Doctors Debate: Should Perioperative Treatment of GEJ/Gastric Cancer Include Radiotherapy?

Mehmet Akce, MD

Perioperative treatment approaches for gastric and gastroesophageal junction (GEJ) cancers are key topics of discussion in oncology. Chemotherapy, chemoradiotherapy (CRT), and targeted therapies are all available as treatments for these diseases, and the main subject of contention is the best sequence to optimize response to therapy while limiting toxicity.

Pretesh Patel, MD

A debate at the 2020 Debates and Didactics in Hematology and Oncology (DDHO) Conference, hosted by the Winship Cancer Institute of Emory University, Atlanta, Georgia, featured 2 members of the Emory University School of Medicine faculty. Mehmet Akce, MD, assistant professor in the Department of Hematology and Medical Oncology and Pretesh Patel, MD, assistant professor and residency program director in the Department of Radiation Oncology, argued their positions on whether perioperative therapy for GEJ/gastric cancers should include radiation.

Akce’s stance was against the use of radiation before surgery, whereas Patel argued that there is validity in administering radiotherapy in this setting.^1,2

Perioperative Therapy for GEJ and Gastric Cancer Should Not Include Radiotherapy

Multimodality treatment has become standard of care for GEJ and gastric cancers, and Akce considers perioperative chemotherapy to be the leading treatment option, based on data from 3 important clinical trials. First, Akce presented data from the MAGIC study.

Data Supporting Perioperative Chemotherapy in GEJ/Gastric Cancers

In the prospective MAGIC trial (ISRCTN93793971), perioperative chemotherapy was compared with surgery alone. Patients with locally advanced resectable gastroesophageal cancer were randomized to either the perioperative chemotherapy arm (n = 250) or the surgery arm (n = 253). Chemotherapy, which was given for 3 cycles preoperatively and 3 cycles postoperatively, consisted of intravenous epirubicin (50 mg/m2) on day 1, cisplatin (60 mg/m2) on day 1, and continuous infusion of intravenous fluorouracil (200 mg/m2/day, [ECF]) for 21 days. The primary end point of the study was overall survival (OS). Secondary end points were progression-free survival (PFS), surgical and pathological assessments of downstaging, the surgeons’ assessments of whether the surgery was curative, and quality of life.³ The primary tumor location was gastric in 74% of patients, GEJ in 11%, and distal esophagus in 14%.

In the perioperative chemotherapy arm, 215 of 237 patients who started treatment completed all 3 cycles of preoperative chemotherapy. A large majority of all randomized patients ultimately underwent surgery: 229 patients (91.6%) in the perioperative chemotherapy arm and 244 patients (96.4%) in the surgery arm. A D2 total resection was performed for 29% of all patients in the study.

The 5-year survival rate was 36% in the perioperative chemotherapy arm versus 23% in the surgery arm. The study investigators determined that the perioperative chemotherapy arm had significantly better OS (HR, 0.75; 95% CI, 0.60-0.93; P = .009) and PFS (HR, 0.66; 95% CI, 0.53-0.81; P < .001) compared with the surgery arm.

After the MAGIC study, the ability of perioperative chemotherapy to improve the curative resection rate, disease-free survival (DFS), and OS in patients with resectable adenocarcinoma of the lower esophagus, GEJ, or stomach was evaluated in a phase 3 trial conducted by the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) and the Fédération Francophone de Cancérologie Digestive (FFCD) Collaborative Groups in France (NCT00002883). This open-label study randomized 224 patients to undergo both surgical resection and perioperative chemotherapy (n = 113) or surgery alone (n = 111). The chemotherapy regimen was given for 2 or 3 cycles preoperatively and 3 or 4 cycles postoperatively and comprised cisplatin (100 mg/m2) on day 1 and a continuous infusion of intravenous fluorouracil (800 mg/m2/day) for 5 days every 28 days.⁴ The primary tumor site was GEJ in 64% of patients, gastric in 25%, and lower esophagus in 11%. Overall, 109 (96.5%) patients who received perioperative chemotherapy underwent surgery, as did 110 (99.0%) of those in the surgery arm. The margin-negative (R0) resection rate was 87% in the perioperative chemotherapy arm versus 74% in the surgery arm. The curative resection rate was significantly improved with perioperative chemotherapy, at 84% compared with 73% in the surgery arm (P= .04).

