Preoperative Radiotherapy Plus Perioperative Chemo Improves pCR Rate but Not Survival in Resectable Gastric/GEJ Cancer

Trevor Leong, MBBS, MD, FRANZCR

The addition of preoperative radiotherapy to perioperative chemotherapy significantly improved pathological complete response (pCR) rates in patients with resectable gastric or gastroesophageal junction (GEJ) cancer but did not translate to a progression-free survival (PFS) or overall survival (OS) benefit, according to data from the phase 3 TOPGEAR trial (NCT01924819).

Findings presented at the 2024 ESMO Congress showed that patients treated with preoperative radiotherapy plus perioperative chemotherapy (n = 286) achieved a pCR rate of 16.8% vs 8.0% for those given perioperative chemotherapy alone (n = 288; P < .0001).

However, the median PFS was 31.4 months in the radiotherapy arm vs 31.8 months in the chemotherapy alone arm (HR, 0.98; 95% CI, 0.79-1.22; P = .86). The median OS was 46.4 months vs 49.4 months, respectively (HR, 1.05; 95% CI, 0.83-1.31; P = .70).

In an interview with OncLive®, lead study author Trevor Leong, MBBS, MD, FRANZCR, detailed the rationale for exploring the addition of preoperative radiotherapy to perioperative chemotherapy in patients with resectable gastric/GEJ cancer, expanded on the findings from the study, and explained the clinical implications of this research.

Leong is a consultant radiation oncologist at the Peter MacCallum Cancer Centre in Melbourne, Australia.

OncLive: What was the design and rationale behind the TOPGEAR trial?

Leong: This was a large, global, randomized, phase 3 trial that tested different treatments for patients with resectable gastric cancer. The optimal treatment for patients with resectable gastric cancer is currently unknown. At the moment, the standard of care [SOC] is perioperative chemotherapy, which is chemotherapy given before and after surgery.

There is some early evidence that shows that radiation added after surgery also improves survival, but that's been a bit uncertain. What [this] trial did was to test the role of radiation preoperatively, where we know it works better and is much better tolerated. This trial basically compared SOC perioperative chemotherapy [vs] perioperative chemotherapy with the addition of preoperative radiotherapy. [This was a] large trial that recruited [547] patients across 15 countries and 3 continents.

What were key efficacy findings reported from this trial?

The aim of this trial was to firstly see whether the addition of radiotherapy improved the pathological outcomes in terms of tumor shrinkage at the time of surgery, [evaluate] the number of patients who had a pCR, and [determine] whether [achieving a pCR] translated to improved outcomes in terms of survival. We finished recruitment in 2021, and patients have now been followed up.

The essential findings of the trial are that [the addition of] radiotherapy significantly improved the pathological outcomes and tumor downstaging. The pCR rate in the chemotherapy group was 8.0% [compared with 16.8%] with the addition of radiotherapy. That was very encouraging.

However, with more than 5 years of follow-up, [the addition of radiotherapy] did not translate into an improvement in OS or PFS.

What are the clinical implications of these results?

These results were highly anticipated. There's been a burning question in the management of gastric/GEJ cancer as to the best treatment. Is it chemotherapy alone, or is it chemotherapy plus radiotherapy in addition to surgery? [Data from prior] trials have been conflicting, and there haven't been a lot of [comprehensive] trials to answer this question.

Our study does provide a definitive answer to that question. It showed that in patients with resectable gastric/GEJ cancer, the addition of radiotherapy does not improve [survival] outcomes. Therefore, we should probably stick with chemotherapy alone. At the same time, the additional radiotherapy did not cause any added toxicity—it was the same in both arms. [The addition of radiotherapy] didn't make surgery more difficult.

[The fact that] radiation did provide improved pCR rates with complete disappearance of cancer is encouraging, and it may lead to future studies. For example, we [could] look at an organ-preservation approach without any surgery. In that sort of approach, we'd be looking at treatments that would enhance our pCR rate, and with the addition of radiation, we can do that.

[These results are] probably a little bit disappointing for radiation oncologists. The trial will be practice changing because there are centers in the world, particularly in the United States, that use perioperative radiation is a SOC for [resectable] gastric cancer. As I mentioned, for GEJ cancers, one of the standard treatments is preoperative chemotherapy and radiotherapy. This trial will also influence how [gastric and GEJ cancers] are managed.

Reference

Leong T, Smithers BM, Michael M, et al. A randomized phase III trial of perioperative chemotherapy (periop CT) with or without preoperative chemoradiotherapy (preop CRT) for resectable gastric cancer (AGITG TOPGEAR): Final results from an intergroup trial of AGITG, TROG, EORTC and CCTG. Ann Oncol. 2024;35(suppl 2):S1249. doi:10.1016/j.annonc.2024.08.2300