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Journal of Clinical Oncology, Vol 21, Issue 3 (February), 2003: 406-412
© 2003 American Society for Clinical Oncology

Thymidylate Synthase Expression in Hepatic Tumors Is a Predictor of Survival and Progression in Patients With Resectable Metastatic Colorectal Cancer

Mithat Gonen, Amanda Hummer, Alice Zervoudakis, Deidre Sullivan, Yuman Fong, Debabrata Banerjee, David Klimstra, Carlos Cordon-Cardo, Joseph Bertino, Nancy Kemeny

From the Departments of Epidemiology and Biostatistics, Medicine, Surgery, and Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY; Department of Medicine, the Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ.

Address reprint requests to Mithat Gonen, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Box 44, New York, NY 10021; email: gonenm{at}mskcc.org.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: To investigate the role of thymidylate synthase (TS),p53, and epidermal growth factor receptor (EGF-R) expressions in hepatic tumors in predicting overall survival (OS), progression-free survival (PFS), and hepatic progression-free survival (HPFS) in patients with resectable metastatic colorectal cancer who were randomly assigned to receive either systemic chemotherapy (SYS) alone or systemic and hepatic arterial infusion (HAI+SYS) chemotherapy following liver surgery.

Patients and Methods: Tissues from metastatic tumors were collected during liver resection from 156 patients, and marker expressions were determined using immunohistochemistry on frozen samples. Univariate associations between marker expressions and baseline variables with OS, PFS, and HPFS were examined. Independent predictors of outcome were determined using a multivariate Cox model.

Results: In multivariate analyses, TSoverexpression was found to be an independent factor of poor prognosis in OS (P < .01), PFS (P = .06), and HPFS (P < .01). In addition, resection margin was a significant independent factor for all three outcomes. Patients who received HAI+SYS experienced delayed progression in general, and in the liver, specifically. Increased levels of serum alkaline phosphatase correlated with hepatic progression. We also found a significant TS-treatment interaction for OS (P = .01) in multivariate analysis. In particular, TS+ patients receiving HAI+SYS had significantly higher survival than those receiving SYS (64 monthsv 21 months; P = .01).

Conclusion: TSlevels in hepatic tumors and resection margin are independent predictors of survival and progression in patients with metastatic colorectal cancer, whereasp53and EGFRare not independent predictors. Treatment with HAI+SYS significantly improved the survival profile of TS+ patients.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
COLORECTAL CANCER is the fourth most commonly diagnosed cancer and ranks second among cancer deaths in the United States. Although it is a highly treatable and often curable disease when localized, the prognosis of metastatic patients is considerably worse. The liver is the most common site of colorectal metastases, and it is often the only organ affected. Fifteen percent of patients present with synchronous disease, and 60% of all metastatic patients will have liver-only or liver-dominant disease. The only potentially curative option for liver metastases is surgery, but even after resection, liver is the most common site of relapse. Regional hepatic arterial infusion chemotherapy along with systemic chemotherapy (HAI+SYS) has been shown to improve 2-year survival when compared with systemic (SYS) chemotherapy alone.1 Stage of primary tumor, number of liver metastases, disease-free interval, preoperative carcino embryonic antigen, tumor size, positive resection margin, and presence of extrahepatic disease are reported to be independent prognostic factors of survival in this patient population.2,3

Numerous studies have linked molecular markers with clinical outcome for colorectal cancer patients.4–21 The expressions in the primary tumor and their association with outcome are well studied.5,6,10,11,15–17,19–20 The marker expressions in hepatic tumors have also been subject of many studies, in both resectable8,9 and unresectable6,7,9,12–14,18 patients. Thymidylate synthase (TS), the target enzyme of fluorouracil (FU)-based chemotherapy, is commonly reported to correlate with response and survival in these settings, along with p53. It is difficult to present a comprehensive account of all reports regarding the utility of molecular markers in colorectal cancer, but Table 1Go summarizes the commonly cited studies reporting on the correlation of TS or p53 and outcome.


