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Keywords:

  • colorectal liver metastases;
  • tumor-normal liver interface;
  • tumor regression;
  • preoperative chemotherapy; Avastin; survival; pathology response; validation; multicenter study

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST
  9. REFERENCES

BACKGROUND

To validate pathologic markers of response to preoperative chemotherapy as predictors of disease-free survival (DFS) after resection of colorectal liver metastases (CLM).

METHODS

One hundred seventy-one patients who underwent resection of CLM after preoperative chemotherapy at 4 centers were studied. Pathologic response—defined as the proportion of tumor cells remaining (complete, 0%; major, <50%; minor, ≥50%) and tumor thickness at the tumor-normal liver interface (TNI) (<0.5 mm, 0.5 to <5 mm, ≥5 mm)—was assessed by a central pathology reviewer and local pathologists.

RESULTS

Pathologic response was complete in 8% of patients, major in 49% of patients, and minor in 43% of patients. Tumor thickness at the TNI was <0.5 mm in 21% of patients, 0.5 to <5 mm in 56% of patients, and ≥5 mm in 23% of patients. On multivariate analyses, using either pathologic response or tumor thickness at TNI, pathologic response (P = .002, .009), tumor thickness at TNI (P = 0.015, <.001), duration of preoperative chemotherapy (P = .028, .043), number of CLM (P = .038, . 037), and margin (P = .011, .016) were associated with DFS. In a multivariate analysis using both parameters, tumor thickness at TNI (P = .004, .015), duration of preoperative chemotherapy (P = .025), number of nodules (P = .027), and margin (P = .014) were associated with DFS. Tumor size by pathology examination was the predictor of pathologic response. Predictors of tumor thickness at the TNI were tumor size and chemotherapy regimen. There was near perfect agreement for pathologic response (κ = .82) and substantial agreement (κ = .76) for tumor thickness between the central reviewer and local pathologists.

CONCLUSIONS

Pathologic response and tumor thickness at the TNI are valid predictors of DFS after preoperative chemotherapy and surgery for CLM. Cancer 2013;119:2778–2788. © 2013 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST
  9. REFERENCES

Colorectal liver metastases (CLM) affect 50% of patients with colorectal cancer and account for two-thirds of deaths from this disease.[1] Neoadjuvant chemotherapy and liver resection is widely used to treat patients with CLM.[2-5] Liver resection for CLM is supported by improved 5-year survival after surgery performed with curative intent.[6, 7] However, approximately 70% of patients develop disease recurrence after resection.[8]

Validated pathologic predictors of response to preoperative chemotherapy are of particular interest, because in addition to predicting patient outcome, they contribute to the evaluation of tumor biology and may be used to tailor postoperative treatment. These markers could be used as end points in studies of the efficacy of new drugs, an approach recently validated by the US Food and Drug Administration for studies in breast cancer,[9] and could also be used as end points in studies of new biomarkers for response to chemotherapy.

Tumor regression after chemotherapy, measured via imaging and pathologic examination of the CLM, has been tested as a prognostic factor for patient outcome in several studies.[10-15] Two different pathologic markers of response to preoperative chemotherapy—pathologic response, defined as the percentage of residual viable tumor cells, and tumor thickness at the tumor-normal liver interface (TNI)—were shown to be associated with survival after resection of CLM in a large single-center cohort.[13, 14] These markers have also shown to be associated with preoperative imaging response described using RECIST (Response Evaluation Criteria in Solid Tumors) and morphologic criteria.[14, 16] However, the applicability of these 2 semiquantitative histopathologic markers in different patient populations has not been confirmed.

