RFS an inadequate surrogate for OS after resection for colorectal liver metastasis
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RFS is not an adequate surrogate for OS among patients who undergo resection for colorectal liver metastases, according to study results presented at Society of Surgical Oncology 2022 International Conference on Surgical Cancer Care.
Analysis of more than 3,000 patients revealed poor correlation between the two outcomes.
“There are two implications of this research,” Brett L. Ecker, MD, fellow in surgical oncology at Memorial Sloan Kettering Cancer Center, told Healio. “First, if we want to accept RFS as an adequate endpoint on its own merit — even if it doesn’t translate to OS improvements — then we need to better understand how patients understand the risks and benefits of therapy in this context. For instance, would patients pick a therapy with a 15% risk of long term neurotoxicity if it doesn’t translate to more cures? We don’t yet understand how this impacts patient decision-making. Second, I think it accelerates the search for new surrogate endpoints, such as the work on [circulating-free DNA].”
Several clinical trials involving patients with colorectal liver metastasis have used RFS as a surrogate endpoint for OS. However, the correlation between these two outcomes in this clinical context had not been evaluated, according to study background.
“RFS is used as the primary endpoint in all adjuvant trials of resected colorectal liver metastases but it’s not known whether this is a good surrogate for OS,” Ecker said. “We know it’s a good surrogate for patients with nonmetastatic colorectal cancer, but a surrogate endpoint should ideally be evaluated in every context for which it’s used.”
Ecker and colleagues used a single-center, prospectively maintained database to examine 2,983 consecutive patients who underwent complete resection of colorectal liver metastases between 1991 and 2019.
They used the Kaplan-Meier method to estimate RFS and OS probabilities at various timepoints, and they used Spearman’s rank correlation to assess pairwise associations. They also performed simulated randomized trials with homogenous arms to examine within-trial concordance of RFS and OS.
During median follow-up of 8.4 years, researchers identified 1,995 (67%) disease recurrences and 1,684 (56%) deaths.
Results showed median RFS of 1.3 years (95% CI, 1.3-1.4) and median OS of 5.2 years (95% CI, 5-5.5).
The majority of deaths (85%; n = 1,428) were preceded by recurrence, with a median 2 years (range, 0-23) between recurrence and death.
Researchers reported weak to moderate pairwise correlations between RFS and OS, with a correlation estimate ranging from 0.3 to 0.56 and maximized for the pair of 5-year RFS and 7-year OS (0.56; standard deviation, 0.13).
In analyses of simulated randomized trials in which results showed a statistical difference in OS between treatment arms, fewer than one-third (29%) also showed a statistical difference in RFS between treatment arms.
“We suspected that there wouldn’t be a strong correlation, given that there was never a significant difference in OS in previous trials where there was a significant difference in RFS,” Ecker told Healio. “However, we didn’t expect to find that the correlation was so weak.”
The findings highlight the critical need for a different surrogate endpoint, Ecker said.
“I think another surrogate endpoint is crucial to hasten trial completion and improve delivery of new therapeutics for our patients,” he said. “It’s not clear what that surrogate will be just yet.”
Perspective
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H. Richard Alexander Jr., MD, FACS
The abstract by Ecker and colleagues addresses an important question in the field of oncology: whether PFS or RFS can be used as a surrogate for OS.
Reliable surrogates for OS that can be identified earlier in the disease course are important for prognosis and treatment planning. Moreover, surrogates for OS would allow for more accelerated discovery of new therapies through the clinical trials process.
PFS or RFS have been established as a surrogate for OS in some clinical settings. For example, there is a fairly strong correlation between PFS and OS among patients with pancreatic cancer. This is due to the fact that patients who have recurrent pancreatic cancer — like other foregut malignancies — generally experience a rapid clinical course, and available therapeutic options have insufficient efficacy to markedly impact the disease course. In contrast, colorectal cancer has a far more indolent clinical behavior than other gastrointestinal adenocarcinomas, such as gastric, esophageal or pancreatic cancers. Moreover, over the past 20 years, there have been an impressive number of new chemotherapeutic, molecularly targeted, biologic agents — including checkpoint blockade — that have resulted in meaningful extension of life for patients with advanced colorectal cancer.
The abstract by Ecker and colleagues represents an analysis of RFS and OS in a unique subset of patients with metastatic colorectal cancer — those who have oligometastatic cancer confined to one organ that is amenable to surgical resection. The analysis included nearly 3,000 patients identified from an institution that has internationally acknowledged expertise in the management of patients with this condition.
The impressive 4-year difference between RFS and OS is not particularly surprising in this clinical setting. Sites of recurrence after hepatic resection for colorectal cancer include the liver in up to half of patients, as well as the lung and abdomen. For these patients, a number of therapeutic options can be used, including resection, liver-directed therapy for recurrent liver lesions, and systemic treatments.
It is likely that recurrence was diagnosed in this cohort using biomarkers, imaging or a combination of the two. Although RFS was not a surrogate for OS, the study clearly demonstrated that RFS is a very important clinical endpoint. It stands to reason that developing better methods of early diagnosis of recurrent colon cancer — such as the quantification of circulating tumor DNA — may provide a window of opportunity for which second-line therapies may been even more effective.
RWJBarnabas Health
Monmouth Medical Center
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Ecker B, et al. Abstract 42. Presented at: Society of Surgical Oncology 2022: International Conference on Surgical Cancer Care; March 9-12, 2022; Dallas.
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