British Journal of Surgery 2021 ;Volum 108.(2) s. 119-127
Systematic review of histological tumour response scoring in resected pancreatic cancer following preoperative
chemo(radio)therapy
Stijn van Roessel, MD, MSc1, Boris V. Janssen, BSc1, Eline C. Soer, MD2, Arantza Fariña Sarasqueta, MD, PhD2, Caroline S. Verbeke, MD, PhD3, Claudio Luchini, MD, PhD4, Lodewijk A.A. Brosens, MD,
PhD5,6, Joanne Verheij, MD, PhD2 and Marc G. Besselink, MD, MSc, PhD1
Affiliations:
1Department of Surgery, Cancer Centre Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
2Department of Pathology, Cancer Centre Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
3Department of Pathology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
4Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
5Department of Pathology, University Medical Centre Utrecht, Utrecht, The Netherlands
6Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
Corresponding author:
Marc G. Besselink, MD MSc PhD
Department of Surgery, Cancer Centre Amsterdam Amsterdam UMC, University of Amsterdam Meibergdreef 9, 1105 AZ Amsterdam Phone: +31 20 566 5570
Email: m.g.besselink@amsterdamumc.nl
Conflict of interest: None declared Funding: No funding obtained Word count: 3,461
ABSTRACT
Word count: 248/250
BACKGROUND
Preoperative chemo(radio)therapy is increasingly used in pancreatic cancer. Histological evaluation of the tumour response provides information on the efficacy of preoperative treatment and is used to determine prognosis and guide decisions on adjuvant treatment. This systematic review aims to provide an overview of the current evidence on tumour response scoring systems in pancreatic cancer.
METHODS
Studies reporting on the assessment of resected pancreatic ductal adenocarcinoma following neoadjuvant chemo(radio)therapy were searched using PubMed and EMBASE. All original studies reporting on histological tumour response in relation to clinical outcome (i.e. survival, recurrence-free survival) or interobserver agreement were eligible for inclusion. This systematic review followed the PRISMA guidelines.
RESULTS
The literature search yielded 1453 studies of which 25 met the eligibility criteria, revealing 13 unique scoring systems. The most frequently investigated tumour response scoring systems were the College of American Pathologists system, Evans scoring system, and MD Anderson Cancer Center system, investigated 11, 9 and 5 times, respectively. Although 6 studies reported a survival difference between the different grades of these three systems, the reported outcomes are often inconsistent. In addition, 12 studies (48%) did not report on crucial aspects of pathology examination such as the method of dissection, sampling approach, and amount of sampling.
CONCLUSIONS
Numerous scoring systems for the evaluation of tumour response after preoperative chemo(radio)therapy in pancreatic cancer exist, but comparative studies are lacking. More comparative data are needed on the interobserver variability and prognostic significance of the various scoring systems before best practice can be established.
INTRODUCTION
Preoperative chemo(radio)therapy is increasingly used in the treatment of patients with borderline resectable and locally advanced pancreatic cancer because of improved patient selection, increased margin-negative resection rates and ultimately improved survival.1, 2 Two recent randomized controlled trials and a meta-analysis of non-randomized studies supported the use of neoadjuvant/induction chemo(radio)therapy in (borderline) resectable pancreatic cancer, although further studies are needed and ongoing.3-5 Histopathological tumour response grading following preoperative treatment is used for several cancers (e.g. oesophageal cancer) and provides additional information that might not be obtained from the traditional histopathologic descriptors.6 Ideally, assessment of the tumour response should reflect the effectiveness of the neoadjuvant agents/regimes and predict patient survival.7, 8
Consensus on how to assess the tumour response to preoperative therapy is lacking. Several systems with different criteria and cut-off values to quantify tumour response have been proposed.9, 10 Some systems estimate the tumour size prior to treatment (generally by looking at the area of fibrosis), whereas other systems focus on residual cancer cells or a combination of both. After quantifying the tumour response (either by degree of regression, residual size of viable tumour or a combination), categorization represents the next challenge. Subdividing the histological tumour response into categories faces a trade-off between obtaining maximum stratification in clinically relevant categories with distinct prognoses while maintaining simplicity to warrant inter-observer agreement and applicability in daily practice.11, 12 In addition to the inherent heterogeneous morphology of pancreatic cancer (pertaining to microscopic inter- and intra-tumoural differences in growth pattern, grade of differentiation, and tumour stroma; all assumed to mirror molecular differences),13 the effect of neoadjuvant therapy is often patchy in distribution.14 Both make the establishment of a prognostic and reproducible system for tumour response scoring in pancreatic cancer challenging.
This systematic review aims to provide an overview of both existing tumour response scoring systems and series that evaluate the prognostic significance or measures of reproducibility of tumour response scoring systems following preoperative chemo(radio)therapy in resected pancreatic cancer.
METHODS Literature search
This systematic review was performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.15 Search strategies were constructed using the following core terms and all synonyms: ‘Pancreatic cancer’, ‘Neoadjuvant’, and
‘Histo(patho)logical assessment’ for both PubMed and EMBASE (exact search is listed in Supplementary Table S1). Literature screening, eligibility assessment, and inclusion were completed independently by two assessors (SvR, BJ) with discrepancy being resolved by discussion. The remaining literature underwent full-text analysis, resulting in the final inclusion.