The aim of this study was to validate the 2 previously described pathologic markers of response to preoperative chemotherapy—pathologic response and tumor thickness at the TNI—in a diverse patient population from several institutions and to test the agreement between local/peripheral pathologists from those institutions and central/expert pathology review.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST
  9. REFERENCES

Patients

This retrospective study was approved by the institutional review boards of all the participating institutions. The study included patients who underwent preoperative chemotherapy followed by resection of CLM with curative intent (from 2001 to 2010) at 4 major hepatobiliary centers (Center Leon Bernard, Lyon, France; Ambroise Pare Hospital, Paris, France; The University of Texas MD Anderson Cancer Center, Houston, Texas; and Medical University of Vienna, Austria). Inclusion criteria were resection of CLM with curative intent within 3 months after completion of preoperative chemotherapy; duration of preoperative chemotherapy less than 10 months; and preoperative chemotherapy consisting of either a fluoropyrimidine-based, fluropyrimidine+irinotecan-based regimen or a fluoropyrimidine+oxaliplatin-based regimen with or without bevacizumab or cetuximab. Patients received preoperative chemotherapy either for initially unresectable or up-front resectable CLM. Adjuvant chemotherapy for primary colorectal cancer was not taken into account except for patients with synchronous CLM. Patients were excluded if they underwent staged liver resection, previous portal vein embolization, radiofrequency ablation concomitant to liver resection, or hepatic artery infusion. Patients with postoperative follow-up time less than 12 months and cause of death other than colorectal cancer were also excluded. Each center selected its patient population on the basis of these predefined criteria independently of the participating pathologists.

For each patient, the following demographic and clinicopathologic factors were collected by review of medical records: age, sex, site of primary tumor, primary tumor lymph node status, timing of detection of CLM in relation to detection of the primary tumor (synchronous or metachronous), type of liver resection (major [resection of ≥3 liver segments] or minor [all other procedures]), number of CLM, diameter of the largest metastasis, preoperative carcinoembryonic antigen (CEA) level, type and number of cycles of preoperative chemotherapy, surgical margin status, postoperative complications, and recurrence status.

Assessment of Pathologic Response and Tumor Thickness at the TNI

Pathologic response and tumor thickness at the TNI were assessed as described previously.[13, 14] All CLM were macroscopically localized in the surgical specimen after correlation with radiologic findings. In patients with multiple CLM, each lesion was sampled extensively from the center to the periphery to include multiple sections of tumor and nonneoplastic liver parenchyma. Hematoxylin and eosin–stained sections were reviewed independently by 2 pathologists: the corresponding institution's gastrointestinal pathologist (C.J., J.S., A.I.L., and A.A.) and the central pathology reviewer (D.M.M). The number of years of experience of these pathologists ranged from 4 to 15 years. All pathologists were blinded from other pathologists' interpretations, clinical information, treatment regimens, and study end points. The pathology parameters assessed by the central pathology reviewer were used for the analyses of predictors of survival and predictors of pathologic response and tumor thickness at the TNI.

For the assessment of pathologic response, residual carcinoma was measured semiquantitatively by estimating the area of residual cancer cells as a proportion of the total tumor area, as described previously.[13] The tumor area included areas of acellular mucin, tumor necrosis, chemotherapy-related tissue injury, and other reparative changes. Pathologic response was categorized as follows: no residual cancer cells, complete response; 1% to 49% residual cancer cells, major response; and 50% or more residual cancer cells, minor response (Figure 1A). In patients with multiple tumor nodules, the mean of the values for the various tumor nodules was used.

image

Figure 1. (A) Photomicrographs of representative examples of complete (a), major (b), and minor (c) pathologic response. (a) Tumor bed with necrotic debris, hyalinized/collagenized tissue, and inflammatory cells with no tumor cells. (b) Neoplastic glands occupying less than half of the tumor bed. (c) Neoplastic glands occupying the majority (>50%) of the tumor bed admixed with minor component of fibrocollagenous stroma with inflammation. (B) Cartoon (a) and photomicrograph (b) demonstrating the correct and incorrect method of measuring tumor thickness at the tumor-normal liver interface. (a) Tumor cells/neoplastic glands are shown as a homogenous dark area of the tumor bed. Different stromal components are shown with other symbols. The outer layer of the circle represents the tumor-normal liver interface. (b) Hematoxylin and eosin–stained section showing normal liver parenchyma in the lower left corner, the tumor-normal liver interface highlighted with a blue dashed line. In both (a) and (b), the green arrow shows the longest area of tumor cells without admixed stroma, necrosis, or inflammation. Red arrows indicate the focus with the layer of tumor cells interrupted by fibrosis/necrosis.

