Br J Cancer. 2016 Sep 6;115(6):655-63. doi: 10.1038/bjc.2016.252.

Role of Histological Regression Grade after two Neoadjuvant Approaches with or without Radiotherapy in Locally Advanced Gastric Cancer

Patricia Martin-Romano1, Jose J. Sola2, Juan A. Diaz-Gonzalez1, Ana Chopitea1, Yohana Iragorri1, Fernando Martínez-Regueira5, Mariano Ponz-Sarvise1, Leire Arbea1, Jose C. Subtil3, David Cano4, Lucia Ceniceros1, J. Legaspi1, Jose Luis Hernandez5and Javier Rodriguez1



1Department of Oncology, Clínica Universidad de Navarra, 31008 Pamplona, Spain

2Department of Pathology, Hospital San Pedro, 26006 Logroño, Spain

3 Department of Gastroenterology, Clínica Universidad de Navarra, 31008 Pamplona, Spain

4Department of Radiology, Clínica Universidad de Navarra, 31008 Pamplona, Spain

5Department of Surgical Oncology, Clínica Universidad de Navarra, 31008 Pamplona, Spain


Address for Correspondence:

Dr. Javier Rodríguez

Department of Oncology

Clínica Universidad de Navarra,

Avenida de Pio XII número 36,

Pamplona 31008

Navarra. Spain




Background: The degree of histopathological response after neoadjuvant therapy in locally advanced gastric cancer (GC) is a key determinant of patients’ long-term outcome. We aimed to assess the pattern of histopathological regression after two neoadjuvant approaches and its impact on survival times.

Methods: Regression grade of the primary tumour (Becker criteria) and the degree of nodal response by a 4-point scale (Grades A-D) were assessed. Grade A—true negative lymph nodes (LNs); Grade B and C—infiltrated LNs with any or little evidence of nodal response; Grade D—complete pathologic response in a previously infiltrated LN. A favourable pathologic response was defined as Becker Ia-b and grade D.

Results: From 2004 to 2014, 80 patients with GC (cT3-4/N+ by CT-scan/EUS) were treated with either preoperative chemotherapy (ChT, n=34) or chemoradiation (CRT, n=46). Patients in the CRT group had a higher likelihood of achieving a Becker Ia-b response (58% vs 32%, P=0.001), a grade D nodal regression (30% vs 6%, P=0.009) and a favorable pathologic response (23% vs 3%; P=0.019). Patients with a grade D nodal response had a longer 5-year PFS and OS compared to those with a grade B or C response. Patients with a baseline negative LN status had similar outcomes irrespective of the preoperative therapy received (5-year OS; ChT vs CRT, 58% vs 51%, P=0.92).

Conclusions: Preoperative chemoradiation increases the likelihood of achieving favorable histopathologic features that correlate with a 5-year OS>70% in GC patients.

PMID: 27537382



Gastric cancer (GC) is one of the leading causes of cancer-related death, despite reduced incidence and mortality rates observed in the last decades (1). Surgical resection is curative in early-stage tumors, although most patients are diagnosed with locally advanced disease involving regional lymph nodes. Disease relapse occur in half of the resected patients during the follow-up. In an attempt to improve such outcomes, several therapeutic approaches have been assessed. When compared to surgery alone, perioperative chemotherapy and adjuvant chemoradiotherapy have improved relapse and survival rates, and therefore both strategies have been established as one standard of care for GC patients (2-4). On the other hand, the use of preoperative chemoradiation is currently considered investigational in GC. Several small non-randomized studies have reported a pathological complete response rate in the range of 20-30% and promising survival times (5-7). Arguments supporting preoperative chemoradiation are an increased resectability and R0 rates, smaller radiation target volumes and reduced displacement of contiguous structures, leading to decreased treatment toxicity and greater patient compliance.

The degree of histopathological response after neoadjuvant therapies along with the pathologic stage have been suggested to strongly dictate prognosis (8, 9). Interestingly, compared to neoadjuvant chemotherapy, the use of preoperative chemoradiation in esophageal and gastroesophageal junction (GEJ) adenocarcinomas yields higher rates of major pathological responses (10). Although in GC patients data are more limited and preliminary, this effect has also been observed. Previous work from our group has suggested that the addition of radiation to a neoadjuvant schedule of chemotherapy increases the likelihood of achieving a higher regression grade (11). A major limitation of that work was the inclusion of patients with GC and GEJ adenocarcinomas, thus precluding firm conclusions.

In the present analysis we hypothesized that the addition of preoperative radiation in GC patients would result in a greater degree of histopathological responses in both, tumor wall and locoregional lymph nodes (LNs). We also hypothesized that a deeper grade of histopathological regression would translate into longer survival times.

