Colorectal Cancer Diagnosis Sequence has Surprising Impact on Outcomes

Will a patient with a single cancer pathology fare better than someone who develops multiple primary malignancies? Not always, according to a retrospective analysis of more than half a million people in the United States with primary colorectal cancer (CRC).

“We found an unexpected survival benefit never before reported when we looked at the diagnosis sequence of colorectal cancer,” states lead author Anjelli Wignakumar, MBBS, BSc (Hons), Clinical Research Fellow with the Ellen Leifer Shulman and Steven Shulman Digestive Disease Center at Cleveland Clinic in Florida.

Study methodology

Using the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, Dr. Wignakumar and her colleagues conducted a retrospective, population-based cohort study that included 592,063 adults diagnosed with colorectal adenocarcinoma of any stage between 2000 and 2020. Patients were categorized into three distinct groups based on their cancer history.

• Group A: Patients with CRC as the only primary malignancy throughout their lifetime (71.8%).
• Group B: Patients diagnosed with CRC as the first of two or more primary malignancies (11.9%).
• Group C: Patients with CRC as the second of multiple primary malignancies (16.3%).

“This stratification allowed the team to examine how the sequence of cancer diagnoses and the presence of other primary malignancies influenced patient outcomes,” says Sameh Rizkalla, MBBCh, MSc, MD, FACS, Project Scientist with the Digestive Disease Institute at Cleveland Clinic Weston Hospital.

Unexpected finding

The researchers hypothesized that Group A would do the best because patients required treatment for a single cancer pathology. They found, however, that Group B actually had the best survival outcomes.

Group B had the longest 5-year mean overall survival (OS) and cancer-specific survival (CSS) at 50.4 and 51.3 months, respectively. In comparison, Group A had an OS of 41.8 months and CSS of 42.2 months, while Group C had the worst outcomes with an OS of 39.2 months and CSS of 39.8 months.

“That's a novel finding not yet seen in any other study,” reports Dr. Wignakumar. “With a sample of over half a million patients from across the United States, it demonstrates a very strong conclusion and something that we didn't expect.”

Additional takeaways

The Cleveland Clinic team noted some other findings in their paper published in the Journal of the American College of Surgeons.

1. Group A patients tended to be younger and presented with more advanced disease and liver and lung metastases.
2. Patients in Group B were less likely to present at an advanced stage and more often underwent surgical treatment.
3. Group C had more right-sided tumors, which are linked to more aggressive cancers.

The results were presented as a podium presentation last year at the American College of Surgeons’ Clinical Congress in San Francisco. It also won first prize for surgical poster presentation at Cleveland Clinic Research Week 2024 and among electronic poster presentations at this year’s International Colorectal Disease Symposium hosted by Cleveland Clinic in Florida.

Future research

“The are a number of potential explanations for what we found, from tumor biology and unique surveillance patterns to a patient’s individual immune response to the cancer or treatment,” explains Dr. Wignakumar.

She plans to explore some of these avenues, including the difference between adjuvant therapy or neoadjuvant therapy among these patient groups.

“By looking at treatment response in patients who only developed colorectal cancer and comparing them with patients who developed colorectal cancer as a second cancer, for example, we may be able to identify more beneficial treatment regimens,” she notes.

Dr. Wignakumar hopes the team’s findings will spark further research that will ultimately lead to practice changes and improved outcomes. “At the end of the day, what we're looking for as clinicians and what patients want to know is will there be a difference in how long a patient lives,” she says.

Potential impacts

Colorectal cancer is the second leading cause of cancer death in the United States. More than 150,000 new cases are expected to be diagnosed in 2025, with nearly 53,000 CRC-related deaths, according to latest estimates from the American Cancer Society.

Research has shown that compared to the general population, individuals with a history of colorectal cancer face an increased risk of developing subsequent primary malignancies, especially cancers of the gastrointestinal tract, prostate, lung, breast, and urinary tract.

“We also know that it is common for colorectal cancer to be diagnosed as a second primary malignancy,” says Dr. Wignakumar. “Depending on the sequence of the patient's presentation, they may need to be treated more aggressively or undergo more aggressive surveillance, such as genetic testing.”

Additional research is needed to understand the differences among these patients and how surveillance strategies and treatments can be tailored to improve outcomes, she adds.