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The tumor thickness at the TNI was measured perpendicular to the TNI at the focus with the maximum number of contiguous tumor cells in millimeters using a ruler or ocular micrometer (Figure 1B). In all tumors, the thickness was measured at multiple foci, and the greatest thickness was used in the analysis. In specimens with multiple tumors, tumor thickness was measured separately for each tumor nodule, and the average thickness was used for analysis, as described previously.[14]

A positive surgical margin was defined as the presence of tumor cells at or within 1 mm of the line of transection.

Statistical Analysis

Quantitative variables are expressed as the median (range) and frequency. Comparisons between groups were analyzed with a chi-square or Fisher exact test for proportions and the Mann-Whitney U test or Kruskal-Wallis H test for continuous variables as appropriate.

Disease-free survival (DFS) rates were calculated from the date of liver resection to the date of last follow-up or recurrence using the Kaplan-Meier method and compared using log-rank tests. DFS was preferred over overall survival as the end point because of its specificity for disease-related outcome and insufficient maturity of the overall survival data from the institutions participating in this study. Univariate and multivariate analyses were used to examine the relationship between DFS and various clinical and pathologic factors. All variables associated with DFS with P ≤ 0.1 in a univariate proportional hazards model were subsequently entered into a Cox multivariate regression model with backward elimination (conditional logistic regression). Statistical significance was defined as P < 0.05.

The pathologic response and tumor thickness at the TNI both reflect tumor regression after preoperative chemotherapy and correlated strongly with each other in our previous study.[14] Due to this interdependence, 3 models of multivariate analysis were created to appropriately assess the impact of these 2 parameters. Model 1 included all factors with P ≤ 0.1 in the univariate analysis except tumor thickness at TNI. Model 2 included all factors with P ≤ 0.1 in univariate analysis except pathologic response. Model 3 included both pathologic response and tumor thickness at TNI with other parameters with P ≤ 0.1 in a univariate model. Because these pathology markers were first described by pathologists at The University of Texas MD Anderson Cancer Center, a level of agreement was assessed between a central pathology reviewer at MD Anderson and local pathologists at the 4 study institutions using Spearman correlation and κ statistics with quadratic weighting.

Statistical analyses were performed with SPSS software (version 19.0, SPSS Inc, Chicago, Illinois).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST
  9. REFERENCES

Study Population

The patient population included 88 men and 83 women with mean age of 60 years (range, 26-85 years). The patients' clinicopathologic characteristics by treating center are summarized in Table 1. The primary tumor characteristics did not significantly differ between the 4 study centers. However, there were differences between the 4 centers with respect to age, sex, type of liver resection, diameter of the largest colorectal liver metastasis, preoperative CEA level, and type and median months of duration of preoperative chemotherapy regimen. Seventy of 106 patients with synchronous primary and liver metastases underwent colon resection followed by preoperative chemotherapy for liver metastases which was followed by liver resection. Eighteen patients underwent preoperative chemotherapy followed by synchronous colon and liver resection. Eight patients underwent preoperative chemotherapy followed by liver resection which was followed by resection of colon tumor. Adjuvant therapy for primary colon cancer was taken into account in 10 patients.

Table 1. Clinicopathologic Characteristics of Patients by Treating Center
CharacteristicsCenter 1 (n=49)Center 2 (n=34)Center 3 (n=43)Center 4 (n=45)P
  1. Patients receiving multiple regimens of preoperative chemotherapy (n=13), only fluropyrimidines (n=4) and cetuximab (n=1) were excluded from this analysis, finally including 153 patients.

