https://orcid.org/0000-0002-7748-3798
Abstract
Background
Following neoadjuvant chemotherapy (NAC) for resectable gastric cancer, the prognostic adequacy of the UICC staging system needs to be investigated. In particular to explore whether the ypTNM curves for radically resected gastric cancer patients receiving NAC follow the stage-matched survival curves of radically resected chemo-naïve patients (pTNM). Further, to disclose any interaction between the TNM-response mode to NAC and stage-specific survival rates, i.e., whether survival for a particular pathological disease stage was dependent on whether this was reached through a downstaging or as stable disease following NAC.
Material and methods
Retrospective study on radically resected patients ≤ 75 years of age with gastric adenocarcinoma stages I-III diagnosed during 2001–2016. The patients constitute two population-based cohorts; the SURG-group with n = 121 patients treated before 2007 when NAC was introduced, and the NAC-group with n = 126 patients diagnosed since early 2007, receiving NAC and subsequent radical resection.
Results
Long-term survival rates were similar when specific ypTNM-stages were compared to their corresponding pTNM chemo-naïve counterparts. The dichotomised N0 vs. N + had a substantial impact on the long-term survival rates in both groups, however, no discrepancy in long-term survival rates between pN0 vs. ypN0, and pN + vs. ypN + was found. The pathological stage determined long-term survival rates irrespective of the baseline disease stage, as no interaction between the response mode and stage-specific survival rates was found.
Conclusions
Survival curves for specific ypTNM-stages following NAC did not differ from the corresponding survival curves of their chemo-naïve pTNM counterparts. The interpretation is that NAC affected the gastric cancer, lymph nodes, and micrometastases, in such a way that the final ypTNM-stage provided similar prognostic information as the chemo-naïve pTNM-stages. Survival rates were contingent on the final ypTNM-stages alone, and not influenced by the response mode to reach that particular disease stage, or predetermined by the original clinical TNM-stage.
Introduction
The Union for International Cancer Control (UICC) TNM-system is used for cancer staging in the West, to aid decisions on treatment and to predict prognosis. Following the advent of neoadjuvant chemotherapy (NAC) for resectable gastric cancer [Citation1,Citation2], a need has emerged to revisit the UICC staging system in terms of its adequacy as a prognostic tool [Citation3–5]. TNM-stages assigned following NAC is marked by the prefix ‘y’ to distinguish them from the chemo-naïve disease stages. However, the framework for assessing anatomic extent of tumour growth is a common one, irrespective of whether neoadjuvant treatment is administered or not. As a consequence, tumours with a complete pathological response corresponding to ypT0N0, or tumours with the theoretical stage ypT0N+, are not addressed. The pathological disease stage assigned following NAC must be considered a compound stage, i.e., a result of both the disease stage at diagnosis and the ensuing response to NAC. For a number of reasons, the response mode of the gastric primary cancer need not directly correlate to the response mode of micrometastases or locally disseminated tumour cells, which may evade the cytotoxic chemotherapy effect and later cause recurrence [Citation6–8]. With that, the final ypTNM-stages could merely represent a cosmetic local down-staging. Published literature is limited and inconclusive on the question of whether ypTNM-stages follow the same survival curves as their chemo-naïve counterparts. Studies mainly comprise oesophageal and GEJ cancer, and many included a mixture of adenocarcinomas and squamous cell carcinomas. The majority of the studies do not use the proper UICC TNM-stages, but resort to ad hoc solutions [Citation9–12].
The aim of the present study was to explore whether the ypTNM survival curves for radically resected gastric cancer patients receiving NAC follow the stage-matched survival curves of radically treated chemo-naïve patients (pTNM). Further, to disclose any interaction between the response mode to NAC and stage-specific survival rates. That is, whether the long-term survival rates for a particular ypTNM-stage are influenced by whether this stage was reached through a downstaging process or by remaining unaltered/upstaged as a non-response to NAC.
