Tumor Rupture Linked to Poorer GI Stromal Tumor Survival

According to a newly published trial looking at whether the quality of surgery affects overall survival in patients with localized gastrointestinal stromal tumors (GIST), tumor rupture was found to be strongly associated with poorer survival, while positive tumor margin was not, leading the researchers to conclude that microscopic margin status “should not be factored into decision-making” regarding adjuvant therapy.

The post hoc analysis of data from a large randomized trial of adjuvant treatment with the tyrosine kinase inhibitor (TKI) in patients with gastrointestinal stromal tumors (GISTs) was conducted to address whether quality of surgery affects overall survival.

“While (tumor rupture) significantly affects prognosis and should be factored into the therapeutic decision-making (R1 resection) without tumor rupture seems not, but it should still be avoided whenever possible because long-term effects on outcome cannot be ruled out at least in a proportion of patients,” wrote researcher Alessandro Gronchi, MD, of Milan, Italy’s Instituto Nazionale dei Tumori, and colleagues in JAMA Surgery.

They added that “a multimodal approach, which includes more liberal use of preoperative imatinib, is generally recommended whenever a positive margin over the organ of origin can be anticipated on a preoperative assessment.”

The researchers wrote that while surgery is the primary therapy for localized GISTs, and complete resection with negative margins (R0) is the goal, “the ultimate significance of a positive microscopic margins resection (R1) for GIST is controversial.”

While several prior studies have identified R1 as an indicator or poorer outcomes in patients with GISTs, others have not shown microscopic margin status to play a role in relapse-free survival or overall survival.

The post hoc observational study included patients participating in a multicenter, international, open-label phase III trial performed between December of 2004 and October of 2008.

The trial, performed at 112 hospitals in 12 countries, was conducted to evaluate the efficacy of adjuvant treatment with imatinib in patients undergoing surgery for localized GISTs.

The study included 908 patients (51% were men, median age, 59 years), with 454 randomized to the adjuvant imatinib arm and 454 randomized to the control arm. The majority of patients (55.5%) had gastric tumors and 31.7% had small bowel tumors.

Median follow-up was 9.1 years (IQR, 8-10 years). A total of 743 patients had R0 surgical margins and 162 patients (17.8%) had an R1 resection, with 97 of these patients (59.9%) experiencing a tumor rupture.

Patients were randomized after surgery to either receive imatinib (400 mg/d) for 2 years or no adjuvant treatment. Randomization was stratified by center, risk category (high vs intermediate), tumor site (gastric vs other), and quality of surgery (R0 vs R1).

Five-year overall survival rates were 93.9% (95% CI, 91.8-95.4) for patients with R0 resection vs 84.4% (95% CI, 77.7-89.3) for patients with R1 resection; while 10-year overall survival rates were 82.6% (95% CI, 79.2-85.5) and 64.4% (95% CI, 55.1-72.3), respectively.

Significant differences in overall survival and relapse-free survival were seen between R1 and R0 resection patients overall (HR, 2.05 for R0, 95% CI, 1.45-2.89) and by treatment arm (HR, 2.65 95% CI, 1.37-3.75 with adjuvant imatinib and HR, 1.86, 95% CI, 1.16-2.99 without adjuvant imatinib, but these differences were not seen when patients with tumor rupture were excluded (HR, 1.05; 95% CI, 0.54-2.01).

A major study limitation cited by the researchers was the lack of information on the number of surgeons performing the procedures and the median number of operations per surgeon.

Given that the study was performed at more than 100 sites and surgery protocols were not standardized, the researchers noted that they “cannot exclude the presence of institution-level and/or surgeon level differences that might have influenced, at least in part, our results.”

Despite this limitation, they concluded that their analysis confirms that status of microscopic surgical margins was not associated with either overall survival or relapse-free survival.

They also wrote that in future studies of localized GIST and inpatient management, tumor rupture should be distinguished from microscopic positive surgical margins, “because their associations with outcomes were shown to be clearly different.”

In an accompanying editorial, Martin Almquist, MD, and Erik Nordenstrom, MD, of Skane university Hospital, Lund, Sweden, wrote that the study findings, along with those from a 2019 study examining the prognostic value of rupture before or during GIST surgery “challenge the common surgical wisdom that free surgical margins in oncological surgery are vital for patient outcomes.”

Given that just 12.8% of patients in the analysis had GIST located outside the stomach or small bowels, the editorial writers noted that the study results may not be generalizable to patients with GIST in other locations.

“As the authors note, rectal GIST might need to be resected with microscopic free margins; the study by Gronchi et al. did not achieve enough power to prove this in the specific subgroup,” they wrote.

1. Among patients undergoing surgical resection of localized gastrointestinal stromal tumors (GIST), tumor rupture was associated with an increased risk of death, independent of imatinib use. Microscopic tumor margin status was not associated with a higher risk of recurrence or death.

2. Be aware that in this study the analysis had GIST located outside the stomach or small bowels and as the editorialists suggest, the study results may not be generalizable to patients with GIST in other locations.

Salynn Boyles, Contributing Writer, BreakingMED™

Cat ID: 188

Topic ID: 77,188,730,188,116,120,192,925