  2. Abbreviations: CEA, carcinoembryonic antigen; CHT, chemotherapy; CLM, colorectal liver metastases; TNI, tumor-normal liver tissue interface.

Age, years, median (range)57 (26-85)63 (37-83)59 (35-80)61 (30-78).016
Sex,     
Men31102324.023
Women18242021 
Primary tumor site,      
Colon40223229.21
Rectum9121116 
Primary positive lymph node,      
Yes29232423.52
No20111922 
CLM synchronous to primary,      
Yes36202624.23
No13141721 
Type of liver resection,      
Major26272614<.001
Minor2371731 
No. of CLM, median (range)2 (1-11)2 (1-4)2 (1-13)1 (1-7).067
Diameter of largest CLM, median (range), cm2.5 (0.5-13)3 (1-7)3 (1-12)1.8 (0.3-10)<.001
Preoperative CEA level, ng/mL, median (range)2.6 (0-859)3 (0 - 387)17 (0-1640)5 (0-153)<.001
Chemotherapy type, no.*     
Fluoropyrimidine+oxaliplatin517160<.001
Fluoropyrimidine+irinotecan161590 
Fluoropyrimidine+oxaliplatin+bevacizumab240240 
Fluoropyrimidine+irinotecan+bevacizumab2043 
Duration of preoperative CHT, months, median (range)2 (1-9)3 (1.5-10)3 (1-10)4.5 (1-10)<0.001
Recurrence, no.     
Yes33242928.88
No16101417 
Pathologic response, no.     
Complete7124.08
Major19152129 
Minor23182012 
Tumor thickness at TNI, no.     
<0.5 mm15299<.001
≥0.5 to <5 mm17252035 
≥5 mm177141 

Among the 65 patients with metachronous CLM, 32 stage III patients received adjuvant chemotherapy for the primary tumor and, at the diagnosis of liver metastases, preoperative chemotherapy for liver metastases. Remaining 33 stage I-II patients with metachronous CLM, received preoperative chemotherapy for either multiple, or larger than 5 cm, or initially unresectable liver metastases.

One hundred four (61%) patients received single line oxaliplatin-based chemotherapy with or without bevacizumab, 49 (28%) patients received single line irinotecan-based chemotherapy with or without bevacizumab, and the remaining 18 (11%) patients received multiple preoperative chemotherapy lines regimens containing both oxaliplatin and irinotecan (n = 13), fluropyrimidines only (n = 4), or cetuximab (n = 1). The preoperative chemotherapy regimen at 1 center included bevacizumab for all patients, whereas another center included all patients without bevacizumab. The other two centers included patients with and without bevacizumab. The majority of patients had multiple liver metastases (104 [60%]). The median diameter of the largest tumor nodule was 3.1 cm (range, 0.3-13 cm). Most patients (93 [54%]) had major hepatectomy. One hundred thirty-three (78%) patients received postoperative chemotherapy. Postoperative reversible complications occurred in 48 (28%) patients, and tumor recurrence occurred in 124 (72%) patients.

Pathologic examination showed complete response in 14 (8%) patients, major response in 84 (49%), and minor response in 73 (43%). Tumor thickness at the TNI was <0.5 mm in 35 (21%) patients, 0.5 to <5 mm in 97 (56%) patients, and ≥5 mm in 39 (23%) patients. Eight (5%) patients had positive surgical resection margin.

Predictors of DFS

The median duration of follow-up for DFS was 42 months (range, 3-121 months). Pathologic response and tumor thickness at the TNI were both associated with DFS as continuous variables (P = .002 and P = .001, respectively). DFS curves for each category of pathologic response and tumor thickness at the TNI are shown in Figure 2. By log-rank test, the survival differences between complete and major response (P = .004) and between major and minor response (P = .049) were statistically significant. For the entire study population, the cumulative 3-year and 5-year DFS rates were 33% and 28%, respectively. The cumulative 3-year and 5-year DFS rates, respectively, by categories of response were as follows: complete response, 77% and 77%; major response, 32% and 31%; and minor response, 26% and 18%.

image

Figure 2. Disease-free survival in patients undergoing resection of colorectal liver metastases stratified by (A) categories of pathologic response and (B) categories of tumor thickness at the tumor-normal liver interface (TNI).