Method
Retrospective, population-based study from Central Norway, with a catchment area of some 700,000 subjects. All patients diagnosed with gastric adenocarcinoma from 01.01.2001 to 31.12.2016 were identified through the Norwegian Cancer Registry (NCR). By reviewing the individual electronic patient journals, a complete registration of the clinico-pathological variables for patients with a histological proven gastric adenocarcinoma could be obtained, including tumours of the gastric cardia Siewert types II/III. The Lauren classification was used for the histological subtyping [Citation13]. In accordance with the national guidelines, patients ≤ 75 years of age, with a WHO performance status of 0–1, and of disease stages Ib-III, were since early 2007 offered a MAGIC-style regimen of perioperative chemotherapy. Of the 1216 consecutive patients diagnosed with gastric adenocarcinoma during the study period, 638 patients were ≤ 75 years of age. Of these, 313 had M + disease at baseline and 27 were medically unfit for curative treatment. An additional 51 patients were excluded from analyses, either due to NAC other than the MAGIC regimen (n = 13), synchronous other malignancies (n = 3), death within 30 days of surgery (n = 5), R1/R2 resection (n = 23), or insufficient data (n = 7), leaving 247 radically resected patients ≤ 75 years of age to be the objective of the present study. The patients constitute two population based cohorts, emanating from two different treatment eras. First, the ‘historic’ cohort with n = 121 patients treated mainly before 2007 with surgery alone, further referred to as the SURG-group. Second, n = 126 patients diagnosed since early 2007, receiving NAC and subsequent radical resection, further referred to as the NAC-group ().
Table 1. Clinico-pathological variables for radically resected gastric cancer patients 2001–2016, aged ≤ 75 years, stratified on an upfront surgery group (SURG-group) and a neoadjuvant chemotherapy group (NAC-group).
Neoadjuvant chemotherapy and surgery
The NAC-group received a MAGIC-style regimen of perioperative chemotherapy consisting of i.v. epirubicin 50 mg/m2 on day 1, i.v. oxaliplatin 130 mg/m2 or i.v. cisplatin 60 mg/m2 on day 1 and oral capecitabin (Xeloda®) 1250 mg/m2 for 21 days (EOX/ECX), with three cycles prior to surgery and three cycles post-surgery for radically resected patients. Surgery was done 4–6 weeks after the last cycle, by default as a modified D2 dissection [Citation14] with intraoperative frozen sections routinely obtained.
Staging and response evaluation
Baseline TNM-stage in the NAC-group was assigned following a standardized computerized tomography scan (CT) designed for optimal gastric distention [Citation15]. Endoscopic ultrasound (EUS), PET-CT, or diagnostic laparoscopy were not part of the diagnostic workup, in accordance with the national guidelines at the time. For study purposes the CT-staging (rTNM) was revisited by a gastroradiologist, and together with the pTNM/ypTNM-stages, retro-classified in accordance with the 8th edition of the UICC TNM-manual. The response mode to NAC was judged by comparing the radiological stage at baseline CT to the pathological stage following NAC. A detailed cross-tabulation of rTNM and ypTNM forthe individual entries, including this cohort, has been previously published [Citation16,Citation17]. Downstaging as a measure of response to NAC was defined as a lowering of disease stage one or more tiers, otherwise the tumours were judged as non-responders [Citation17,Citation18]. Survival curves were derived for each final pathological TNM-stage, stratified on the SURG-group and the NAC-group. To disclose any interaction, survival curves for each ypTNM-stage in the NAC-group were further split according to the response mode. That is, separate curves for patients that reached a particular disease-stage through down-staging and for those that were assigned this stage through stable disease or were upstaged. The censoring date was 31.12.2021, providing a minimum follow-up of five years. The study was approved by the Norwegian Regional Ethics Committee (case number 2016/2173), and the manuscript was prepared in accordance with the STROBE guidelines [Citation19].
Statistics
Continuous variables were summarized by the mean. Categorical variables were cross-tabulated and analysed using the χ2–statistic. Overall survival was counted from the time of diagnosis, survival-curves constructed by the Kaplan-Meier method, and compared using the log-rank test. A multivariable Cox proportional hazard analysis for each final pathological disease-stage individually, assessed any impact from NAC on hazard of death. Age, gender, tumour location, Lauren classification, and NAC vs. chemo-naïve were entered as independent variables. The level of statistical significance was defined at p = 0.05. Analyses were done using IBM SPSS Statistics version 29.
Results
Of the 126 patients receiving NAC and radical resection, 111/126 (88%) completed all three preoperative cycles. A total of 89/126 (70%) commenced postoperative chemotherapy, with 67/89 (75%) completing the three postoperative cycles, adding up to 67/126 (53%) able to complete all six perioperative cycles.
According to the TNM response mode, 67/126 (53%) were classified as responders following NAC and 59/126 (47%) as non-responders (). There were significantly more non-responders completing the postoperative chemotherapy (p = 0.033). A pathological complete response, ypT0N0, was found in 15/126 patients (12%), of these 13/15 (86%) had completed all planned preoperative cycles without any dose reductions.
Table 2. Clinico-pathological variables for patients with gastric cancer radically resected after neoadjuvant chemotherapy, stratified on the response mode.
Long-time survival rates for radically resected patients based on the pathological TNM-stage
By comparing the long-term survival rates for the individual pTNM disease stages to the corresponding ypTNM-stages, no significant difference was observed for stage-specific OS (). The same conclusion was reached by further analysing on the specific sub-stages; SURG p0/IA vs. NAC yp0/IA (log-rank p = 0.403), SURG pIB vs. NAC ypIB (log-rank p = 0.192), SURG pIIA vs. NAC ypIIA (log-rank p = 0.727), SURG pIIB vs. NAC ypIIB (log-rank p = 0.078), SURG pIIIA vs. NAC ypIIIA (log-rank p = 0.119), and SURG pIIIB vs. NAC ypIIIB (log-rank p = 0.713). For the disease stage IIIC no comparison could be done, since no patients were diagnosed with the disease stage ypIIIC following NAC and radical surgery. Similarly, for the fifteen patients with pathological complete response to NAC (ypT0N0), no comparable SURG-group existed. Of note though, the disease specific 5-year survival was 100% for this particular subgroup.
Figure 1. Kaplan–Meier plots of overall survival stratified on the pathological TNM-stage in the SURG-group (pTNM, n = 121) and the NAC-group (ypTNM, n = 126). pTNM stage I vs. ypTNM stage I (log-rank p = 0.877), pTNM stage II vs. ypTNM stage II (log-rank p = 0.215) and pTNM stage III vs. ypTNM stage III (log-rank p = 0.574).
Since the dichotomised variable pN0/pN + has a strong impact on long-term survival rates [Citation20,Citation21], and since focus on the ypN status has been demanded in particular [Citation3,Citation9,Citation22,Citation23], long-term survival rates for the (y)pN0 and (y)pN + subsets were examined. As expected, the dichotomised N0 vs. N + had a substantial impact on the long-term survival rates both in the SURG-group and in the NAC-group. However, no discrepancy in long-term survival rates between pN0 vs. ypN0 (log-rank p = 0.630) or pN + vs. ypN+ (log-rank p = 0.405) was found ().
Figure 2. Kaplan-Meier plots of overall survival stratified on the pathological N-category in the SURG-group (pN) and the NAC-group (ypN). pN0 (n = 66) vs. ypN0 (n = 68) log-rank p = 0.630. pN+ (n = 55) vs. ypN+ (n = 58) log-rank p = 0.405.
Multivariable analysis of long-term survival rates, stratified on the pathological TNM-stage
To adjust for possible confounders, a multivariable Cox proportional hazard analysis was performed, stratified on the merged pathological disease stages pTNM and ypTNM. NAC proved to have no post hoc impact on HR for death, global HR 1,060 (95% CI 0.744–1.511) p = 0.436. This was a persistent finding across all pathological disease stages individually. For pathological stage I, NAC vs no NAC, HR 0.673 (95% CI 0.248–1.824), p = 0.436. For stage II HR 1.437 (95% CI 0.688–2.998), p = 0.334, and for the pathological stage III HR 0.888 (95% CI 0.542–1.455), p = 0.636. The final pathological stage per se determined the hazard of death, with no impact from whether chemotherapy was delivered or not, or predetermined by the baseline TNM stage.
Interaction between the TNM response mode and the stage specific survival rates
Long-term survival rates were stage by stage stratified on the response mode to identify any interaction. That is, whether long-term survival for a specific ypTNM-stage was influenced by whether this stage was reached through a downstaging response to NAC or remained unaltered/upstaged as non-responders to NAC. Although numbers are small, no such interaction emerged ().
Figure 3. Kaplan-Meier plot of the pathological stage-specific overall survival for the NAC group comparing the responders (n = 67) to the non-responders (n = 59). ypTNM stage I; responder (n = 32) vs. non-responder (n = 2), log-rank p = 0.556. ypTNM stage II; responder (n = 28) vs. non-responder (n = 17), log-rank p = 0.279. ypTNM stage III; responder (n = 7) vs. non-responder (n = 40), log-rank p = 0.524.
For the pathological N-category isolated, no difference in long-term survival rates was found within the NAC-group comparing the ypN0 responders to the ypN0 non-responders, (log-rank p = 0.614) and the ypN + responders to the ypN + non-responders (log-rank p = 0.964) (). That is, long-term survival rates were not contingent on whether the ypN0/N + status was reached through a downstaging response to NAC or remained unaltered/upstaged by virtue of being non-responder.
Figure 4. Kaplan-Meier plots of overall survival for the NAC group stratified on the ypN-category and the response mode. ypN0; responder (n = 53) vs. non-responder (n = 15), log-rank p = 0.614. ypN+; responder (n = 14) vs. non-responder (n = 44), log-rank p = 0.964.
Discussion
In accordance with a linear model of tumour progression, the clinical T- and N-stage predict the load of micrometastases released prior to the diagnosis, presumably normally distributed around some mean level for each stage [Citation24,Citation25]. By this reasoning, an ypTNM-stage may not be considered a true tumour stage in a similar manner, but rather the result of a complex interaction between the baseline disease stage and the ensuing response to NAC. However, different cellular clones and microenvironments may cause the response mode of the gastric primary not to be directly correlated to the response mode of metastatic lymph nodes or distant micrometastases [Citation26–29]. Hence, the final ypTNM-stage may not necessarily reflect the amount of residual micrometastases or regional tumour deposits, which later may cause recurrence and in the end determine the long-term survival rates [Citation6,Citation7]. The three postoperative cycles of chemotherapy may also grant a survival benefit, obviously with no bearing on the ypTNM-stages, possible further adding to limit the capabilities of the ypTNM-stages to reliably predict long-term survival rates.
The main finding of the present study was that long-term survival rates were similar when specific ypTNM-stages were compared to their corresponding pTNM chemo-naïve counterparts (). NAC seemed to impacted lymph nodes and micrometastases in such a way that the final ypTNM-stages provided similar prognostic information as the chemo-naïve pTNM-stages, irrespective of the initial baseline disease stage. This was a persistent finding also when the dichotomised pathological N0/N + status between the chemo-exposed and the chemo-naïve groups was compared (). The findings are supported by the Cox regression analyses, proving that for any particular pathological disease stage, hazard ratios for death were not dependent on whether NAC was delivered or not, but rested on the final disease stage per se. These findings are in line with that reported from some small retrospective studies on oesophageal, GEJ [Citation11,Citation30], and gastric cancer [Citation18], with the exemption of patients harbouring ypT3/4 N2-3 disease, that in two studies were found to have significantly improved median survival compared to stage-matched chemo-naïve patients [Citation18,Citation30]. Published literature on the topic is, however, limited and divergent. A Chinese study reported on an overall increased risk of death for patients with a specific ypTNM-stage compared to their pTNM chemo-naïve counterparts, (global HR 1.35 95% CI 1.09 − 1.67, p < 0.01). The significance was driven by findings for stage I and stage III disease, with no difference in hazard between ypTNM and pTNM stage II disease [Citation10]. On the other hand, the Worldwide Esophageal Cancer Collaboration (WECC) in a recent study concluded with an inferior survival for ypTNM categories I and II compared to their stage-matched chemo-naïve counterparts, but with no differences in survival for stage III disease [Citation31].
A second issue is the question of interaction, i.e., whether long-term survival rates for a particular ypTNM-stage was influenced by the response mode to reach that stage. Published data on this topic is conspicuously absent. In the present study no such interaction could be identified (). That is, survival rates for a specific ypTNM-stage was not influenced by whether this was reached through a downstaging response to NAC or remained unaltered/upstaged as non-responder to NAC. However, numbers are small. By virtue, yp-stage III disease largely comprised non-responders and yp-stage I disease largely responders. For the intermediate yp-stage II, survival curves visually diverged, and a type II-error cannot be ruled out.
Concerning nodal status, conflicting results are reported regarding the question of whether patients downstaged to N0 (cN+ → ypN0) have inferior survival compared to patients with baseline N0 [Citation21,Citation32,Citation33]. In the present paper, no such difference in overall survival was found ().
A limitation of the present study is its retrospective nature and a limited sample size, although comparable to that reported from RCTs on the subject [Citation34]. Subset analyses may be prone to type II-errors. This is also why we did not pursue the question of how the number of postoperative cycles delivered could influence the long-term survival rates. Further, the assessment of interaction rests on the concept of response mode, which is sensitive to the accuracy of the baseline CT-staging. For T-category this is commonly reported at around 70–90%, for N-category at around 70–80% [Citation35–37].
The strengths of the present study includes its population based nature, eliminating selection bias. The patients were treated in ‘two different time eras’, but preoperative workup and surgery performed was standardized and unaltered throughout the study period. For patients receiving NAC, this was by default delivered as a modified MAGIC regimen. Although this was recently replaced by the FLOT4 regimen in European guidelines [Citation1,Citation2], the research questions explored in the present paper is not limited to the MAGIC regimen or to gastric cancer in particular, but is considered to be of principal relevance.
Conclusion
Survival curves for individual ypTNM disease stages following NAC did not differ from the corresponding survival curves of their chemo-naïve pTNM counterparts. The interpretation is that NAC affected the primary gastric cancer, lymph nodes, and micrometastases in such a way that the final ypTNM provided similar prognostic information as the chemo-naïve pTNM stages. No interaction between the response mode to NAC and the stage-specific long-term survival rates was found. This suggests that survival rates are dependent on the final ypTNM-stage alone and not influenced by the response mode to reach that particular disease stage or predetermined by the initial TNM-stage.
Author’s contributions
All the authors conceived the idea, designed the work and obtained the data. A.D Sandø and E.A Bringeland analysed and interpreted the data. A.D. Sandø and E.A Bringeland wrote the manuscript and prepared the figures and tables. E.A. Bringeland and J.E Grønbech critically revised the manuscript. All authors are accountable for the contents of this work. All authors read and approved the final manuscript.
Ethical approval
Research in this study has been performed in accordance with the Declaration of Helsinki and has been approved by the Norwegian Regional Ethics Committee (case number 2016/2173). We confirm that all methods were carried out in accordance with the relevant guidelines and regulations. ‘The need for informed consent was waived by the ethics committee, Regional Ethics Committee Midt-Norge, because of the retrospective nature of the study.’
Disclaimer
The study has used data from the Cancer Registry of Norway. The interpretation and reporting of these data are the sole responsibility of the authors, and no endorsement by the Cancer Registry of Norway is intended nor should be inferred.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The datasets generated and analysed during the present study are not publicly available due to hospital policy, but are available from the corresponding author on reasonable request.
Additional information
Funding
References
- Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer.N Engl J Med. 2006;355(1):11–20. doi:10.1056/NEJMoa055531.
- Al-Batran SE, Homann N, Pauligk C, et al. 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(10184):1948–1957. doi:10.1016/S0140-6736(18)32557-1.
- Lin JX, Yoon C, Desiderio J, et al. Development and validation of a staging system for gastric adenocarcinoma after neoadjuvant chemotherapy and gastrectomy with D2 lymphadenectomy. Br J Surg. 2019;106(9):1187–1196. doi:10.1002/bjs.11181.
- Mranda GM, Xue Y, Zhou XG, et al. Revisiting the 8th AJCC system for gastric cancer: a review on validations, nomograms, lymph nodes impact, and proposed modifications. Ann Med Surg (Lond). 2022;75:103411.
- Blumenthaler AN, Newhook TE, Ikoma N, et al. The ypT category does not impact overall survival in node negative gastric cancer. J Surg Oncol. 2021;123(4):911–922. doi:10.1002/jso.25081.
- Sosa MS, Bragado P, Aguirre-Ghiso JA. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer. 2014;14(9):611–622. doi:10.1038/nrc3793.
- Goss PE, Chambers AF. Does tumour dormancy offer a therapeutic target? Nat Rev Cancer. 2010;10(12):871–877. doi:10.1038/nrc2933.
- Weston WA, Barr AR. A cell cycle centric view of tumour dormancy. Br J Cancer. 2023. doi:10.1038/s41416-023-02401-z.
- Li Z, Wang Y, Shan F, et al. ypTNM staging after neoadjuvant chemotherapy in the Chinese gastric cancer population: an evaluation on the prognostic value of the AJCC eighth edition cancer staging system. Gastric Cancer. 2018;21(6):977–987. doi:10.1007/s10120-018-0830-1.
- Li Z, Wang Y, Ying X, et al. Different prognostic implication of ypTNM stage and pTNM stage for gastric cancer: a propensity score-matched analysis. BMC Cancer. 2019;19(1):80. doi:10.1186/s12885-019-5283-3.
- Thomaschewski M, Hummel R, Petrova E, et al. Impact of postoperative TNM stages after neoadjuvant therapy on prognosis of adenocarcinoma of the gastro-oesophageal junction tumours. World J Gastroenterol. 2018;24(13):1429–1439. doi:10.3748/wjg.v24.i13.1429.
- Rice TW, Ishwaran H, Kelsen DP, et al. Recommendations for neoadjuvant pathologic staging (ypTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals. Dis Esophagus. 2016;29(8):906–912. doi:10.1111/dote.12538.
- Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. an attempt at a histo-clinical classification. Acta Pathol Microbiol Scand. 1965;64(1):31–49. doi:10.1111/apm.1965.64.1.31.
- Songun I, Putter H, Kranenbarg EM, et al. Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol. 2010;11(5):439–449. doi:10.1016/S1470-2045(10)70070-X.
- Shimizu K, Ito K, Matsunaga N, et al. Diagnosis of gastric cancer with MDCT using the water-filling method and multiplanar reconstruction: CT-histologic correlation. AJR Am J Roentgenol. 2005;185(5):1152–1158. doi:10.2214/AJR.04.0651.
- Sandø AD, Fougner R, Grønbech JE, et al. The value of restaging CT following neoadjuvant chemotherapy for resectable gastric cancer. A population-based study. World J Surg Oncol. 2021;19(1):212. doi:10.1186/s12957-021-02313-3.
- Sandø AD, Fougner R, Røyset ES, et al. Response evaluation after neoadjuvant chemotherapy for resectable gastric cancer. Cancers (Basel). 2023;15(8):2318. doi:10.3390/cancers15082318.
- Prasad P, Sivaharan A, Navidi M, et al. Significance of neoadjuvant downstaging in gastric adenocarcinoma. Surgery. 2022;172(2):593–601. doi:10.1016/j.surg.2022.03.005.
- Vandenbroucke JP, von Elm E, Altman DG, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. Ann Intern Med. 2007;147(8):W163–94. doi:10.7326/0003-4819-147-8-200710160-00010-w1.
- Sada YH, Smaglo BG, Tan JC, et al. Prognostic value of nodal response after preoperative treatment of gastric adenocarcinoma. J Natl Compr Canc Netw. 2019;17(2):161–168. doi:10.6004/jnccn.2018.7093.
- Wu L, Xing Z, Huang M, et al. Nodal downstaging to ypN0 after neoadjuvant chemotherapy positively impacts on survival of cT4N + GC/GEJ patients. J Surg Oncol. 2022;126(8):1403–1412. doi:10.1002/jso.27065.
- Zhong Q, Chen QY, Parisi A, et al. Modified ypTNM staging classification for gastric cancer after neoadjuvant therapy: a multi-institutional study. Oncologist. 2021;26(1):e99–e110. doi:10.1634/theoncologist.2020-0022.
- Li Z, Xiao Q, Wang Y, et al. A modified ypTNM staging system-development and external validation of a nomogram predicting the overall survival of gastric cancer patients received neoadjuvant chemotherapy. Cancer Manag Res. 2020;12:2047–2055. doi:10.2147/CMAR.S236696.
- Allgayer H, Leupold JH, Patil N. Defining the "metastasome": perspectives from the genome and molecular landscape in colorectal cancer for metastasis evolution and clinical consequences. Semin Cancer Biol. 2020;60:1–13. doi:10.1016/j.semcancer.2019.07.018.
- Reiter JG, Makohon-Moore AP, Gerold JM, et al. Reconstructing metastatic seeding patterns of human cancers. Nat Commun. 2017;8(1):14114. doi:10.1038/ncomms14114.
- Wu P, Gao W, Su M, et al. Adaptive mechanisms of tumor therapy resistance driven by tumor microenvironment. Front Cell Dev Biol. 2021;9:641469. doi:10.3389/fcell.2021.641469.
- Knight WRC, Baker CR, Griffin N, et al. Does a high mandard score really define a poor response to chemotherapy in oesophageal adenocarcinoma? Br J Cancer. 2021;124(10):1653–1660. doi:10.1038/s41416-021-01290-4.
- Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer. 2009;9(4):302–312. doi:10.1038/nrc2627.
- Stoecklein NH, Klein CA. Genetic disparity between primary tumours, disseminated tumour cells, and manifest metastasis. Int J Cancer. 2010;126(3):589–598. doi:10.1002/ijc.24916.
- Kamarajah SK, Navidi M, Wahed S, et al. Significance of neoadjuvant downstaging in carcinoma of esophagus and gastroesophageal junction. Ann Surg Oncol. 2020;27(9):3182–3192. doi:10.1245/s10434-020-08358-0.
- Rice TW, Lerut TE, Orringer MB, et al. Worldwide esophageal cancer collaboration: neoadjuvant pathologic staging data. Dis Esophagus. 2016;29(7):715–723. doi:10.1111/dote.12513.
- Zanoni A, Verlato G, Giacopuzzi S, et al. ypN0: does it matter how you get there? Nodal downstaging in esophageal cancer. Ann Surg Oncol. 2016;23(Suppl 5):998–1004. doi:10.1245/s10434-016-5440-8.
- Ikoma N, Estrella JS, Hofstetter W, et al. Nodal downstaging in gastric cancer patients: promising survival if ypN0 is achieved. Ann Surg Oncol. 2018;25(7):2012–2017. doi:10.1245/s10434-018-6471-0.
- 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.
- Kwee RM, Kwee TC. Imaging in local staging of gastric cancer: a systematic review. J Clin Oncol. 2007;25(15):2107–2116. doi:10.1200/JCO.2006.09.5224.
- Kwee RM, Kwee TC. Imaging in assessing lymph node status in gastric cancer. Gastric Cancer. 2009;12(1):6–22. doi:10.1007/s10120-008-0492-5.
- Yan C, Zhu ZG, Yan M, et al. Value of multidetector-row computed tomography in the preoperative T and N staging of gastric carcinoma: a large-scale Chinese study. J Surg Oncol. 2009;100(3):205–214. doi:10.1002/jso.21316.