Left vs. Right: Anatomic Location Matters for Clinical Outcomes in Advanced Colorectal Cancer

Left vs. Right: Anatomic Location Matters for Clinical Outcomes in Advanced Colorectal Cancer

A retrospective analysis of the CALGB/SWOG 80405 (Alliance) study reported that the location of the primary tumor matters in treatment outcomes of both overall survival (OS) and progression-free survival (PFS) in metastatic colorectal cancer (mCRC), and that patients with primary tumors on the right side of the colon were at a significantly 55% higher risk for death compared with patients with primary tumor location on the left side.

Dr. Alan P. Venook
“Sidedness is a surrogate for tumor biology,” said presenter Alan P. Venook, MD, of the University of California, San Francisco (Abstract 3504).

A population-based analysis of more than 200,000 cases of colorectal cancer corroborated these findings with a less pronounced effect—a 25% higher risk for death with right-sided tumors (Abstract 3505).

The results of both studies were presented on June 5.

Dr. Kimmie Ng
“We have known for a while that tumors on the right side are clinically, pathologically, genetically, and molecularly different from those that arise on the left side,” said discussant Kimmie Ng, MD, MPH, of the Dana-Farber Cancer Institute. “There are always concerns about making generalizations based on the rigors of a clinical trial [such as CALBG/SWOG 80405]. The value of [the study described in Abstract 3505] is that it confirms in a real-world population what was seen in a clinical study,” she added.

The CALGB/SWOG 80405 (Alliance) study, first presented at the 2014 ASCO Annual Meeting, reported no significant difference in OS and PFS when patients with KRAS wild-type (KRAS WT) mCRC were treated with bevacizumab or cetuximab, both in combination with leucovorin/fluorouracil/oxaliplatin (FOLFOX) or leucovorin/fluorouracil/irinotecan (FOLFIRI). However, in light of a small series of studies that showed cetuximab did not work when the primary tumor was on the right side of the colon, Alliance investigators reanalyzed their data.

CALGB/SWOG 80405 Reanalysis

The total patient population with KRAS WT mCRC either on the left side (732 patients) or the right side (293 patients) was included in the retrospective analysis; tumors in the transverse colon were excluded. When the primary tumor location was on the left side of the colon, median survival was significantly longer (33.3 vs. 19.4 months for the right-sided tumors; p < 0.0001).

In addition, OS for cetuximab and bevacizumab, each in combination with chemotherapy, were also dependent on the location of the primary tumor. OS with cetuximab was superior to bevacizumab when the primary tumor was on the left side (36.0 vs. 31.4 months for bevacizumab). A similar trend was seen for PFS (12.4 vs. 11.2 months for bevacizumab).

However, bevacizumab was superior to cetuximab when the primary tumor location was on the right side (OS: 24.2 vs. 16.7 months for cetuximab; PFS: 9.6 vs. 7.8 months for cetuximab).

In an exploratory analysis of patients with KRAS-mutant mCRC, location of the primary tumor did not matter. OS was 23.1 months if the primary tumor was on the right side and 30.3 months when it was on the left; this result was not statistically significant.

A retrospective post-hoc analysis of FIRE-3 (presented during the 2014 ASCO Annual Meeting) showed that sidedness is prognostic for PFS and OS, with right-sided tumors having worse outcomes, Dr. Ng noted. “Dr. Venook’s study confirmed the prognostic impact of sidedness within a much larger cohort,” she said. She noted that both studies found sidedness predictive of differential benefit between cetuximab versus bevacizumab within each tumor location.

Population-Based Analysis

An analysis in a population-based cohort also concluded that outcomes were worse when the primary tumor was on the right side of the colon. “The relation between tumor location and survival across the spectrum is uncertain,” said presenter Deborah Schrag, MD, MPH, FASCO, of the Dana-Farber Cancer Institute, setting up an analysis for stage III and IV disease.

Dr. Schrag presented data from 18 tumor registries in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. Incident primary CRC cases were identified for 2000 to 2012. Mortality was followed through the end of 2013. However, the large, representative cohorts lacked chemotherapy and molecular data.

Of all 138,059 right-sided tumors, 28% were identified as stage III disease and 19% as stage IV. Of all 97,311 left-sided tumors, 27% were stage III and 20% were stage IV.

For stage IV disease (70,794 patients), incidence rates were 38%, 28%, and 26%, for right-sided, left-sided, and rectal cancers, respectively. Incidence did not change when examined over 4-year intervals from 2000 to 2012. With median OS of 9.5 months for right-sided tumors and 15.5 months for left-sided tumors, patients with right-sided tumors were at a 25% increased risk for death.

For stage III disease, Dr. Schrag reported similar observations, although the effect was weak and attenuated—risk for death for right-sided tumors was 12%; the effect was not seen for stage II tumors.

Worse prognosis may be explained by “lead time,” as right-sided tumors occur with occult bleeding and late symptoms while left-sided tumors bleed and symptoms start early, she pointed out. “The difference in timing of symptoms detected results in lead time for left-sided tumors that may make survival appear longer,” Dr. Schrag said.

Implications for Clinical Practice

First-line cetuximab and bevacizumab have different treatment effects in subgroups defined by sidedness, Dr. Venook said. “This analysis suggests that patients with primary tumor location on the right side should not be treated with EGFR inhibitors such as cetuximab,” he said. “In addition, bevacizumab in combination with chemotherapy is the treatment of choice for patients with right-side tumors, regardless of KRAS status.”

“Retrospective ad hoc analyses can change practice but each of us has our own threshold for doing so. These results will factor in when making sequence-of-treatment decisions but would not preclude my use of either agent, at least as of today,” he said.

Dr. Ng indicated that it is probably premature to start making treatment decisions based on the conclusions of the CALGB/SWOG 80405 study. However, she did agree that caution should be exercised before considering an EGFR antibody for patients with right-sided cancer and that sidedness should be considered in sequencing decisions after a discussion of the risks and benefits.

Moving Forward

There is good reason to think of the right side as different from the left side of the colon, Dr. Venook explained. He indicated that during embryonic development the right side of the colon originates from the midgut and the left side from the hindgut, with the transverse colon acting as an anatomical bridge between the two.

Dr. Venook believes that the side of the primary tumor is actually a surrogate for biologic variability across the colon. The biology of the tumor may determine why patients with KRAS WT mCRC on the right have worse clinical outcomes than patients with KRAS WT mCRC on the left, he said. Alliance investigators plan to conduct a molecular profiling of the tumors.

Dr. Ng indicated that although the studies confirmed the prognostic association between left- versus right-sided tumors, additional factors may also factor into the explanation—embryonic origins, lead-time bias, and environmental and epidemiologic factors. For example, higher amounts of fusobacteria on the right side may contribute to worse outcomes, she suggested.

She indicated that molecular features associated with the right versus the left side occur gradually—from the distal to the proximal colon and that “tumor location should be viewed as a continuum.”

–Alexander Castellino, PhD