The outcome of patients with locally advanced gastric adenocarcinoma treated with preoperative chemotherapy alone (ChT group) was compared to that of patients treated with neoadjuvant chemotherapy followed by preoperative concurrent chemoradiotherapy (CRT group). Tumor regression grade in both groups was homogeneously evaluated according to Becker regression criteria in the surgical specimen: grade 1a (complete tumor regression), grade 1b (1-10% of vital tumor tissue), grade 2 (residual tumor per tumor bed of 10-50%), and grade 3 (>50% of viable tumor remaining) (8). Patients with either grade Ia or Ib were considered to have a major pathologic response. Several attempts have been made to evaluate the degree of pathologic remission in upper GI malignancies, but no grading system has been developed to date to quantify the magnitude of therapy-induced nodal regression in GC patients. We thus decided to incorporate a four-point scale derived from the Miller and Payne grading system for breast cancer (12). The scale describes the pathologic features of LNs after neoadjuvant therapy as follows: Grade A—true negative LNs with no evidence of preoperative therapy effect; Grade B—infiltrated LNs with no evidence of any effect of preoperative therapy; Grade C—infiltrated LNs with evidence of some degree of histological regression due to preoperative therapy; Grade D—complete pathologic response in a previously infiltrated LN. This grading system seems especially relevant in the subgroup of patients with tumor-free LNs that includes patients with truly negative LNs from baseline (grade A) and patients with a complete nodal response (grade D) after neoadjuvant approach. Remarkably, the addition of preoperative radiation correlated with a two-fold increase in the likelihood of achieving a major pathological response (<10% of vital tumor tissue; 58% vs 32%; P=0.001) and with a 5-fold increase in the likelihood of achieving a grade D nodal regression (30% vs 6%; P=0.009). The use of preoperative radiation also increased the proportion of favorable pathologic responses (Becker grade 1a-b response and grade D nodal regression; 23% vs 3%; P=0.02). Importantly, by multivariate analysis, the only factor that correlated with the achievement of a deeper tumor and nodal pathologic response was the use of preoperative radiation.

The impact of the pathological regression grade after neoadjuvant therapy on the long term outcome was also evaluated. Consistent with previously published reports, tumor regression grade according to Becker criteria was not found to correlate with patients’ prognosis (13). On the contrary, patients with tumor-free LNs had a significantly longer 5-year survival compared to ypN+ patients (58% vs 40%; P=0.03). A recently published study has reassured the prognostic relevance of nodal status after neoadjuvant therapy, with node-positive patients displaying a 3-fold likelihood of death (HR 3.36; 95% CI 1.7-6.63; P<0.001) (14).

To rule out the importance of the degree of nodal regression we excluded patients with a grade A nodal response, that is, patients with truly negative LNs from baseline. Results from this analysis showed an improvement in survival in patients with a grade D nodal response when compared to patients with Grades B and C nodal response (Figure 1), suggesting that not only the nodal status but also the type of nodal response may correlate with long-term outcome. Finally, we found that 5-year overall survival in patients with Becker 1a-b and either grade A and D nodal (ypN0) response, was greater than 60% (Figure 2), reinforcing the idea that prognosis is strongly correlated with pathologic stage, regardless of clinical stage at diagnosis.

Despite the increased chance of pathological regression with neoadjuvant chemoradiation, there was no survival differences in our patient population. Unbalanced baseline characteristics may be responsible for similar long-term outcomes between both treatment groups. In fact, in the CRT group, 90% of patients had lymph node involvement (cN+), in contrast to less than 60% of patients in the ChT group, suggesting more advanced disease and thus a baseline worse prognosis in this group. However, ypTN stages in both groups were similar after neoadjuvant treatment. One may speculate that preoperative CRT would have modified the initial poor prognosis of these GC patients, turning it into that of patients with less locally advanced tumors.

One of the advantages of preoperative therapies is a higher rate of treatment compliance, nearly 80%. In contrast, compliance rates decline dramatically in the adjuvant setting, where only 42% and 64% of patients completed the initially planned treatment, as observed in the MAGIC and INT-0116 trials (2, 3). According to our results, more than 90% of the patients completed the initially planned neoadjuvant therapy. Nevertheless, prospective studies evaluating the use of preoperative radiation with both 3D and IMRT techniques have demonstrated grade 3-4 adverse events in approximately 50% of patients, with hospitalization rates of 30% (15). In line with these results, almost 30% of our patients required hospital admission mainly due to gastrointestinal grade 3 adverse events (77%) caused by direct damage to healthy gastric mucosa included in the radiation field. Morbidity and mortality rates in the CRT group were 7% and 2%, respectively. Radiation field or dose administered in these patients were consistent to the International Commission of Radiation Units and Measurements (ICRU) recommendations. Thus, these complications were unexpected and may not be related to the radiation therapy. Indeed, studies evaluating preoperative strategies have reported similar morbidity (7-47%) and mortality (3-10%) rates (2-7, 10). Strict eligibility and intensive clinical follow-up seem mandatory in an attempt to improve tolerance and to balance toxic effects and efficacy.

