Alliance Trials: Advancing Colorectal Cancer Care & GI Cancer Research – March 2026 Focus

March is Colorectal Cancer Awareness Month, and as we move through 2026, significant research efforts are underway to improve outcomes for those affected by gastrointestinal (GI) cancers. The Alliance for Clinical Trials in Oncology, a network spanning over 115 institutions across the United States and Canada, is at the forefront of these advancements, conducting a wide range of clinical trials designed to address the complex challenges posed by these diseases.

The Burden of GI Cancers and Shifting Trends

Gastrointestinal cancers represent a substantial global health burden, remaining a leading cause of cancer-related illness and death worldwide. Colorectal cancer (CRC) specifically continues to be a major oncologic challenge. The American Cancer Society estimates that in 2026, approximately 158,850 new cases of colorectal cancer will be diagnosed in the U.S., with 55,230 resulting in fatalities. Colorectal cancer remains a significant public health concern.

However, the landscape of colorectal cancer is evolving. While incidence and mortality rates continue to decline among older adults (65 years and older), a concerning trend is emerging: rates are increasing among individuals younger than 65, particularly in cancers located in the distal colon and rectum. Incidence is rising by 3% annually in the 20-49 age group and by 0.4% in those aged 50-64, while decreasing by 2.5% in those 65 and older. This shift underscores the urgent need for improved screening strategies and continued research into the causes of early-onset colorectal cancer. Notably, disparities exist, with the Alaska Native population experiencing the highest incidence and mortality rates globally – more than double those observed among White Americans. The American Indian population also faces a disproportionately high burden of the disease.

Alliance Trials: Addressing Key Challenges

The Alliance’s research portfolio reflects a commitment to tackling these challenges on multiple fronts. Several new trials opened in 2026 are focused on improving not only treatment efficacy but also care delivery, prevention, and the overall patient experience. Here’s a closer look at some key studies:

Improving Family Communication After Genetic Testing (Alliance A212101)

Identifying hereditary cancer risk is crucial, as up to 30% of colorectal cancer cases may have a genetic basis, with around 15% linked to inherited genetic variants. The Alliance A212101 trial (NCT07143487) investigates the most effective way to communicate genetic testing results within families. The study, co-chaired by Heather Hampel of City of Hope and Frank Sinicrope of Mayo Clinic, compares two approaches: patients sharing results directly with relatives (proband-mediated communication) versus healthcare professionals contacting relatives directly (provider-mediated communication). The primary goal is to determine if provider outreach can improve genetic testing rates among at-risk family members and encourage preventative measures for those who test positive for a pathogenic variant. The trial anticipates enrolling 4,186 participants and is expected to be completed by November 2032.

Optimizing Chemotherapy Dosing with the PAGODA Trial (Alliance A232402 CD)

Chemotherapy-induced side effects often lead to treatment delays and dose reductions, potentially impacting effectiveness. The PAGODA trial (NCT07283939), led by Gabriel Brooks of Dartmouth Geisel School of Medicine, evaluates a structured strategy for adjusting chemotherapy doses during FOLFOX treatment (oxaliplatin, folinic acid/leucovorin, and fluorouracil) for GI cancers. The trial compares a proactive, algorithm-guided approach (PAGODA – Proactive Graduated Dose Modification Algorithm) to standard clinician-directed dosing. The primary endpoint is the proportion of chemotherapy cycles with unplanned treatment delays, with secondary endpoints including time to toxicity, incidence of neutropenia, and relative dose intensity. This trial, enrolling 420 participants, aims to provide a standardized framework for managing chemotherapy dosing and minimizing disruptions to treatment.

Exploring Ablative Therapy for Metastatic Disease (ERASur Trial)

The ERASur trial (NCT05673148), led by Eric Miller of The Ohio State University Medical Center, is investigating whether adding total ablative therapy (TAT) – using techniques like stereotactic ablative radiotherapy (SABR) and surgical resection – to standard chemotherapy can improve outcomes for patients with limited metastatic colorectal cancer. The phase 3 trial enrolls patients with up to four metastatic sites (excluding liver-only metastases) and randomizes them to receive either chemotherapy alone or chemotherapy plus TAT. The primary endpoint is overall survival, with secondary endpoints including event-free survival and adverse events. With an estimated enrollment of 364 participants, the study aims to determine if ablating all known metastatic sites can improve outcomes in carefully selected patients.

Intensifying Chemotherapy for Gastroesophageal Adenocarcinoma (Alliance A022102)

For patients with advanced, unresectable, or metastatic HER2-negative esophageal, gastroesophageal junction, or gastric adenocarcinoma, the Alliance A022102 trial (NCT05677490) is evaluating whether modified FOLFIRINOX (mFOLFIRINOX) – a more intensive chemotherapy regimen – improves outcomes compared to modified FOLFOX (mFOLFOX). The trial will also assess the potential benefit of adding nivolumab, an immunotherapy drug, to either regimen. The primary endpoint is overall survival, with secondary endpoints including progression-free survival and objective response rate. This phase 3 study aims to determine if a more aggressive chemotherapy approach, potentially combined with immunotherapy, can improve survival for patients with this challenging cancer.

Addressing Cancer-Associated Anorexia (Alliance A222004)

Cancer-associated anorexia, or loss of appetite, is a common and debilitating complication of advanced malignancies. The Alliance A222004 trial (NCT04939090), led by Aminah Jatoi of Mayo Clinic, is comparing olanzapine (an antipsychotic medication that can stimulate appetite) to megestrol acetate (a commonly used appetite stimulant) in patients experiencing this issue. The primary endpoint is the change in appetite score from baseline to four weeks, with secondary endpoints including weight gain and changes in anorexia/cachexia symptoms.

Supporting Physical Function During Chemotherapy (DEFEND Trial)

The DEFEND trial (NCT07059884), led by Jennifer Ligibel of Dana-Farber Cancer Institute and Kathryn Schmitz of UPMC Hillman Cancer Center, is evaluating whether a structured exercise program delivered via telehealth can aid patients maintain physical function during outpatient cytotoxic chemotherapy. Participants will complete supervised resistance exercise sessions twice weekly and unsupervised aerobic exercise sessions three times per week, using provided equipment and activity trackers. The study aims to determine the feasibility of integrating remotely delivered exercise into cancer care.

Financial Toxicity and Cancer Care (PROOF Trial)

Financial hardship is a significant concern for many cancer patients, impacting treatment adherence and quality of life. The PROOF trial (NCT06963723), led by Victoria Blinder of Memorial Sloan Kettering Cancer Center, is evaluating whether regular digital screening for financial hardship can improve outcomes among adults with advanced or metastatic cancer. Participants will be randomized to either monthly financial screening or enhanced usual care, with the primary endpoint being patient-reported financial worry.

Beyond Treatment: Prevention and Early Detection

The Alliance’s commitment extends beyond treatment to include prevention and early detection. Project REACH (NCT05008848) is a phase III trial evaluating a text-based smoking cessation program for rural cancer survivors, including those with a history of colorectal cancer. Another observational study (Alliance A212102, NCT05334069) is collecting blood samples to support the development of blood-based multicancer early detection tests. The AYA ACCESS study (NCT07091617) is exploring a digital chatbot-enabled genetic service model to improve access to genetic counseling and testing for adolescents and young adults with cancer.

These ongoing and newly launched trials demonstrate the Alliance’s dedication to advancing GI cancer care through comprehensive research. As we continue to learn more about these diseases, and as screening and treatment options evolve, clinical trials will remain essential for improving outcomes and enhancing the lives of patients and their families. For more detailed information, please visit the official Alliance for Clinical Trials in Oncology website.