Nonsurgical Options for Early Rectal Cancer Continue to Show Promise

Almost 80% of patients with early-stage rectal cancer remained surgery-free for a year or longer after treatment with chemoradiation therapy (CRT), a large randomized study showed.

Among 341 patients who chose not to have upfront surgery (total mesorectal excision, TME), 78.5% of those randomized to CRT remained TME-free at 12 months, as did 60% of the patients randomized to a short course of radiotherapy (RT) alone. Both organ-preserving strategies were associated with low rates of adverse events in the STAR-TREC study.

Though still early, the results support a response-adapted organ-preservation strategy, suggesting better 12-month outcomes with CRT, reported researchers led by Simon Bach, MD, of University College London, in Lancet Oncology.

Organ-preservation strategies for rectal cancer are not new, but most studies to date focused on “opportunistic” organ preservation, involving patients who received CRT as part of routine care for locally advanced disease to reduce the risk of pelvic recurrence after radical surgery, Bach told MedPage Today. In general, the studies showed that as many as 20% of patients had complete resolution of tumors with CRT and might have avoided surgery.

“What is new in STAR-TREC is that we tested organ preservation as a deliberate strategy in patients with early- and intermediate-stage rectal cancer who would normally proceed straight to radical surgery,” said Bach. “In this group, chemoradiotherapy is not required to achieve high levels of local control, so it isn’t part of standard treatment. We found that four out of five patients who received chemoradiotherapy still retained their rectum at 1 year.”

“We also showed that the organ-preservation approach was associated with less serious toxicity than radical surgery, and with improvements in quality of life over the first 12 months,” he added. “This may seem intuitive, but very few studies have actually documented quality of life, which makes the finding important.”

“The key unresolved issue is the need for longer follow-up to be confident the cancers do not return,” said Bach. “We would expect the majority of recurrences to occur within the first 2 years, and our next readout from the trial will be at 36 months.”

Results of STAR-TREC and other studies, including the multicenter randomized TESAR trial published earlier this year, inform decision-making in clinical practice and expand the use of organ-preservation strategies.

In TESAR, limited surgery followed by CRT failed to show noninferiority to upfront TME for locoregional recurrence at 3 years (5% vs 1.1% in 200 randomized patients).

However, four of the five total recurrences in both groups were successfully salvaged, resulting in a 3-year unsalvageable rate of 1.1% with adjuvant CRT and 0% with TME. Moreover, local excision plus CRT substantially reduced treatment-related morbidity and stoma rates.

“These findings challenge [completion] TME as the standard of care for patients with locally excised high-risk pT1 and low-risk pT2 rectal cancer,” the TESAR authors concluded.

Together, the two studies provide much-needed high-level clinical evidence supporting organ preservation in early-stage rectal cancer, according to authors of an invited commentary.

“The new findings of the STAR-TREC and TESAR trials further consolidate the shift in clinical thinking, in which selective organ preservation also in patients with early and intermediate tumors can safely be integrated into routine decision-making alongside radical surgery,” concluded Ralf-Dieter Hofheinz, MD, of the University of Heidelberg Mannheim in Germany, and Emmanouil Fokas, MD, of University Hospital Cologne in Germany.

The influence of organ-preservation studies is reflected in a clinical guideline recently adopted by the European Society for Medical Oncology, which “explicitly suggests distinct treatment algorithms for rectal cancer, based on the intention of treatment,” Hofheinz and Fokas added. “One algorithm centered on planned radical surgery and one dedicated to organ preservation.”

Follow-up continues in STAR-TREC, a multicenter, open-label phase II/III trial conducted in five countries. Eligible patients had early-stage rectal adenocarcinoma (MRI-defined T1-3bN0). Phase II objectives related to feasibility, as patients were randomly assigned to CRT, short-course RT, or TME. During phase III, patients could choose TME or organ preservation, and those who opted for organ preservation were randomized to CRT or RT.

The overall objective was to determine whether CRT or RT could increase organ preservation and reduce surgery, toxicity, and quality-of-life harm without compromising oncologic outcomes.

The primary endpoint of phase III was organ preservation at 30 months, defined as no TME, stoma, or local recurrence. After an interim analysis of the phase II data showed a TME-free survival benefit with CRT (12 vs 7.6 months for RT), the endpoint was changed to a modified intention to treat (ITT) analysis of 12-month outcome data.

Investigators at 37 sites enrolled a total of 503 patients with phase II and III combined. The modified ITT analysis included 426 patients, 120 from phase II and 306 from phase III. Data analysis included 409 evaluable patients: 163 randomized to CRT, 168 to RT, and 78 to primary TME.

Analysis of TME-free survival at 12 months continued to show an advantage for CRT over RT (78.5% vs 60.6%) among those who opted for organ preservation. The difference translated into a hazard ratio of 1.90 (95% CI 1.29-2.81).

The most common serious adverse events were gastrointestinal disorders (2% with CRT, 4% with RT, 8% with TME) and procedural complications (2%, 3%, and 6%). One patient who underwent primary TME died after an anastomotic leak.