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On log-rank test, the survival differences between patients with tumor thickness at the TNI <0.5 mm and 0.5 to <5 mm and the survival difference between patients with tumor thickness at the TNI 0.5 to <5 mm and ≥5 mm were statistically significant (P = 0.002). The cumulative 3-year and 5-year DFS rates, respectively, by categories of tumor thickness at the TNI were as follows: <0.5 mm, 58% and 58%; 0.5 to <5 mm, 31% and 24%; and ≥5 mm, 15% and 11%.

Results of univariate and multivariate analyses of the predictors of DFS are shown in Tables 2 and 3, respectively. On univariate analysis, factors associated with worse 3- and 5-year survival were high preoperative CEA level, duration of preoperative chemotherapy >3 months, minor versus major or complete pathologic response, major versus complete pathologic response, tumor thickness at the TNI ≥ 0.5 mm, and positive resection margin. In model 1 of multivariate analysis, minor and major pathologic response were associated with shorter DFS (for minor pathologic response, P = .002 and HR = 6.33; for major pathologic response, P = .009 and HR = 4.72). In model 2, a higher tumor thickness at TNI independently predicted a shorter DFS (for tumor thickness ≥5mm, P<.001 and HR = 3.89; for tumor thickness from 0.5 mm to <5 mm, P = .015 and HR = 2.07). Finally, in model 3, tumor thickness at TNI was independently associated with DFS (P = .004 and HR = 2.71 for tumor thickness ≥5mm; P = .015 and HR = 2.03 for tumor thickness from 0.5 mm to <5 mm). In all three models of multivariate analysis, duration of chemotherapy >3 months, number of tumor nodules ≥3, and positive resection margin were independent predictors of worse 3- and 5-year survival.

Table 2. Univariate Analysis of Factors Associated with Disease-Free Survival
CharacteristicsNo. of Patients3-Year DFS, %5-Year DFS, %PHR (95% CI)
  1. Abbreviations: CEA, carcinoembryonic antigen; CI, confidence interval; CLM, colorectal liver metastases; DFS, disease-free survival; HR, hazard ratio; TNI, tumor-normal tissue interface.

  2. a

    Missing data for 28 patients.

  3. b

    Patients with complete versus major versus minor response.

  4. c

    Patients with major versus minor response.

  5. d

    Patients with TNI thickness <0.5 mm versus ≥0.5 mm and <5 mm versus ≥5 mm.

  6. e

    Patients with TNI thickness ≥0.5 mm and <5 mm versus ≥5 mm.

Sex   .821.04 (.72-1.50)
Men883430  
Women833227  
Age, years   .68.92 (.64-1.34)
<60883230  
≥60833426  
Synchronous CLM   .56.92 (.63-1.34)
Yes1063730  
No652626  
Primary tumor site   .71.93 (.64-1.35)
Colon1233130  
Rectum483627  
Primary tumor lymph node status   .251.24 (.85-1.81)
Positive993026  
Negative723732  
Chemotherapy   .0881.39 (.95-2.02)
Irinotecan602521  
Oxaliplatin1113733  
Bevacizumab   .38.85 (.59-1.23)
Yes753735  
No962924  
Months of chemotherapy   .0561.43 (.99-2.07)
≤3853935  
>3862821  
CEA level ≥5 ng/mLa   .0051.69 (1.17-2.44)
Yes732117  
No704438  
No. of CLM   .091.46 (.94-2.26)
<31113530  
≥3603025  
Diameter of largest CLM ≥3 cm   .171.28 (.89-1.85)
Yes822925  
No893731  
Pathologic response     
Complete147777
Major843231.001b6.81 (2.13-21.8)
Minor732618.049c4.69 (1.47-15)
Tumor thickness at TNI     
<0.5355858
≥0.5 to <5 mm973124<.001d4.54 (2.41-8.45)
≥5 mm391511.003e2.39 (1.34-4.27)
Positive margin     
No1633530
Yes800.0032.86 (1.37-5.94)
Table 3. Multivariate Analysis of Factors Associated with Disease-Free Survival
CharacteristicsModel 1Model 2Model 3
HR (95% CI)PHR (95% CI)PHR (95% CI)P
  1. Abbreviations: CI, confidence interval; CLM, colorectal liver metastases; HR, hazard ratio; TNI, tumor-normal liver interface.