Investigators reported that the 5-year OS rate was better with perioperative chemotherapy (38%) compared with the 24% observed with surgery alone (HR, 0.69; 95% CI, 0.50-0.95; P = .02). The 5-year DFS rate was also improved with perioperative chemotherapy, at 34% versus 19% with surgery alone (HR, 0.65; 95% CI, 0.48-0.89; P = .003).

Both the MAGIC and FNCLCC/FFCD trials significantly improved survival with the perioperative chemotherapy approach.

The final study highlighted to support Akce’s stance in favor of perioperative chemotherapy without radiation was the phase 2/3 FLOT4 trial (NCT01216644).

“My position on this is based on the best available data from the FLOT4 trial. I support the utilization of perioperative chemotherapy in GEJ and gastric adenocarcinoma,” Akce told Targeted Oncology in an interview.

This randomized, multicenter study compared the use of 4 preoperative and 4 postoperative 2-week cycles of fluorouracil (2600 mg/m2 24-hour infusion), leucovorin (200 mg/m2), oxaliplatin (85 mg/m2), and docetaxel (50 mg/m2), all given on day 1 (FLOT), versus 3 preoperative and 3 postoperative 3-week cycles of epirubicin (50 mg/m2) on day 1, cisplatin (60 mg/m2) on day 1, and either fluorouracil (200 mg/m2/day continuous infusion [ECF]) or capecitabine (1250 mg/m2 orally [ECX])on days 1 to 21 as treatment for patients with locally advanced resectable adenocarcinoma of the GEJ or stomach.⁵

Of the 716 patients enrolled in FLOT4, 360 were assigned to ECF/ECX and 356 were given the FLOT regimen. The primary end point was OS in the intention-to-treat population. The primary tumor location was gastric in 44% of patients and GEJ in 56%. More than 90% of patients in both arms completed all cycles of preoperative chemotherapy. In the FLOT arm, 97% of patients proceeded with surgery; 95% proceeded with surgery in the ECF/ECX arm. The R0 resection rate was 85% in the FLOT arm versus 78% in the ECF/ECX arm (P = .016).

The median OS in the ECF/ECX arm was 35 months (95% CI, 27.35-46.26) versus 50 months in the FLOT arm (95% CI, 38.33-not reached). The HR for the difference between the 2 arms was 0.77 (95% CI, 0.63-0.94; P = .012). The ECF/ECX arm had a median DFS of 18 months compared with 30 months in the FLOT arm (HR, 0.75; 95% CI, 0.62-0.91; P = .0036).

“There could still be a role for using neoadjuvant chemoradiation in GEJ adenocarcinoma based on the CROSS trial.In order to better answer the question for GEJ adenocarcinoma, we need to wait for the results of the ESOPEC trial [NCT02509286], which compares [the] CROSS trial regimen with [the] FLOT trial regimen in locally advanced GEJ and distal esophageal adenocarcinoma.6 Once the ESOPEC trial answers the question, oncologists can have better discussions about how to treat GEJ cancer. So far, the evidence from the FLOT4 trial supports the perioperative chemotherapy approach for GEJ and gastric cancers,” Akce stated during the interview.

Notably, in a separate interview with Targeted Oncology, Patel agreed that there is a role for chemotherapy in the perioperative setting for GEJ and gastric cancers, but that is where the agreements between the physicians end.

“Both neoadjuvant chemoradiation and perioperative FLOT chemotherapy are active regimens for locally advanced gastroesophageal cancer. Accurate identification of the epicenter of the tumor and Siewert classification is recommended in all cases,” Patel noted.

Akce’s main reason for exclusion of radiation from perioperative GEJ/gastric cancer treatment is that the bulk of the randomized trials did not include patients with gastric cancer and/or had a limited number of patients with GEJ cancer. Additionally, Akce noted in his presentation that in the CROSS and MAGIC trials, the experimental arm was compared with surgery only, in contrast to the FLOT4 trial, which demonstrated superiority of the FLOT regimen to the MAGIC trial’s ECF regimen.

Chemotherapy Should Be Combined With Radiation in Perioperative GEJ/Gastric Cancer Therapy

Patel began his presentation with data from the CROSS trial. In an interview, Patel explained why this trial’s findings provide the best support for his argument that neoadjuvant chemoradiation is superior to perioperative chemotherapy for gastroesophageal cancer treatment.