Eligibility criteria
The following eligibility criteria were applied: studies had to be A) original research, B) describing scoring systems that examine histological tumour response, C) in relation to measures of prognostic significance or reproducibility, D) in surgical specimens from patients who underwent pancreatic surgery for pancreatic ductal adenocarcinoma following preoperative chemotherapy or chemoradiotherapy.
For studies to be included based on prognostic significance, studies had to contain outcomes of the scoring system in relation to overall survival (OS), disease-free survival (DFS) or recurrence-free survival (RFS), described by either Kaplan-Meier survival estimates or hazard ratios from univariate or multivariate analysis. For studies to be included regarding reproducibility, studies had to report measures on interobserver variability (multiple raters assessing the same sample), generally expressed in a kappa value. Case-series only reporting on a selection of patients (for example only patients with complete response) instead of consecutive patient series were not included, nor were those only reporting on tumour response after only radiation therapy.
Data extraction and analysis
Two independent assessors (SvR, BJ) performed the data extraction. Discrepancies were resolved by discussion between authors. From included literature, the following information was extracted: first author, year of publication, study design, sample size, resectability status, type of neoadjuvant therapy, histopathological information (method of dissection, sampling approach [e.g. sampling of all that was not entirely normal, of all that looked like tumour, of most of the tumour], and amount of samples [e.g.
number of slides, median and range]), scoring system, distribution of patients over different categories, which groups were compared, type of statistical analysis, outcome measures regarding prognostic significance (in terms of overall survival, disease-free survival, and recurrence-free survival), and results regarding interobserver agreement (in terms of kappa or other concordance/discordance measures). A qualitative analysis of the data from the included studies was performed. Based on this qualitative analysis, an overview was created of the tumour response scoring systems that were used, and studies reporting on the various scoring systems were summarized in tables. Due to statistical limitations and the nature of the data, we were unable to perform a meta-analysis (e.g. pooled survival analysis).
Methodology assessment
To evaluate the methodology of each scoring system systematically, the PROBAST (Prediction model Risk Of Bias ASsessment Tool) tool was modified according to characteristics deemed relevant for a tumour response scoring system (based on items from the TRIPOD [Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis] statement).16, 17 Scoring systems were evaluated based on five Risk of Bias (ROB) aspects and two Applicability aspects, with each domain being judged as high risk of bias/poor applicability (0 points), low risk of bias/good applicability (1 point), or unclear (0 points), see Table 1. This methodology assessment was performed by two independent assessors (SvR, BJ). Discrepancies were resolved by discussion between authors.
RESULTS Literature search
In total, the literature search yielded 1448 unique studies. Additional searching yielded another five studies. After screening 1453 articles, 54 were selected for full-text screening and eventually 25 studies were included in this systematic review (see PRISMA flow chart, Figure 1). Of those, 23 studies reported on one or more scoring systems in relation to clinical outcome, and 2 studies evaluated the interobserver agreement of multiple scoring systems.
Tumour response scoring systems
Overall, 13 unique tumour response scoring systems were identified (Table 2). The most frequently reported scoring systems were the College of American Pathologists (CAP) system, Evans system, and MD Anderson Cancer Center (MDACC) system, which were assessed 11, 9, and 5 times, respectively.
The first published system, the Evans system (1992), is a 5-tiered, percentage-based system scoring the extent of destroyed tumour.9 The College of American Pathologists system (2010) is a descriptive 4-tiered system based on the amount of residual cancer,18 which is a modification of the Ryan scheme for rectal cancer.19 The 3-tiered MD Anderson Cancer Center system was proposed in 2012 as a modification of the 4-tiered College of American Pathologists system by combining grade 2 and 3 in addition to introducing a threshold value for the percentage of residual cancer.20 In addition to these frequently used systems, ten other systems were identified (also in Table 2), which were evaluated in ten studies altogether.
Pathology assessment
Nearly half of the included studies (12/25) did not report on crucial aspects of histopathology examination such as the method of dissection, sampling approach and amount of sampling (Table 3).
The remaining studies reported on at least one of these aspects (in varying levels of detail). Six studies reported the dissection method,21-26 eight studies reported on the sampling approach,20, 23, 26-31 and three studies reported the number of slides that were assessed (Kalimuthu et al., range of 7-20 slides per specimen; Chatterjee et al. mean number of slides 14 with a range of 3-45; Zhang et al., 1 slide per specimen).20, 31, 32 Only two studies reported on both the sampling approach and the amount of samples,20, 31 and one study reported on both the dissection method and the sampling approach.26
Association with clinical outcome
All clinical outcomes reported by the included studies are presented in Table 2. Of all studies analysed, 21 (84%) included patients who received chemoradiotherapy. The remaining studies included patients who only received neoadjuvant chemotherapy. Of the studies reporting on the College of American Pathologists system, two studies, including a total of 468 patients, demonstrated a survival difference between grades, although in both studies groups were combined (grade 0 vs. 1/2 [mOS not reached vs.