  2. CEA was not included in the multivariate analyses because of missing data for 28 patients. Model 1 and model 2 included all factors significant in univariate analysis except tumor thickness at TNI and pathologic response, respectively. Model 3 included all factors significant in univariate analysis.

Irinotecan      
Yes1.17 (.78-1.74).451.03 (.68-1.57).871.03 (.68-1.58).86
No      
Months of chemotherapy      
≤3      
>31.52 (1.05-2.22).0281.48 (1.01-2.17).0431.55 (1.06-2.28).025
Pathologic response      
Complete      
Major4.72 (1.47-15.14).0091 (.63-1.57)1
Minor6.33 (1.97-20.31).0023.61 (.93-13.88).064
Tumor thickness at TNI      
<0.5 mm      
≥0.5 to <5 mm2.07 (1.15-3.71).0152.03 (1.21-3.32).015
≥5 mm3.89 (2.06-7.37)<.0012.71 (1.25-6.06).004
No. of CLM      
<3      
≥31.60 (1.03-2.50).0381.61 (1.03-2.51).0371.55 (1.05-2.28).027
Positive margin      
No      
Yes2.66 (1.25-5.64).0112.50 (1.18-5.30).0162.57 (1.21-5.49).014

Predictors of Pathologic Response and Tumor Thickness at the TNI

Results of a univariate analysis of predictors of pathologic response and tumor thickness at the TNI are shown in Table 4. Tumor size was the only predictor of pathologic response. Predictors of smaller tumor thickness at the TNI were smaller tumor size, oxaliplatin-based chemotherapy, and use of bevacizumab.

Table 4. Univariate Analysis of Predictors of Pathologic Response and Tumor Thickness at TNI
CharacteristicsPathologic ResponseTumor Thickness at TNI
Complete (n=14)Major (n=84)Minor (n=73)P<0.5 mm (n=35)≤0.5 to <5 mm (n=97)≥5 mm (n=39)P
  1. a

    Patients receiving multiple regimens of preoperative chemotherapy (n=13), fluropyrimidines only (n=4), and cetuximab (n=1) were excluded from this analysis for a total of 153 patients.

  2. Abbreviations: CEA, carcinoembryonic antigen; CLM, colorectal liver metastases; TNI, tumor-normal tissue interface.

Men, no.74140.75204424.18
Age, y, median (range)60 (36-71)60 (26-83)60 (34-85).7261 (26-85)60 (30-83)58 (34-83).48
Synchronous CLM, no.85444.81246022.56
Rectal primary, no.63636.70164022.28
Positive lymph node primary, no.65043.49176022.39
CEA, ng/mL, median (range)2.5 (1-50)4 (0-1640)5 (0-963).932.7 (0-113)4 (0-1640)6 (0-859).22
Duration of preoperative chemotherapy, months, median (range)3 (2-12)3 (0-10)3 (0-11).683 (0-12)4 (0-11)3 (0-6.5).08
Chemotherapy regimens, no.a        
Oxaliplatin±bevacizumab105640.31236815.018
Irinotecan±bevacizumab22223 72416 
Bevacizumab, no.a        
Yes54125.315488.036
No73738 154423 
No. of CLM, median (range)2 (1-7)2 (1-13)2 (1-13).842 (1-13)2 (1-13)2 (1-11).996
Diameter of the largest CLM, cm, median (range)1.1 (0.3-4.5)2.5 (0.5-9.5)3 (0.3-13).0022 (0.3-8)3 (0.3-9.5)3.5 (1-13)<.001
Tumor thickness at TNI <0.5 mm14 (100)20 (23.8)1 (1.4)<.001
Complete pathologic response14 (40)00<.001