“The CROSS trial [was] a phase 3 randomized trial comparing neoadjuvant chemoradiation followed by surgery [versus] surgery alone for locally advanced esophageal and gastroesophageal [junction] cancer. With a median follow-up of 84 months, this trial showed a median overall survival of 48.⁶ months versus 24.0 months favoring the chemoradiation arm (HR, 0.68; 95% CI, 0.53-0.88; P = .003). Chemoradiation improved R0 resection compared [with] surgery alone. In addition, after chemoradiation, pN0 [no regional lymph node metastasis] was 69% versus 26% with surgery alone, and pathologic complete response was [seen in] 29% of patients [in the chemoradiation arm]. Chemoradiation was not associated with an increase in toxicity or surgical morbidity and mortality,” he stated.

CROSS enrolled 368 patients. Sixteen patients in the study died due to treatment-related causes. Nine of the patients who died had received neoadjuvant CRT. Another 23 patients in the study died due to reasons unrelated to disease; of these patients, 13 were from the neoadjuvant CRT arm and 10 were from the surgery-only arm.

The overall conclusion of the CROSS investigators, led by P. van Hagen, was that neoadjuvant CRT followed by surgical resection has long-term OS benefits and an acceptable rate of adverse events and therefore should be considered as standard-of-care treatment for locally advanced resectable esophageal or GEJ cancer.⁷

Akce did not discount the data from the CROSS trial. He agreed that if CRT is a physician’s treatment of choice for a patient in this population, they should consider applying the CROSS regimen.

“I will always go with the evidence-based approach for which we have seen the best available data. If someone is going to utilize chemoradiation in the front line, the CROSS regimen would be the one that I would support,” Akce mentioned during the interview.

The second study used to back Patel’s argument was POET, the first randomized, controlled phase 3 trial to compare chemotherapy with CRT before surgery. The study investigated OS at 3 years as its primary end point in 119 patients with locally advanced adenocarcinoma of the GEJ. The secondary end points included PFS and local PFS. It should be noted, however, that the study was closed early due to poor accrual.^2,8

The median OS was 21.1 months in the perioperative chemotherapy arm compared with 30.8 months in the CRT arm (HR, 0.65; 95% CI, 0.42-1.01; P = .055). The 3-year OS rate was 26.1% in the perioperative chemotherapy arm versus 46.7% in the CRT arm; the 5-year OS rates were 24.4% and 39.5%, respectively. The OS trend was consistent across different baseline characteristics.

Improvement in PFS was also observed in patients who received neoadjuvant CRT (HR, 0.64; 95% CI, 0.39-1.06; P= .03). In terms of local PFS, CRT demonstrated a significant improvement over perioperative chemotherapy (HR, 0.37; 95% CI, 0.16-0.85; P = .01).

Overall, the study’s primary end point was not met due to early termination of the trial, but investigators led by Michael Stahl, MD, found the improvement in local PFS and strong trend toward improved OS with chemoradiation notable.

Further, the phase 2 randomized NeoRes trial (NCT01362127), demonstrated that adding radiotherapy to perioperative chemotherapy to treat carcinoma of the esophagus or GEJ increased the histological complete response and R0 resection rates, whereas it decreased lymph node metastasis.^2,9

Among 181 patients, CRT led to a histological complete response in 28% of patients compared with only 9% in the perioperative chemotherapy arm (P = .002). The rate of lymph node metastasis in the trial was 35% with CRT versus 62% with perioperative chemotherapy (P = .001). Finally, the R0 resection rate in patients who received CRT was 87% compared with 74% in the perioperative chemotherapy group (P = .04). Notably, no difference in OS was observed in this trial.

During his presentation, Patel also mentioned that the balance of toxicity and efficacy of neoadjuvant CRT also differs depending on the type of radiation administered. Compared with photon radiotherapy, proton radiotherapy may improve this balance, and it is being tested in an actively recruiting phase 3 randomized trial, NRG GI006.

Patel’s key message in the debate was that “both neoadjuvant chemoradiation and perioperative FLOT are active regimens in the treatment of gastroesophageal cancer, with similar 5-year survival rates. Pathologic response, a known prognostic factor, and acute toxicity favor chemoradiation.”

