Why this matters
Total neoadjuvant therapy for locally advanced rectal cancer continues to evolve, with different combinations of radiotherapy and systemic therapy being tested to improve tumor response while maintaining acceptable toxicity.
Liposomal irinotecan provides an alternative way of delivering irinotecan and may potentially increase tumor exposure while modifying the toxicity profile.
The phase II LipCap study tested a TNT regimen incorporating liposomal irinotecan with capecitabine during long-course chemoradiotherapy, followed by additional consolidation chemotherapy using the same systemic combination.
The early result shows a moderate pathological response rate with relatively limited grade 3-4 toxicity, but the absence of a control arm makes comparisons with established TNT regimens difficult.
Study design
LipCap was a prospective phase II trial enrolling patients with locally advanced rectal cancer defined as cT3-4NanyM0 disease.
Treatment began with long-course chemoradiotherapy:
- 50.4 Gy in 28 fractions
- concurrent capecitabine
- concurrent liposomal irinotecan
After chemoradiotherapy, patients received:
- 4-6 cycles of consolidation liposomal irinotecan plus capecitabine
The primary endpoint was pathological complete response.
Secondary endpoints included:
- major pathological response
- clinical complete response
- treatment-related adverse events
- 3-year progression-free survival
- 3-year overall survival
A total of 60 patients were enrolled between February 2024 and March 2025.
All 60 initiated long-course chemoradiotherapy.
Fifty-seven proceeded to consolidation chemotherapy.
Forty-seven ultimately underwent surgical resection.
Key results
All 47 patients undergoing surgery achieved an R0 resection.
Among these surgically treated patients, pathological complete response was observed in:
- 10 of 47 patients
- 21.3%
Major pathological response, defined as TRG 0-1, occurred in:
- 23 of 47 patients
- 48.9%
Among the 10 patients who did not undergo surgery, 3 achieved a clinical complete response.
Across the full study cohort, the overall complete response rate combining pathological and clinical complete response was:
- 13 of 60 patients
- 21.7%
Toxicity
Grade 3-4 adverse events occurred in:
- 16.7% of patients
The most common severe adverse events were:
- diarrhea: 10.0%
- leukopenia: 5.0%
The reported toxicity profile therefore appears manageable within this single-arm experience.
However, without a contemporary comparator, it is not possible to conclude that liposomal irinotecan is less toxic than other TNT regimens.
Interpretation
The main contribution of LipCap is feasibility.
The investigators were able to integrate liposomal irinotecan with capecitabine during long-course chemoradiotherapy and continue the same systemic backbone during consolidation chemotherapy.
The regimen produced a pathological complete response rate of 21.3% among patients undergoing surgery and an overall complete response rate of 21.7% in the entire enrolled cohort.
Those results demonstrate activity, but they are not obviously superior to the response rates already achievable with established TNT strategies.
This distinction matters.
Without randomization or an internal control group, comparisons with trials such as RAPIDO, PRODIGE 23, OPRA, or contemporary immunotherapy-based TNT approaches would be indirect and potentially misleading.
The toxicity profile may ultimately prove to be one of the more interesting aspects of the regimen. Grade 3-4 adverse events occurred in 16.7% of patients, with diarrhea as the most common severe toxicity.
But again, the study does not establish that this regimen is safer than standard TNT.
The current results therefore support further evaluation rather than a change in treatment strategy.
Limitations
This was a single-arm phase II trial.
Only 60 patients were enrolled.
The pathological complete response analysis included only 47 patients who proceeded to surgery.
Three additional complete responses were clinical rather than pathological.
There was no randomized or contemporaneous control group.
Progression-free survival and overall survival are not yet mature.
The study therefore cannot determine whether the novel systemic regimen improves long-term disease control over established TNT approaches.