40 months; p = 0.011] in Macedo et al.; grade 0/1 vs. 2/3 [mOS 72 vs. 35 months; p < 0.001] in Truty et al.).33, 34 Three further studies, including 196 patients, did not find significant differences in survival between patients, even though patients with different College of American Pathologists scores were combined.23, 24, 35 From the studies reporting on the Evans system, only one study found a survival difference between groups (Evans 1/2A vs. 2B/3/4/5 [13.1% vs. 71.3%; p = 0.01] in Murata et al. [n = 40]), whereas two other studies did not (Evans 1/2A/2B vs. 3/4 [HR 1.264; p = 0.327] in Akita et al. [n = 83]; Evans 1 vs. 2A/2B/3/4 [mOS 19 months vs. 32 months; p=0.42] in Heinrich et al. [n = 24]).21, 36, 37
Three studies investigated the MD Anderson Cancer Center system. All three studies, with a total of 1148 patients (although potentially double-counting patients due to same centre and overlap of study period), demonstrated a survival difference between grouped MD Anderson Cancer Center grades (grade 0/1 vs. 2 [mOS 73 months vs. 29 months; p < 0.001] in Cloyd et al.; grade 1 vs. 2/3 [HR 1.52; p
= 0.03] in Chatterjee et al.; grade 0/1 vs. 2 [mOS 54 months vs. 44 months; p = 0.02] in Lee et al.).25, 26,
38
Interobserver agreement
Two studies assessed interobserver variability. In one study slides of 14 patients were assessed by four raters, and the authors used as a concordance measure the Kendall’s Concordance Coefficient (KCC), which can be interpreted as regular kappa (<0.20=poor, 0.21–0.4 fair, 0.41–0.6 moderate, 0.61–0.8 good, 0.81–1.00 very good interobserver agreement).32, 39 According to the authors, the MD Anderson Cancer Center system performed best (Kendall’s Concordance Coefficient range: 0.00-0.67), followed by the Evans (Kendall’s Concordance Coefficient range: 0.36-0.74) and College of American Pathologists systems (Kendall’s Concordance Coefficient range: 0.18-0.4).32 In another study, slides of 29 patients were assessed by 2 raters according to 5 scoring systems (Evans, College of American
Pathologists, MD Anderson Cancer Center, Hartman, and iDworak), and results were also presented as the Kendall’s Concordance Coefficient.29 The iDworak is a system created by Insilla et al., based on the Dworak score which is used for colorectal cancer.29, 40 According to their study, the iDworak and Hartman systems performed best (0.913 and 0.830, respectively), followed by the College of American Pathologists system, Evans and MD Anderson Cancer Center systems (0.644, 0.566, 0.521, respectively).29
Overall assessment of scoring systems
Methodology assessment of all encountered scoring systems is shown in Figure 2. The College of American Pathologists system and MD Anderson Cancer Center system score best on overall methodological quality (4.5 out of 7 points).
DISCUSSION
This systematic review provides outcomes from 13 different tumour response scoring systems following preoperative chemo(radio)therapy in resected pancreatic cancer. The College of American Pathologists, MD Anderson Cancer Center, and Evans systems are the most widely used and studied, whereas the College of American Pathologists and MD Anderson Cancer Center system have the best methodological quality, although both systems still have imperfections. Some studies have compared the most important tumour response scoring systems regarding interobserver variability but large studies comparing these scoring systems regarding prognostic significance are lacking. Information on relevant details of histopathology assessment is often lacking.
Contradicting findings have been reported regarding the prognostic accuracy of the most commonly used systems. Whereas some studies show accurate discrimination of prognosis by the College of American Pathologists scoring system,33, 34 others do not.23, 24, 35 Grouping of different tumour response grades is often performed to increase statistical power in analysing the prognostic accuracy and to find clinically relevant cut-offs. The MD Anderson Cancer Center system originated from the College of American Pathologists system and was created by combining College of American Pathologists grade 2 and 3 as those were found to correlate with a similar prognosis. Several studies reported increased predicted accuracy by the three-tiered MD Anderson Cancer Center system,25, 26, 38 although two of the three categories were often combined, turning it basically into a dichotomous system. These studies were also reported by the same institution (MD Anderson) and may have contained the same patients due to overlapping study periods.25, 26, 38
The majority of included studies were relatively small, as approximately 60% of the studies reported on less than 100 patients. Complete response rates (when similarly interpreted from each system) varied from 0 to 11% in the included studies, which demonstrates that a large number of patients is required to achieve accurate survival estimates for this small group of patients. It should be kept in mind, however, that even the group with complete response is highly heterogeneous in terms of initial tumour characteristics (such as T stage, N stage, tumour grade), type of neoadjuvant regimen, and resectability status. Large international prospective studies with standardized data collection are required to overcome these issues. It also remains unknown to which extent preoperative radiotherapy contributes in tumour response. Of all studies analysed in this systematic review, 21 (84%) included patients who
received chemoradiotherapy. The effect of radiotherapy on tumour response is unfortunately not reported separately, which hampers exact interpretation of its effect. A further problem that has not been addressed so far, is the fact that the biological effects and especially the kinetics of the treatment- induced cellular changes, may well differ between chemo- and radiotherapy. Indeed, experience from treatment of rectal cancer shows that the full cytoreductive effect of radiotherapy develops over a longer period of time than that of chemotherapy.41, 42 Unfortunately, corresponding insight is currently lacking for pancreatic cancer.
