colorectal Cancer: The ORCHESTRA Randomized Clinical Trial

Open-label, phase 3 clinical trial, 382 patients were randomized to receive chemotherapy alone or chemotherapy plus tumor debulking. The overall survival rates were not statistically different, with a median overall survival in the chemotherapy alone group of 27.5 m vs 30.0 m in the chemotherapy plus tumor debulking group hence tumor debulking added to palliative systemic chemotherapy did not result in significantly improved survival compared with chemotherapy alone in patients with multiorgan metastatic colorectal cancer.

Atezolizumab plus FOLFOX for Stage III Mismatch Repair–Deficient Colon Cancer

This is a strong adjuvant signal in resected stage III dMMR colon cancer, adding atezolizumab to mFOLFOX6 cut the risk of recurrence or death in half and improved 3-year DFS from 76% to 86%. OS hasn’t separated yet, but that may be confounded by immunotherapy at relapse. Toxicity was higher, as expected, with more grade 3–4 events and immune-related adverse events (AE)s, but overall manageable. This feels practice changing for stage III dMMR disease.