Agreement Between Local Pathologists and Central Pathology Reviewer for the Measurement Pathologic Markers of Response to Chemotherapy

The local pathologists and the central pathology reviewer agreed with respect to categorization of both pathologic response and tumor thickness at the TNI in 116 (68%) patients. In 167 (98%) patients, there was agreement for 1 of the 2 parameters. Disagreement for both parameters was observed in only 4 (2%) patients.

The median difference for pathologic response between the measurements by the local pathologists and the measurements by the central reviewer was 5%. There was complete agreement in assessment of response between the central pathology reviewer and local pathologists in the complete response category. Of the 84 patients classified by the central pathology reviewer as having a major response, 9 (11%) were classified as minor responders by a local pathologist. Of the 69 patients classified by the central pathology reviewer as having a minor response, 2 (3%) were classified as major responders by a local pathologist. Figure 3A shows a strong linear correlation between pathologic response measured by local pathologists and pathologic response measured by the central pathology reviewer. The overall κ between the central pathology reviewer and local pathologists for the 3 categories of pathology response was 0.82 (ie, an almost perfect agreement).

image

Figure 3. Scatter plot correlating measurements of (A) pathologic response and (B) tumor thickness at the tumor-normal liver interface (TNI) between the central pathology reviewer and local pathologists.

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The median difference for tumor thickness at the TNI between the measurements by the local pathologists and the measurements by the central pathology reviewer was 0.5 mm. Of the 35 patients classified by the central pathology reviewer as having tumor thickness of <0.5 mm, 7 (20%) were classified as having thickness ≥0.5 mm by a local pathologist. Of the 97 patients classified by the central pathology reviewer as having tumor thickness of 0.5 mm to <5 mm, 16 (16%) were classified in a different category by a local pathologist. Of the 39 patients classified by the central pathology reviewer as having tumor thickness of at least 5 mm, 12 (31%) were classified as having tumor thickness of 0.5 mm to <5 mm by a local pathologist. Figure 3B shows a strong linear correlation between tumor thickness measured by local pathologists and tumor thickness measured by the central pathology reviewer. The overall κ between central pathology reviewer and local pathologist was 0.76 (substantial agreement).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST
  9. REFERENCES

This study validates pathologic response and tumor thickness at the TNI as predictors of DFS in an independent, multicenter series of patients with CLM who underwent resection after routinely used preoperative chemotherapy regimens. In addition, our findings indicate good interobserver agreement between the central pathology reviewer and local pathologists in the measured values of these 2 parameters.

Pathologic response to preoperative chemotherapy has been shown to be of prognostic significance in cancers of solid organs, including the breast, esophagus, and rectum.[17-19] Given the approximate 2- and 5-year median time to recurrence or death after hepatectomies for colorectal cancer, implementation of a pathologic response end point would substantially increase interest in novel drug development in this setting. In addition, studies designed to assess potential biomarkers for response to chemotherapy in cancer of solid organs frequently use pathologic response as a primary or secondary end point.[20, 21] Our findings suggest that pathologic response and tumor thickness at TNI may also be suitable end points for studies of biomarkers assessment for response to chemotherapy in patients with CLM.