Only two studies evaluated the interobserver agreement of tumour response scoring in resected pancreatic cancer following neoadjuvant therapy. One study based on only 14 specimens showed more favourable results for the MD Anderson Cancer Center system, which the authors attributed to the
‘oversimplification’ of the system (three grades in the MD Anderson Cancer Center system vs. four in College of American Pathologists and five in Evans).32 A more complex system (i.e. more categories) is likely more susceptible to higher interobserver variability, whereas fewer tiers naturally result in higher levels of agreement (at the cost of discriminative ability). The results are meanwhile difficult to interpret, since the authors present ranges of kappa per scoring system (MD Anderson Cancer Center range Kendall’s Concordance Coefficient: 0.00-0.67; Evans range Kendall’s Concordance Coefficient: 0.36- 0.74; College of American Pathologists range Kendall’s Concordance Coefficient: 0.18-0.4) instead of one kappa value per scoring system. In contrast, the other interobserver study based on 29 specimens concluded that the MD Anderson Cancer Center system performed worse than College of American Pathologists and Evans.29 When it comes to interobserver variability, this study favoured the iDworak and Hartman systems.29 As such, new systems or systems that were originally developed for other cancers demonstrate promising characteristics, but require further (external) validation. The study by Insilla et al. is in line with the findings by Kalimuthu et al., as it indicates that the most frequently used scoring systems (MD Anderson Cancer Center, College of American Pathologists and Evans) suffer from interobserver variation, which still presents one of the main unaddressed issues in this setting. In general, results from both interobserver studies should be interpreted with appropriate caution as they are both retrospective, and sample sizes are considerably small (both n < 30).29, 32
Another review on tumour response scoring was recently published by the MD Anderson group, in which they conclude that the MD Anderson Cancer Center system was found to be an independent prognostic
marker with improved interobserver agreement.43 However, at present, these observations are not uncontested. First, because multiple tumour response scoring systems have shown to be independent prognostic markers. Second, when it comes to interobserver agreement, Kalimuthu et al. attribute the superiority of the MD Anderson Cancer Center system to ‘oversimplification’,32 whereas the other interobserver study (performed by Insilla et al.) showed that interobserver agreement was poorer for the MD Anderson Cancer Center system as compared to 4 other scoring systems.29 As such, current evidence is contradictory and insufficient for the recommendation of a particular system as best practice.
The approach and amount of sampling are known to influence multiple pathology-based parameters, including TNM staging and margin status.44, 45 Similarly, the approach to and amount of sampling will likely influence the assessment of tumour response after neoadjuvant therapy due to the often patchy nature of tumour response.13, 14 This is of particular importance for assessment of complete and near- complete response. Only five studies indicated how a diagnosis of (near-) complete response was reached by stating which additional steps were taken when no tumour was found upon initial evaluation.20, 26, 27, 30, 31 Of note, not a single study provided information on the initial sampling approach.
It is important to note that the number of slides only indicate the extensiveness of sampling, as the number of slides depends on the size of the lesion. For example, for a fairly small, but critically located borderline resectable pancreatic cancer, the number of slides may be significantly smaller than for a large locally advanced pancreatic cancer. By reporting both 1) the number of slides (supplemented by the median and range), and 2) the sampling approach, more representative reporting of the sampling extent may be established. We are aware that descriptions of the sampling approach are still subjective and leave room for interpretation, however, without any information on the sampling approach, it remains difficult to interpret results and outcomes of patients with complete response, let alone compare results from different studies. From this point of view, future studies should at least report very clearly the method of dissection, the approach of sampling, and the amount of sampling.
A worldwide survey-based study from 2019 showed that for esophagogastric cancer, the College of American Pathologists and Mandard systems are used most frequently (range: 29 – 36%, and range:
25 – 36%, respectively), with 28 – 39% of pathologists using ≥ 7 other systems.46 For rectal cancer, the College of American Pathologists and Dworak systems are used most frequently (38% and 24%,
respectively), with 38% of pathologists using ≥ 6 other systems.46 These survey outcomes highlight the persistent differences in practice between pathologists and suggest that robust evidence is lacking also for these types of cancer. Chetty et al. investigated interobserver variability of tumour response scoring in rectal cancer and concluded that the most commonly used systems demonstrated poor interobserver agreement (Mandard kappa 0.28 and Dworak kappa 0.35).47 Trakarnsanga et al. compared the predictive accuracy in C-indices of four tumour response scoring systems in rectal cancer and concluded that the American Joint Committee on Cancer system (comparable to the College of American Pathologists system in pancreatic cancer) performed best with a C-index of 0.69.48 For oesophageal cancer, the Becker and Mandard systems have demonstrated relatively high kappa values (Mandard weighted kappa 0.68, Becker weighted kappa 0.78).49 Furthermore, the percentage-based system by Wu et al. also showed an excellent interobserver agreement (kappa 0.84) in oesophageal cancer.12 Tumour response scoring in other cancers generally appear to achieve higher interobserver agreement than found within pancreatic scoring systems (except for rectal cancer), potentially related to the heterogeneous presentation of pancreatic cancer itself and its response to neoadjuvant therapy.
