ARTIST/gastric cancer

[busy body]

Wanted some other opinions about this... I was reading the ARTIST trial again and I really think that dropping adjuvant XRT from the NCCN treatment for R0 patients with a D2 resection after preop chemo seems questionable. Some points from the trial include

-the DFS was 0.08.
-They only got 127 events instead of a planned 227 making the power of the study weak and drawing conclusions from the data should be questioned.
-This was done in South Korea and Capecitabine works better in this Asian populations (more efficacious and so the benefit of chem is maximized in this trial compared to other populations)

I am not one to want to radiate my own stomach but when I look at the DFS curves I am pretty convinced I would.
Thoughts

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[Palex80]

Sorry, but i am not convinced. The sole randomized for adjuvant RCT in gastric cancer comes from the MacDonald-trial and that trial had severe flaws, mainly in the field of a proper lymphadenectomy. Still ARTIST showed some potential benefit in N+ patients.

Our current policy is to do perioperative chemotherapy (neoadjuvant + adjuvant). Patients undergoing resection with or without preoperative chemotherapy who did not have a D2-lymphadenectomy, get RCT.
The rest get RT.

Exceptions are R1-recected cases as well as cases of massive nodal involvement in the presence of D2-lymphadenectomy. There we offer RCT too.

I understand that postoperative RCT is a big thing in the US, yet "it's a US thing". Europe goes for perioperative chemotherapy.

ARTIST only gave cisplatin/capecitabine, current optimal combinations are 3-drug-based, mainly FLOT, which includes taxanes on top of oxaliplatinum and 5FU.
Thus one could make the argument here that the comparison arm of ARTIST with chemo only was not up-to-date, since it included only a 2-drug-regimen.

 

[busy body]

I agree FLOT is becoming the new standard in Western populations but the pharmcogenomics of the south korean/asian population (5FU sensitive) is different. That chemo seemed to work pretty well. If you look at the DFS in Artist for Stage III/IV, the patients did really well compared when comparing to stage for stage across other trials (including the data from ASCO on FLOT).

At tumor board I am going to say perioperative chemo is standard of care but I can't help but think we are drawing conclusions on underpowered trial (only 11% were node positive). Maybe my complaint should be about statistical manipulation. ARTIST was underpowered because the patients did better than expected and when you do a subset analysis on an underpowered population your setting yourself for misguided conclusions.

 

[fiji128]

In patients who get neoadjuvant chemo followed by D1/2 surgery and are margin negative, I don't think there is a roll for adjuvant RT. A link to an excellent review article on the use of RT in gastric cancer is bellow. (CRITICS trail was reported at ASCO in 2016 I believe)

To quote a paragraph, "A meta-analysis comprising many of these trials confirmed the positive effect of neoadjuvant chemotherapy on OS, R0 resection rate, and primary tumor downstaging.27 As a result, there has been fierce debate over the past decade regarding whether adjuvant chemoradiotherapy or perioperative chemotherapy provides the best outcomes in patients with locally advanced gastric cancer.28 Although the ARTIST trial shed some light on this question, extrapolating these results is problematic for numerous reasons. Fortunately, the recently presented CRITICS trial, which is not yet available in manuscript form, should help guide treatment decisions.29 In this study, all patients received 3 cycles of neoadjuvant ECF or epirubicin, oxaliplatin, and 5-FU (EOF) prior to undergoing definitive surgical resection. Following surgery, patients were treated according to preoperative randomization, which consisted of an additional 3 cycles of ECF or EOF or chemoradiotherapy with concurrent XP. Extent of surgical resection was greater than that seen in the Intergroup 0116 study, with nearly 90% of patients receiving at least D1 lymphadenectomy and a median of 20 lymph nodes removed. The 5-year OS was approximately 41% in both arms, and although these results appear to compare favorably to both the MAGIC and Intergroup 0116 trials, there was no evidence of superiority for either arm. Grade 3 hematologic toxicity was slightly higher in the perioperative chemotherapy arm (44% vs 34%), but patients in both arms had difficulty completing protocol treatment (47% for perioperative chemotherapy, 52% for adjuvant chemoradiotherapy). In light of these findings, we do not recommend adjuvant chemoradiotherapy for patients who undergo R0 resection following neoadjuvant ECF unless they are unable to tolerate multiagent chemotherapy in the postoperative setting or are enrolled in a clinical trial."

The Role of Radiotherapy in the Management of Gastric Cancer | Gotoper.com

 

[evilbooyaa]

We all have to remember that ARTIST didn't have neoadjuvant (prior to surgery) chemotherapy. The original question is not relevant or at least is not phrased correctly, because ARTIST didn't look at patients who got chemotherapy prior to surgery. They were looking to see in those who underwent surgery first, could you omit radiation.

Perioperative chemo combined with adjuvant radiation, per the CRITICS abstract, has no overall survival benefit in the whole population. That is the first randomized evidence we have in regards to this situation. We'll have to wait for the paper to see if there are subsets that do (intestinal type, pN+ are the main ones I'd be interested in, given results of the ARTIST trial showing individual benefit for each of those factors). Also interested in their DFS and LR numbers (see if we're dealing with an issue similar to LAP07 for pancreatic cancer).

Currently, either perioperative chemo (FLOT is becoming more popular here) or resection followed by adjuvant chemo (chemoRT for N+) are fine options for newly diagnosed locally advanced gastric cancer. I'm not sure why periop chemo is cat 1 and McDonald regimen isn't, but that probably has something to do with the fact that I count only 4 of the numerous people on the gastric cancer NCCN committee that are radiation oncologists.

In patients undergoing surgical resection first (per NCCN) T3 or N+ means chemoRT per MacDonald is the category 1 recommendation. In patients who have undergone D2 LND, chemotherapy alone is listed as an option. I'm not sure I agree with THAT given that N+ had a benefit in ARTIST with radiation.

Realistically, I don't know that I've ever seen a gastric cancer (in my unscreened population), that with upfront resection that was not 1) T2-T3+ or 2) pN+, and thus got adjuvant chemoRT.

In my opinion, the way it's going to shake out is like this: People will probably get neoadjuvant chemotherapy (we'll have to see what TOPGEAR shows about neoadjuvant chemoRT), then they'll get surgery. People with ypN0 and like ypT2 or less disease will probably just finish out their chemo and call it a day and be OK. I think people with ypN+ or ypT3+ disease will have at least a DFS benefit with addition of RT. Just what I think is going to happen.

To OP - In somebody who undergoes surgery first and has a D2 lymphadenectomy - the DFS is bordering significance because you're looking at all comers. Only 35+27 out of their 228 + 230 patients were pN0 (13%). I agree that basing a recommendation on 13% of a study population that didn't reach the total number of events necessary isn't ideal, but if you look at the scatterplot from figure 4, the N0 sample size is too small to make any distinctive conclusions one way or the other.

Reference: http://ascopubs.org/doi/abs/10.1200/jco.2014.58.3930