The pathologic markers validated in this study could also make it possible to tailor postoperative chemotherapy in patients with CLM on the basis of the response to preoperative chemotherapy. At present, patients with CLM usually receive the same chemotherapy regimen before and after surgery regardless of the response to preoperative chemotherapy.[2] In the future, patients who do not respond adequately to preoperative chemotherapy as judged on the basis of measurement of our 2 validated prognostic markers could be switched to a different and hopefully more effective chemotherapy regimen after resection of the metastases. This concept has never been evaluated and could be tested prospectively.

Several criteria have been described for categorization of regression of colorectal metastases after chemotherapy. In a single-institution study of patients undergoing resection after preoperative chemotherapy without inclusion of bevacizumab, tumor regression grade based on semiquantitative assessment of fibrosis and residual tumor cells in resected CLM was associated with survival outcome.[11] In a large single-institution study, Adam et al[12] demonstrated superior survivor outcome of patients with complete pathologic response. Blazer et al[13] showed that pathologic response categorized as complete, major, or minor response was associated with overall survival on multivariate analysis. Subsequently, Maru et al[14] showed that tumor thickness at the TNI was associated with recurrence-free survival and preoperative imaging response. The latter study showed that the highest uninterrupted tumor thickness at TNI for 1 tumor nodule and the mean of all maximum tumor thicknesses of multiple tumors was significantly associated with DFS. Since the response of preoperative chemotherapy is heterogenous in different tumor nodules, mean of maximum tumor thickness at TNI was used for the correlation in patients with multiple tumors in this study and a prior study.[14] Using only the maximum thickness in case of multiple tumors would likely to skew the data toward the tumors with poor response. The present study is a validation of the studies by Blazer et al[13] and Maru et al[14] with a focus on DFS. The tumor thickness at the TNI was found to be a better predictor of DFS in a multivariate analysis that included both pathologic response and tumor thickness at TNI. However, due to the interdependence of these two parameters, we propose that both the parameters should be included in the pathology report because they were significant in multivariate analyses when one of them was excluded. Although not included in this study, a scoring system that includes these 2 parameters and other parameters, including tumor size, number of tumor nodules, and margin status, to predict patient outcome of CLM may contribute significantly in postoperative management of patients with CLM.

There were significant differences in clinical and treatment characteristics between the patients at the study 4 centers. Validation of the 2 tested pathology markers in this heterogeneous patient population supports application of these markers in a wide population of patients with resected CLM. The significance of these pathology parameters as markers of chemotherapy response is enhanced by good agreement between the central pathology reviewer and the local pathologists. In a very small percentage of cases (2%), there was disagreement in categorization of both parameters. The higher rate of agreement with respect to just 1 of the 2 pathologic markers as compared with agreement with respect to both markers favors including information about both markers in the surgical pathology report.

The present study also validated previously described predictors of pathology response and tumor thickness at the TNI. Tumor size was the predictor of pathologic response in the present study and in previous studies by Adam et al[12] and Blazer et al.[13] Similar to a previous study by Maru et al,[14] an oxaliplatin-based chemotherapy regimen and bevasizumab were associated with thin tumor thickness at the TNI in the present study.

In conclusion, this study is the first to validate the pathologic markers of response to chemotherapy as predictors of DFS in patients undergoing resection of CLM. The pathologic response and tumor thickness at the TNI are reliable criteria that may be used in routine clinical practice and are new end points for the assessment of biomarkers of chemotherapy response.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST
  9. REFERENCES

The University of Texas MD Anderson Cancer Center was supported in part by the National Institutes of Health through Cancer Center Support Grant CA016672.

CONFLICT OF INTEREST

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST
  9. REFERENCES

Dipen Maru received research funding from Taiho Pharma Inc. USA. Jean-Nicolas Vauthey received honorarium from Roche and sanofi-aventis and research funding from Rosche. Thomas Gruenberger is a consultant and received honorarium from Roche and Merck Serano. He is also a consultant for sanofi-aventis and has received funding from Amgen. Benoist received honorarium from Roche and Merck Serano.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. CONFLICT OF INTEREST
  9. REFERENCES
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