The degree of tumour response is expected to correlate with disease-free survival and overall survival after surgery. Hence, tumour response scoring could be used to stratify patients in postoperative clinical trials and to identify those patients who are most likely to benefit from adjuvant treatment due to a high risk of disease recurrence. Second, tumour response scoring could potentially guide the choice of adjuvant (chemo)therapy. Little or no tumour response in the resection specimen would indicate that the tumour is resistant to earlier administered agent(s) and as such guide clinicians to administer adjuvant therapy that targets different biological mechanisms. Third, tumour response scoring could function as a potential surrogate outcome in studies comparing the effectiveness of various neoadjuvant regimens. More extensive tumour response in one treatment group could indicate superior treatment effect.
In summary, this systematic review provides an overview of studies investigating tumour response scoring systems following preoperative chemo(radio)therapy in resected pancreatic cancer. There is currently little to no evidence that a particular system outperforms others, and there are only a few studies that compare systems. This makes the identification of a preferred scoring system difficult. Even
if a scoring system may show (relatively) favourable reproducibility, a weak prognostic significance would limit its utility in clinical practice. Nevertheless, accurate tumour response scoring systems to determine the efficacy of neoadjuvant regimes in ongoing and future randomized studies are highly desirable. Further, large pragmatic studies in this field are clearly needed.
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Table 1. Methodology assessment of tumour response scoring systems
Item Criteria
Risk of bias 1. Meaningful stratification: the system has ≥ 3 tiers, allowing for clinically meaningful stratification between groups, as a dichotomous tumour response scoring system was deemed less informative.20, 26
Risk of bias 2. Internal validity: the scoring system is based on the assessment of presence of residual (viable) tumour, without any assumptions on tumour size prior to neoadjuvant treatment (by, for example, estimating the tumour size prior to treatment by looking at the area of fibrosis).
Risk of bias 3. Objective definitions: categories with unambiguous definitions based on residual tumour.
Risk of bias 4. Validation: the scoring system is validated in an independent cohort (i.e. having significantly correlated with clinical outcomes in ≥ 2 separate cohorts).
Risk of bias 5. Prognostication: correlation with overall survival and progression-free survival without combining different categories.
Applicability 1. Ease of use: the tumour response scoring system is deemed to be (relatively) easily applied in daily practice by most pathologists, and does not require the use of additional tools (i.e.
computational systems).
Applicability 2. Reproducibility: demonstrating moderate (kappa: 0.5 – 0.7; 0.5 points) or good interobserver agreement (kappa > 0.7; 1 point).
Table 2. Different scoring systems following neoadjuvant therapy in resected pancreatic cancer
Scoring system Grade Criteria
Evans et al. (1992)9 1
2a 2b 3 3M 4 4M
Characteristic cytologic changes of malignancy are present, but little (< 10%) or no tumour, Cell destruction is evident.
Destruction of 10–50% of tumour cells Destruction of 51–90% of tumour cells
< 10% viable appearing tumour cells present Sizable pools of mucin are present.
No viable tumour cells present Acellular pools of mucin are present Moutardier et al. (2004)30 1
2 3 4 5
Tumour progression Stable disease Minor response Major response Complete response College of American Pathologists
(CAP).
Washington et al. (2010)18
0 1 2 3
No viable cancer cells
Single cells or rare small groups of cancer cells
Residual cancer with evident tumour regression, but more than single cells or rare small groups of cancer cells
Extensive residual cancer with no evident tumour regression Chun et al. (2011)50 Major response
Partial response Minor response
> 95% fibrosis 50-94% fibrosis
< 50% fibrosis MD Anderson (MDACC)
Chatterjee et al. (2012)20 0 1 2
No residual carcinoma
Minimal residual carcinoma (single cells or small groups of cancer cells; < 5% residual carcinoma)
5% or more carcinoma Hartman et al. (2012)51 Marked response
Minimal to moderate response
Poor response
No residual tumour or rare, single cancer cells or small groups of cancer cells (glands) with marked cytopathic effect present within a fibrotic stroma.
Residual tumour present; includes small groups of cells/glands without evidence of cytopathic effect, cells/ glands outside the main fibrotic mass, and or 0,5% of the main fibrotic mass with cancer glands, with or without cytopathic effect.
No definitive evidence of treatment effect; extensive (90%) residual cancer; only minimal cytopathic effect, and baseline fibrosis present.
Townend et al. (2017)22 1 < 65%
2 ≥ 65% < 65% histopathological tumour viability
≥ 65% histopathological tumour viability Residual tumour index (RTI)
Panni et al. (2018)52
1 2 3
‘Tumour bed’ size (cm) / residual tumour (%) ≤ 0.2
‘Tumour bed’ size (cm) / residual tumour (%) 0.2 to 2
‘Tumour bed’ size (cm) / residual tumour (%) >2 He et al. (2018)53 Limited response
Partial response
Pathological complete response
Primary tumour > 1 cm or metastasis Primary tumour < 1 cm
No residual tumour Residual tumour cellularity (RTC)
Rowan et al. (2019)54 1
2 < 4 % residual carcinoma
4 or more % residual carcinoma
Area of residual tumour (ART)
Okubo et al. (2019)23 ART ≤ 220 mm2
ART > 220 mm2 Area of residual tumour ≤ 220 squared millimeters Area of residual tumour > 220 squared millimeters Microscopic focus size (MFS)
Zhang et al. (2020)31 MFS ypT0 MFS ypT1 MFS ypT2
No evidence of primary tumour Largest single MFS on one slide ≤ 2 cm Largest single MFS on one slide > 2 cm iDworak.
Insilla et al. (2020)29 Grade 0 Grade 1 Grade 2 Grade 3 Grade 4
Dominant tumour mass with poor prognosis.
Dominant tumour mass with obvious fibrosis.
Dominant fibrotic tissue with few neoplastic cells/glands, easy to find.
Dominant fibrotic tissue with very few neoplastic cells/glands, difficult to find
Complete regression.
Table 3. Studies describing scoring systems following neoadjuvant therapy in resected pancreatic cancer in relation to clinical outcome or interobserver agreement
Author
(year) Total
n Resectability
status Dissection method, sampling approach and amount
Distribution Analysis Outcome
Scoring system: College of American Pathologists (CAP) Macedo et
al. (2019)33 274 RPC=61 BRPC=127 LAPC=70 Unknown=16
n.r. CAP 0=13
CAP 1/2=124 CAP 3=83
KM analysis/Logrank
CAP 0 (n=13) vs. CAP 1/2 (n=124)
CAP 1/2 (n=124) vs. CAP 3 (n=83)
CAP 0 (n=13) vs. CAP 1/2 (n=124)
Median OS NR vs. 40.3 months p=0.011
40.3 vs. 26.1 months p < 0.001
NR vs. 40.3 months p=0.245
Bolton et al. (2018)35 195
(62) RPC=133
BRPC=62 n.r. CAP 0=4
CAP 1=10 CAP 2=24 CAP 3=24
KM analysis/Logrank
CAP 0/1 (n=14) vs. CAP 2/3 (n=48) KM 2-year survival rate/Logrank CAP 0 (n=3) vs. CAP1/2/3 (n=50)
p=0.13
100% vs. 36%
p=0.06 Truty et al.
(2019)34 194 BRPC=123
LAPC=71 n.r. CAP 0=20
CAP 1=55 CAP 2=95 Cap 3=24
Multivariate Cox (Adjusted for CA19- 9 response, > 6 chemo cycles) CAP 0/1 (n=75) vs. CAP 2/3 (n=119) KM analysis/Logrank
CAP 0/1 (n=75) vs. CAP 2/3 (n=119)
HR 0.16 (0.1-0.4) p < 0.001
Median OS 72.1 vs. 34.5 months p < 0.001
Peng et al.
(2019)24 71 BRPC=71 Dissection:
multivalving + orange peeling Sampling: n.r.
CAP 0=4 CAP 1=12 CAP 2=42 CAP 3=13
KM analysis/Logrank
CAP 0/1 (n=16) vs. CAP 2 (n=42) vs.
CAP 3 (n=13)
Median OS 50.0 vs. 31.7 vs. 23.2 p=0.563
Scoring system: Evans Murata et
al. (2012)21 40 (only T3)
LAPC=40 Dissection: axial slicing Sampling: n.r.
Evans 1/2A=27
Evans 2B or higher=13 KM analysis/Logrank
Evans 1/2A (n=27) vs. Evans 2B or higher (n=13)
3-year OS rate:
29.6% vs. 68.4%, p=0.094 3-year RFS rate:
13.1% vs. 71.3%, p=0.01 Akita et al.
(2017)36 83 RPC=65
BRPC=18 n.r. Evans 1=11
Evans 2A=31 Evans 2B=27 Evans 3=11 Evans 4=3
Univariate Cox
Evans 1/2 (n=69) vs. Evans 3/4 (n=14) ref
HR 1.264 (0.791 - 2.019)
p=0.327
Heinrich &
Shafer et al. (2008)37
24 RPC=24 n.r. Evans 1=11
Evans 2A=5 Evans 2B=8 Evans 3=0 Evans 4=0
Univariate Cox Cut-off:
Evans 0/1 (n=11) vs. Evans 2/3/4 (n=13)
Median OS 32.4 vs. 19.1 months p=0.42
Scoring system: MD Anderson Cancer Center (MDACC, Chatterjee 2012) Cloyd et al.
(2017)25 583 RPC=425 BRPC=110 LA=45
Dissection:
multivalving (SMA margin entirely submitted) Sampling: n.r.
MDACC 0/1=
77 (13%) MDACC 2=
506 (87%)
KM analysis/ Logrank
< 5% residual cells (n=77) vs.
≥ 5% residual cells (n=506)
Median OS 73.4 vs. 28.8 months p=<0.001
Chatterjee et al.