The present study has identified a subgroup of patients with baseline tumor-free lymph nodes (Grade A). Grade A and D responses are seen in ypN0 patients, with a mandatory clarification: the pathologic features of grade D patients indicate positive lymph nodes at diagnosis. No survival differences in either PFS or OS were observed between patients with grades A or D nodal regression. Patients with a Grade A nodal response seem to have an excellent clinical outcome, regardless of the type of neoadjuvant therapy received, with a 5-year long-term survival >50% in both therapeutic groups (Figure 3). This may point to a limited value of adding radiation therapy in the neoadjuvant strategy of those patients with a truly negative lymph node status. On the other hand, radiation increases the likelihood of achieving a grade D nodal regression, a known indicator of long-term outcome (14). Accurate preoperative assessment of the nodal stage seems then to be a major challenge in the attempt to provide tailored management plan for these patients. The main issue of concern for individualized strategies is our ability to accurately predict the clinical nodal category. Although CT-scan and EUS are the standard imaging techniques, both tests are extremely imprecise. Particularly, accuracy for nodal assessment is below 40% (16). Whether alternative radiological evaluations, such as the combination of EUS and laparoscopic ultrasonography might increase the current accuracy deserves further research (17)[29].

Importance of the study: induction chemotherapy followed by chemoradiation in the preoperative setting in GC patients seems to increase the likelihood of achieving favorable histopathological features, which might eventually impact long-term outcome. Our results suggest that CRT may be an essential part of the preoperative treatment in fit patients with baseline nodal metastatic disease. Prospective randomized trials are ongoing.



Figure 1. PFS (A) and OS (B) according to nodal response (excluding grade A patients; n=48).



Figure 2. PFS (A) and OS (B) according to tumor and nodal response (Becker 1a–b and grade A&D patients; n=77).

Figure 3. PFS (A) and OS (B) by treatment group in patients with nodal response grade A (n=29).



  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA: a cancer journal for clinicians. 2015;65(2):87-108.
  2. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. The New England journal of medicine. 2001;345(10):725-30.
  3. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. The New England journal of medicine. 2006;355(1):11-20.
  4. Ychou M, Boige V, Pignon JP, Conroy T, Bouche O, Lebreton G, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(13):1715-21.
  5. Ajani JA, Mansfield PF, Janjan N, Morris J, Pisters PW, Lynch PM. Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2004;22.
  6. Ajani JA, Mansfield PF, Crane CH, Wu TT, Lunagomez S, Lynch PM, et al. Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005;23(6):1237-44.
  7. Ajani JA, Winter K, Okawara GS, Donohue JH, Pisters PW, Crane CH. Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006;24.
  8. Becker K, Mueller JD, Schulmacher C, Ott K, Fink U, Busch R, et al. Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy. Cancer. 2003;98(7):1521-30.
  9. Davies AR, Gossage JA, Zylstra J, Mattsson F, Lagergren J, Maisey N, et al. Tumor stage after neoadjuvant chemotherapy determines survival after surgery for adenocarcinoma of the esophagus and esophagogastric junction. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32(27):2983-90.
  10. Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer HJ, Riera-Knorrenschild J, et al. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009;27(6):851-6.
  11. Diaz-Gonzalez JA, Rodriguez J, Hernandez-Lizoain JL, Ciervide R, Gaztanaga M, San Miguel I, et al. Patterns of response after preoperative treatment in gastric cancer. International journal of radiation oncology, biology, physics. 2011;80(3):698-704.
  12. Smith IC, Heys SD, Hutcheon AW, Miller ID, Payne S, Gilbert FJ, et al. Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2002;20(6):1456-66.
  13. Becker K, Langer R, Reim D, Novotny A, Meyer zum Buschenfelde C, Engel J, et al. Significance of histopathological tumor regression after neoadjuvant chemotherapy in gastric adenocarcinomas: a summary of 480 cases. Annals of surgery. 2011;253(5):934-9.
  14. Smyth EC, Fassan M, Cunningham D, Allum WH, Okines AF, Lampis A, et al. Effect of Pathologic Tumor Response and Nodal Status on Survival in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016;34(23):2721-7.
  15. Chakravarty T, Crane CH, Ajani JA, Mansfield PF, Briere TM, Beddar AS, et al. Intensity-modulated radiation therapy with concurrent chemotherapy as preoperative treatment for localized gastric adenocarcinoma. International journal of radiation oncology, biology, physics. 2012;83(2):581-6.
  16. Blank S, Lordick F, Bader F, Burian M, Dobritz M, Grenacher L, et al. Post-therapeutic response evaluation by a combination of endoscopy and CT scan in esophagogastric adenocarcinoma after chemotherapy: better than its reputation. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2015;18(2):314-25.
  17. Mortensen MB. Pretherapeutic evaluation of patients with upper gastrointestinal tract cancer using endoscopic and laparoscopic ultrasonography. Danish medical journal. 2012;59(12):B4568.



Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann