Role of Adjuvant Chemoradiation Under Study in Gastric Cancer

Ongoing research is seeking to determine the role of adjuvant chemoradiation in gastric cancer and the patients who stand to benefit the most from this approach among perioperative and adjuvant chemotherapy, which is well established as a standard of care, explained Katelyn M. Atkins, MD, PhD.

Several trials have assessed the use of adjuvant chemoradiation, Atkins said. For example, the phase 3 ARTIST trial (NCT00323830) examined capecitabine/cisplatin vs capecitabine/cisplatin plus concurrent capecitabine radiotherapy in patients with completely resected gastric cancer and D2 lymph node dissection.1 In addition, the ARTIST-2 trial (NCT01761461) evaluated adjuvant chemotherapy and/or chemoradiotherapy following D2 gastrectomy in those with stage II/III gastric cancer,² and the phase 3 CRITICS study (NCT00407186) assessed adjuvant chemotherapy or chemoradiotherapy in those with resectable gastric cancer.³

Although these studies have not yet established a clear role for adjuvant chemoradiation, the research results have provided some insights into which patient subgroups may benefit most from this approach: namely, patients with positive margins after surgery, residual disease, inadequate lymph node sampling, and those who have had less than a D1 resection.

“When thinking about radiation therapy for [patients with] gastric cancer, it is important to have a strong multidisciplinary discussion for each patient,” Atkins said. “We really want to discuss all the important factors and treatment options of those who might be best suited for combination therapies and when there might be a potential role for radiation. This should all be discussed up front [so that] the best treatment strategy [is selected] for each patient.”

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, Atkins, a radiation oncologist at Cedars-Sinai Medical Center, examined the evolving role of radiotherapy in the treatment of patients with gastric cancer, the subgroups who might derive the most benefit from this approach, and ongoing research efforts that are seeking to address remaining questions with this modality.

OncLive^®: What data support the use of adjuvant chemoradiation in gastric cancer?

Atkins: The collective studies looking at adjuvant chemoradiation therapy include the Intergroup 0116 study [NCT02640898], the phase 3 ARTIST and ARTIST-2 trials, and the phase 3 CRITICS study. Each [study] provided a different look into the potential benefits [of this approach] and the population of patients who might benefit from it. In particular, the ARTIST, ARTIST-2, and CRITICS trials failed to show an overall benefit with adjuvant chemoradiation in the overall populations examined. Each of these trials had many nuances and details on what subgroups may be more [suited for treatment]. It was difficult to define a clear role for adjuvant chemoradiation, but some subgroups might particularly benefit from it.

Which patient subgroups stand to derive the most benefit from this approach?

The short answer is that the standard of care for gastric cancer, right now, is perioperative chemotherapy or adjuvant chemotherapy. The role for adjuvant chemoradiation is not clearly defined, but who we might consider it for, after discussing it in a multidisciplinary setting, are patients with [any of the following]: positive margins after surgery, residual disease, inadequate lymph node sampling, [or] less than a D1 resection. These are patients who, [based on data from] some prior trials, might most benefit from a local control [strategy with] radiation after surgery.

What is the role of perioperative chemotherapy in this disease?

Perioperative chemotherapy really hit the stage with the phase 2 MAGIC trial [NCT01160419], which demonstrated a marked survival benefit with perioperative epirubicin, cisplatin, and 5-fluorouracil [5-FU; ECF] chemotherapy. What was really interesting in that trial was [that] you could not truly distinguish the benefit of pre- vs postoperative chemotherapy. [However], we do know that the tolerability of chemotherapy before surgery is much greater than [when it] is given after surgery.

[Although numerous] chemotherapy and systemic therapy trials [have been done], the landmark [trial that] really [established] the standard of care for gastric cancer was the phase 2/3 FLOT4 study [NCT01216644], which was published in Lancet in 2019. [The study] took the winning arm of MAGIC, with ECF or epirubicin, cisplatin, and capecitabine [ECX], and [compared it with] 5-FU, leucovorin, oxaliplatin, and docetaxel [FLOT] chemotherapy. Results [demonstrated] a marked survival benefit with FLOT vs ECF or ECX, with a median survival of 50.0 months in the FLOT group vs 35.0 months in the ECF or ECX group. This really marked a new standard of care for gastric cancer.

Are any recent or ongoing radiation studies generating excitement? What efforts are you waiting to learn more about?

Now that we have FLOT, where do we go from here? Does radiation have a role? How do we incorporate this? What do we think about when we try to [incorporate] those 2 factors? We know that FLOT increased the pathologic complete response [pCR] rate in the FLOT trial, but we do know that might be able to be improved upon [further]. This again raises the question of [where] radiation might come into play. Extrapolating from other disease sites and trials in other spaces is the idea that moving chemoradiation before surgery, where it is more tolerable, might increase pCR rates and the rate of R0 resections, which can be associated with more favorable survival. In this case, the ongoing phase 3 ESOPEC trial [NCT02509286] and the phase 2/3 TOPGEAR trial [NCT01924819] are testing the role of FLOT vs chemotherapy or chemoradiation.

Given that chemotherapy and radiation both have their toxicities, is it concerning that patients who received neoadjuvant treatment may not be as fit for surgery?

The first things [that we know] about toxicity and tolerability come from the existing treatment paradigms, which indicate that treatments after surgery are hard. Completion rates of chemotherapy or chemoradiation after surgery are substantially lower. We are already at a starting point where the baseline is [composed of] very difficult therapies to initiate, complete, and pursue after surgery.

We do know that tolerability is better before surgery, whether it is radiation or chemotherapy, but that does raise another good question: What does that mean for fitness going into surgery? What does it mean for [using] a local treatment before surgery? Are we allowing increased risk for distant metastatic spread if we are not giving full systemic doses of chemotherapy for a number of weeks before surgery? What [would] the recovery and recuperation be from the adverse effects [AEs] of chemoradiation therapy before surgery? Those are all valid [questions], and [we know that] AEs [from] chemoradiation before surgery can be substantial [in certain patients] across disease sites. However, we do give chemotherapy alone and with radiation preoperatively in several diseases in properly selected patients, and with good supportive management, these patients can get through these treatments well.

References

1. Lee J, Lim DH, Kim S, et al. Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. J Clin Oncol. 2012;30(3):268-273. doi:10.1200/JCO.2011.39.1953.
2. Park SH, Zang DY, Han B, et al. ARTIST 2: interim results of a phase III trial involving adjuvant chemotherapy and/or chemoradiotherapy after D2-gastrectomy in stage II/III gastric cancer (GC). J Clin Oncol. 2019;37(suppl 15):4001-4001. doi:10.1200/JCO.2019.37.15_suppl.4001
3. Cats A, Jansen EPM, Grieken NCT, et al. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet. 2018;19(5):616-628. doi:10.1016/S1470-2045(18)30132-3