(2017)38
398 n.r. n.r. MDACC 0=9 (2.3%)
MDACC 1=54 (13.6%) MDACC 2=335 (84.2%)
Multivariate Cox (adjusted for tumour grade, R, ypT and ypN)
MDACC 1 (n=54) vs. MDACC 2/3 (n=335)
HR 1.52 (1.03-2.24) p=0.03
Scoring system: Multiple systems Rowan et
al. (2019)54 76 n.r. n.r. CAP 1=4
CAP 2=26 CAP 3=46 Evans 1=2 Evans 2A=44 Evans 2A=26 Evans 3=4 TSR < 4%=38 (50%) TSR > 4%=38 (50%)
CAP
KM analysis/Logrank CAP 1,2 and 3 seperate Evans
KM analysis/Logrank Evans 1,2A,2B and 3 seperate TSR
Multivariate Cox (Adjusted for T)
<4% (n=38) vs. > 4% (n=38)
p=0.61
p=0.8
HR 1.954 (1.01-3.77) p=0.046
KM analysis/ Logrank
<4% (n=38) vs. > 4% (n=38) Median OS n.r.
p=0.055 Chatterjee
et al.
(2012)20
223 n.r. Dissection: n.r.
Sampling approach:
in case of pCR, cytology and imaging studies were reviewed.
Sampling amount:
mean number of slides 14 (range 3- 45).
CAP 0=6 (2.7%) CAP 1=36 (16.1%) CAP 2=124 (55.6%) CAP 3=57 (25.6%) Evans I=18 (8.1%) Evans IIA=39 (17.5%) Evans IIB=124 (55.6%) Evans III=36 (16.1%) Evans IV=6 (2.7%)
Mutivariate Cox (adjusted for ypT stage, ypN stage, R)
CAP 2/3 (n=181) vs. CAP 0/1 (n=42) ref
HR 1.89 (1.09-3.28) p=0.01
Lee et al.
(2016)26 167 n.r. Dissection:
multivalving (SMA margin entirely submitted) Sampling approach:
in case of HTRG 0/1 the entire pancreas, common bile duct and ampulla of Vater were submitted to confirm the absence of PDAC
Sampling amount:
n.r.
CAP 0=3 CAP 1=18 CAP 2=95 CAP 3=51 MDACC 0/1=21 MDACC 2=146
Multivariate Cox (adjusted for grade, ypN, ypT)
MDACC 0/1 ref (n=21) vs.
MDACC 2 (n=146) KM analysis/ Logrank MDACC 0/1 (n=21) vs.
MDACC 2 (n=146)
HR 1.80 (0.86-3.78) p=0.12
Mean OS 54.0 vs 44.4 months p=0.02
Chuong et
al. (2016)27 36 BRPC=36 Dissection: n.r.
Sampling approach:
if no residual tumour was identified, the entire residual area with fibroses was submitted.
Sampling amount:
n.r.
CAP 0=4 (11%) CAP 1=13 (36%) CAP 2=15 (42%) CAP 3=4 (11%) Evans IV=4 (11%) Evans III=6 (17%) Evans IIB=11 (31%) Evans IIA=11 (31%) Evans I=4 (11%)
CAP analysis
KM analysis/Logrank
Evans 2B/3/4 (n=32) vs. Evans I (n=4)
CAP no significance, no details given.
Median OS 22.9 vs. 14.5 months p=0.019
Kim et al.
(2019)28 32 RPC=6 BRPC=20 LAPC = 4 Unknown = 2
Dissection: n.r.
Sampling approach:
pathologic treatment response was graded based on the slide with the greatest amount of tumour according to CAP and Evans Sampling amount:
n.r.
CAP 1=5 CAP 2=18 CAP 3=9 Evans 4=0 Evans 3=10 Evans 2B=8 Evans 2A=7 Evans 1=7
KM analysis/ Logrank 1) CAP 1, 2, 3 seperate 2) Evans 1, 2a, 2b and 3 seperate
3) CAP 1/2 (n=23) vs. CAP 3 (n=9) 4) Evans 1, 2A and 2B (n=22) vs. Evans 3 (n=10)
Median OS 1) CAP 1=NR CAP 2=34.2 months CAP 3=12.6 months p=0.0051
2) Evans 1=12.6 months Evans 2A=NR Evans 2B=18.8 months Evans 3=NR p=0.0406 3) NR vs. 12.6 months p=0.0023 4) 13.5 vs. 24.7 months p=0.0208
Kalimuthu et al.
(2016)32
14 BRPC=14 Dissection: n.r.
Sampling approach:
n.r.
Sampling amount:
range 7-20 slides per specimen
Raters (n=4x14):
Distribution among tiers not reported.
Kendall concordance coefficient (KCC), comparable to kappa:
<0.20=poor 0.21–0.4=fair 0.41–0.6=moderate 0.61–0.8=good 0.81–1.00=very good
KCC range:
CAP 0.18-0.4 Evans 0.36-0.74 MDACC 0.00-0.67
Insilla et al.
(2020)29 29 LAPC=29 Disection: n.r.
Sampling approach:
not specifically (“All scores were assigned after the complete evaluation of all slides and not based on representative tumour samples”) Sampling amount:
n.r.
Raters (n =2x29) Distribution among tiers not reported.
Kendall concordance coefficient (KCC), comparable to kappa:
<0.20=poor 0.21–0.4=fair 0.41–0.6=moderate 0.61–0.8=good 0.81–1.00=very good
KCC range:
CAP 0.644 Evans 0.566 MDACC 0.521 Hartman 0.830 iDworak 0.913
Scoring system: Other systems
He et al.
(2018)53 186 BRPC=85
LAPC=97 n.r. LR=135
NCR=29 PCR=18
Multivariate Cox (adjusted for radiation modality, chemo regiment, R, Perineural Invasion, N) PCR (n=18) vs. LR (n=135) ref
HR 0.41 (0.17 - 0.97) p=0.044
Chun et al.
(2011)50 107 n.r. n.r. Major=21
Minor or Moderate=86 Multivariate Cox
Major (n=21) vs. Minor or Moderate (n=86)
HR 2.26 (1.11 - 4.61) p=0.025
Panni et al.
(2018)52 105 n.r. n.r. RTI ≤ 0.35=23
RTI > 0.35=82 RTI < 0.2=26 RTI 0.2 - 2=64 RTI > 2=15
Multivariate Cox (Adjusted for N)
RTI < 0.35 (n=31) vs. RTI > 0.35 (n=82)
KM analysis/Logrank
RTI < 0.35 (n=31) vs. RTI > 0.35 (n=82)
KM analysis/Logrank
RTI < 0.2 (n=26) vs RTI < 2 (n=15)
HR 2.40 (1.01 - 5.66) p=0.05
Median OS NR vs. 1.82 years p < 0.01 Median OS n.r.
p < 0.01 Chen et al.
(2013)55 83 n.r. n.r. Major=21 (25%)
Partial=58 (70%) Minor=4 (5%)
KM analysis/Logrank
Minor/partial (n=62) vs. major (n=21)
Median OS 20 vs. 88 months p=0.003 White et al.
(2005)10 67 n.r. n.r. None=3
Minimal=5 Small=13 Moderate=25 Large=8
Multivariate Cox
(Adjusted for presence of tumour necrosis, differentiation, N and R) None to moderate (n=46) vs.
Large (n=8)
No HR or CI given p < 0.01
Moutardier et al.
(2004)30 61
(40) RPC=40 Dissection: n.r.
Sampling approach:
When no residual tumour was found on the first microscopic examination, serial sections of the pancreatic specimen were performed.
Sampling amount:
n.r.
Tumour progression=5 Stable disease=15 Minor response=10 Major response=6 Complete response=3
KM analysis/Logrank Major/Complete (n=9) vs.
All other (n=31)
Median OS n.r. (months) p < 0.005
Townend et
al. (2017)22 42 n.r. Dissection: axial slicing Sampling: n.r.
< 65% =21
≥ 65% =21
KM analysis/Logrank
< 65% (n=21) vs. > 65% (n=21) 2-year survival=
45% vs. 90%
p=0.022 Okubo et
al. (2019)23 63 RPC=12 BRPC=34 LAPC=13 MPC=4
Dissection: axial slicing
Sampling approach:
all H&E slides were digitally analyzed Sampling amount:
n.r.
Small ART=40 Large ART=23
KM analysis/Logrank
Small ART (n=40) vs. large ART (n=23)
Multivariate Cox
(Adjusted for sex, age, R, vasc.
Invasion)
Small ART (n=40) vs. large ART (n=23)
2-year survival=
84% vs. 44%
p<0.01 P=0.10
Zhang et
al. (2020)31 106 RPC=13 BRPC=30 LAPC=63
Dissection: n.r.
Sampling approach:
If no tumour cells were identified, the remaining lesional area was entirely submitted and reviewed Sampling amount:
MFS is determined on 1 slide
MFS ypT0=9 MFS ypT1=85 MFS ypT2=12
KM analysis/Logrank
MFS ypT0/1 (n=94) vs. ypT2 (n=12) Multivariate Cox (no details shown) MFS ypT0/1 (n=94) vs. ypT2 (n=12)
OS / DFS P<0.001 DFS: p=0.003 OS: p=0.001
Abbreviations: CAP = College of American Pathologists, FOLRINOX = leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin, KM = Kaplan-Meier, OS = overall survival, vs = versus, NR = not reached, n.r. = not reported, RFS = recurrence-free survival, ref = reference, SMA = superior mesenteric artery, MDACC = MD Anderson Cancer Center, R = margin status, ypT = pathological T stage, ypN = pathological N stage, TSR = residual tumour cellularity, HTRG = histologic tumour regression grading, KCC = Kendall concordance coefficient, LR = limited response, NCR = near complete response, PCR = complete response, RTI = residual tumour index, H&E = hematoxylin and eosin, ART = area of residual tumour, MFS = microscopic focus size, RPC = resectable pancreatic cancer, BRPC = borderline resectable pancreatic cancer, LAPC = locally advanced pancreatic cancer, MPC = metastatic pancreatic cancer.
FIGURES
Figure 1. PRISMA Flow chart
Records identified through database searching
(n=2,093)
ScreeningIncludedEligibilityIdentification Additional records identified through other sources
(n=5)
Records after duplicates removed (n=1,453)
Records screened (n=1,453)
Records excluded (n=1,399)
Full-text articles assessed for eligibility
(n=54)
Full-text articles excluded (n=29), with reasons:
- No full-text available (n=8) - No original data (n=8)
- Abstract/conference paper (n=10) - No outcomes on scoring (n=3) Studies included in
qualitative synthesis (n=25)
Studies included in quantitative synthesis
(meta-analysis) (n=0)
