Higher 60-day mortality with primary tumor resection plus systemic Tx versus systemic Tx alone

Compared with systemic treatment alone, primary tumor resection (PTR) followed by systemic treatment carried a higher incidence of 60-day mortality in patients with metastatic colorectal cancer (mCRC) who had primary tumors with symptoms that were either minimal or not present at all.

According to the recent CAIRO4 study from the Danish and Dutch Colorectal Cancer Group, postoperative mortality was also significantly higher in patients treated with PTR who had elevated serum levels of lactate dehydrogenase, neutrophils, aspartate aminotransferase, and/or alanine aminotransferase.

Results are published in JAMA Surgery.

“A majority of patients (55%-71%) with synchronous metastatic colorectal cancer (mCRC) have few or no symptoms from the primary tumor. Although primary tumor resection (PTR) is indicated in case of bleeding, obstruction, and perforation, the need for PTR in patients with an asymptomatic primary tumor remains unclear. The National Comprehensive Cancer Network advises against performing PTR in patients with colorectal cancer (CRC) without symptoms of the primary tumor and synchronous unresectable metastases but emphasizes that data from randomized clinical trials (RCTs) are needed,” explained Dave E.W. van der Kruijssen, MD, of University Medical Center Utrecht, Utrecht University, the Netherlands, and colleagues.

For this randomized, multicenter, phase III study, van der Kruijssen and colleagues randomized 196 patients (median age: 65 years; 57% male) with mCRC to systemic treatment alone or primary tumor resection (PTR) followed by systemic treatment, which was comprised of fluoropyrimidine-based chemotherapy with bevacizumab.

Inclusion criteria included histologically verified colorectal cancer, unresectable metastases, and a primary tumor with few or absent symptoms. The goal was to assess 60-day mortality differences between the two groups, as well as the risk factors associated with that 60-day mortality.

In the intention-to-treat analysis, 60-day mortality was significantly lower in patients treated with systemic treatment only, compared with those treated with PTR plus systemic treatment (3% versus 11%, respectively; P=0.03). Upon per-protocol analysis, these incidences were only slightly different, at 2% versus 10%, respectively (P=0.048).

Patient characteristics associated with significantly higher 60-day mortality included elevated serum levels of the following:

  • Lactate dehydrogenase: elevated in 58 patients, of whom 10 died (17%; 95% CI: 10%-29%; P=0.46).
  • Aspartate aminotransferase: elevated in 41 patients, 9 of whom died (22%; 95% CI: 12%-37%; P<0.001).
  • Alanine aminotransferase: elevated in 23 patients, 7 of whom died (30%; 95% CI: 16%-51%; P=0.002).
  • Neutrophils: elevated in 15 patients, 4 of whom died (27%; 95% CI: 11%-52%; P=0.04).

“Of 39 patients in the PTR arm with 2 or 3 of the aforementioned biochemical (LDH, aspartate aminotransferase, alanine aminotransferase, neutrophils) and/or patient characteristics (right-sided tumor), 5 patients (13%; 95% CI, 6%-27%) died within 60 days. There were 14 patients with 4 or 5 characteristics, and 6 patients (43%; 95% CI, 21%-67%) died within 60 days. None of the 44 patients with 1 characteristic or no unfavorable characteristics died within 60 days,” noted researchers.

Adverse events at 60 days were similar, with grade 3 and 4 adverse events seen in 30% of patients treated with systemic treatment versus 23% in those treated with PTR (P=0.25). In patients treated with systemic treatment only, the most common adverse events included diarrhea (9%) and pain (8%); while in PTR-treated patients, infections (6%), pain (4%), and wound infections (3%) were most common. In the systemic treatment arm, only one grade 4 adverse events occurred, caused by neutropenia, compared with three in the PTR arm, including acute kidney insufficiency, a thromboembolic event, and postoperative hemorrhage.

Hospitalization occurred in 19% of patients treated with systemic therapy alone, compared with 97% of those treated with PTR and systemic therapy. Treatment for toxicity was required in 39% of patients in the systemic therapy arm, while 33% had symptoms requiring surgical intervention. Surgery was the most common reason for hospitalization (98%), followed by postoperative complications (9%). Median hospitalization was 0 days in the systemic treatment arm, compared with 6 days in PTR patients (P˂0.001).

“The favorable outcome of systemic therapy alone is because of the effective oxaliplatin-based chemotherapy and irinotecan-based chemotherapy regimens available for CRC treatment. FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin) chemotherapy or FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) chemotherapy plus bevacizumab results in an approximately 50% tumor response rate with another 30% chance of stable disease. The use of FOLFOX-based chemotherapy can render nonresectable metastatic disease resectable in 10% to 20% of patients. In many of these patients, the primary tumor becomes clinically imperceptible and may be a complete pathologic response in 15% to 40% of cases,” wrote Yuman Fong, MD, of the City of Hope Medical Center, Duarte, California, in an accompanying editorial.

“These data support systemic therapy with oxaliplatin-based chemotherapy as standard for asymptomatic CRCs in the setting of nonresectable metastases and encourage re-evaluation of patients after 2 to 4 chemotherapy cycles to determine if the metastatic disease has been converted to resectable. Less surgery up front may result in more effective surgery later with a possible curative outcome,” Fong concluded.

Study limitations include the limited sample size and number of events, failure of some patients to undergo allocated treatments, and the larger number of men in the PTR arm.

  1. In patients with metastatic colorectal cancer (mCRC), treatment with primary tumor resection (PTR) followed by systemic treatment brought about a higher 60-day mortality compared with systemic treatment alone.

  2. Postoperative mortality was significantly higher in patients treated with PTR who had elevated serum levels of lactate dehydrogenase, neutrophils, aspartate aminotransferase, and/or alanine aminotransferase.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

This work was funded by the Dutch Cancer Society and Hoffmann-La Roche Ltd.

van der Kruijssen reported a grant from Dutch Cancer Society and an unrestricted grant from Hoffmann-La Roche Ltd during the conduct of the study.

Fong is a consultant for Medtronic and Johnson & Johnson.

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Topic ID: 78,23,730,16,188,23,935,192,925,159

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