Following the strong data indicating a benefit for neoadjuvant CRT as treatment of GEJ/gastric cancers, Akce explained why he still cannot fully support this treatment strategy.

“My biggest stance against Dr Patel’s argument is that the trials he presented predominantly included distal esophagus tumors. They included squamous histologies as well. The CROSS trial, in particular, does not really answer the question our debate was centered around. The data I can support from CROSS [are] only applicable to GEJ cancer,” Akce said.

Doctors Go Head-to-Head on Toxicity in Head-to-Head Trials

The presentations by Akce and Patel during their debate at 2020 DDHO both touched on the toxicities often seen with both perioperative chemotherapy and neoadjuvant CRT. The key issue is preventing toxicities that will delay the time to surgery.

In response to a question regarding known chemotherapy toxicities, Akce told Targeted Oncology, “It all depends on the type of chemotherapy. If we’re discussing carboplatin plus paclitaxel as used in the CROSS trial, 95% of patients in the study received their full dose of chemotherapy, and 92% had their full dose of radiation. Also, 94% of patients in the chemoradiation arm underwent surgery, and 99% in the surgery-only arm underwent surgery.”

“Overall, toxicity did not seem to impact the rate of patients who made it to surgery, which is the goal here.”

In response to the criticisms surrounding the toxicities with CRT, Patel noted that “the primary modern comparator to neoadjuvant chemoradiation is perioperative docetaxel, oxaliplatin, leucovorin, and fluorouracil [FLOT]. While there are no head-to-head comparisons of these 2 regimens, they result in similar 40% 5-year OS for patients with adenocarcinoma. However, FLOT is associated with worse toxicity rates compared with neoadjuvant chemoradiation in the CROSS trial. Pathologic clearance of lymph nodes and complete pathologic response were numerically lower with FLOT compared with CROSS; both of these pathologic factors are prognostic for OS. One of the criticisms of the CROSS trial is that 25% of patients had squamous cell carcinoma, a group known to have more favorable outcomes. However, subset analysis of the patients with adenocarcinoma confirmed the survival advantage of chemoradiation and showed a pathologic complete response rate of 23%.”

Patel also explained that toxicity is an important factor that could impact the way CRT is administered to patients in community clinics, stating, “the increased toxicity of FLOT and 25% rate of hospitalization require careful monitoring in all settings. Neoadjuvant chemoradiation is associated with more favorable acute toxicity.”

_References

_{1. Akce Mehmet. Pre-operative therapy in GE junction and gastric cancer must not include radiation. Presented at: 2020 Debates and Didactics in Hematology and Oncology; July 16-18, 2020; Sea Island, GA.}

_{2. Patel Pretesh. Neoadjuvant chemoradiation for gastro-esophageal cancer. Presented at: 2020 Debates and Didactics in Hematology and Oncology; July 16-18, 2020; Sea Island, GA.}

_{3. Cunningham D, Allum WH, Stenning SP, et al; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006. 355 (1):11-20. doi: 10.1056/NEJMoa055531}

_{4. Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011. 29 (13); 1715-1721. doi: 10.1200/JCO.2010.33.0597}

_{5. Al-Batran SE, Homann N, Pavligk C, et al; FLOT4-AIO Investigators. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019. 393: 1948-1957. doi: 10.1016/ S0140-6736(18)32557-1}

_{6. Hoeppner J, Lordick F, Brunner T, et al. ESOPEC: prospective randomized controlled multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (NCT02509286). BMC Cancer. 2016;16:503. doi:10.1186/s12885-016-2564-y}

_{7. Shapiro J, van Lanschot JJ, Hulshopf M, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015.16:1090-1098. doi: 10.1016/ S1470-2045(15)00040-6}

_{8. Stahl M, Walz MK, Riera-Knorrenschild J, et al. Preoperative chemotherapy versus chemoradiotherapy in locally advanced adenocarcinomas of the oesophagogastric junction (POET): Long-term results of a controlled randomised trial. European Journal of Cancer. 2017. 8: 183-190. doi: 10.1016/j.ejca.2017.04.027}

_{9. Klevebro F, von Dobeln G, Wang N, et al. A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction. Ann Oncol. 2016. 27;(4): 660-667. doi: 10.1093/annonc/mdw010}