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  		Table 1. Literature Summary for Molecular Markers and Outcome in Colorectal Cancer
 
This article presents the largest group of patients with metastatic colorectal cancer who received adjuvant chemotherapy and for whom TS, p53, and epidermal growth factor receptor (EGF-R) expressions in hepatic tumors are available. We examine these markers (TS, p53, and EGF-R) in relation to overall survival (OS), progression-free survival (PFS), and hepatic progression-free survival (HPFS) on 156 patients with metastatic colorectal cancer who underwent liver resection and received adjuvant chemotherapy. These patients were enrolled in a randomized study of SYS versus HAI+SYS.1 We also include in our analyses several factors that are reported to be of prognostic importance in the literature to confirm whether molecular markers are independent predictors of outcome. In addition, taking advantage of the fact that the data come from a randomized study, we explore the influence of marker expression within each treatment group.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
A total of 156 patients with colorectal cancer were randomly allocated after complete resection of the liver metastases. Seventy-four of them were randomly assigned to receive HAI+SYS, and 82 were assigned to receive SYS alone. HAI therapy consisted of floxuridine (FUDR) and dexamethasone. The SYS therapy was fluorouracil and leucovorin (FU/LV) or FU alone by continuous infusion. The trial was designed to compare SYS and HAI+SYS, and the results of this primary comparison were reported elsewhere.1 All survival data were updated before the analyses were undertaken. Samples from hepatic tumors were obtained during liver resection. Tissues from 12 patients were not available; hence, the analyses were based on the remaining 144 patients. All marker expressions were determined using immunohistochemical staining on paraffin sections.

Immunohistochemistry of TS
An avidin-biotin-peroxidase method and an antigen-retrieval method were used to perform immunohistochemistry on 5-µm-thick tissue sections. To enhance epitope exposure, slides were pretreated by microwave treatment. Slides were placed in boiling 0.01 M critic acid at pH 6 for 15 minutes. Sections were cooled and incubated with primary antibody at 4°C overnight. The primary antibody used was anti-TS purified rabbit polyclonal provided by Frank Maley (New York State Laboratories, Albany, NY). Secondary reagents of biotinylated goat antirabbit antibodies were then applied for 30 minutes, and then sections were incubated with avidin-biotin-peroxidase complexes for an additional 30 minutes. The final chromogen used was diaminobenzidine, and the nuclear counterstain used was hematoxylin. The TS levels of tumor cells were evaluated with light microscopy as follows: positive (>= 20% cells showed nuclear staining) and negative (< 20% cells showed nuclear staining).10,20

Immunohistochemistry of p53
An avidin-biotin-peroxidase method was used to perform immunohistochemistry of 4- to 6-µm-thick tissue sections. To reduce nonspecific background staining, tissue sections were placed in a solution of normal horse serum, diluted with bovine serum albumin, for 30 minutes at room temperature. Sections were then incubated with primary antibody at a concentration of 200 ng/mL at 4°C. The primary antibody used was mouse monoclonal antibody PAb1801 obtained from Oncogene Science, Inc. (Manhasset, NY). After rinsing with PBS, the slides were incubated with secondary biotinylated horse antimouse antibodies (Vector Laboratories, Inc, Burlingame, CA) at 1:500 dilution. The slides were then rinsed with phosphate-buffered saline and incubated with avidin-biotin-peroxidase complexes (Vector Laboratories, Inc.) at 1:25 dilution for 30 minutes at room temperature. The final chromogen used was diaminobenzidine, and the nuclear counterstain used was hematoxylin. Slides were observed by light microscopy, and p53 levels of tumor cells were evaluated by the following criteria: positive (>= 20% cells showed nuclear staining) and negative (< 20% cells showed nuclear staining).

Immunohistochemistry of EGF
An avidin-biotin-peroxidase method and an antigen-retrieval method were used to perform immunohistochemistry on 5-µm-thick tissue sections. To enhance epitope exposure, slides were pretreated by pepsin. Slides were placed in a 37°C water bath for 30 minutes. Sections were cooled and incubated with primary antibody at 4°C overnight. The primary antibody used was anti-EGF-R mouse monoclonal antibody obtained from BioGenex/Calbiochem (San Ramon, CA). Secondary reagents of biotinylated goat antirabbit antibodies were then applied for 30 minutes, and then sections were incubated with avidin-biotin-peroxidase complexed for an additional 30 minutes. The final chromogen used was diaminobenzidine, and the membrane counterstain used was hematoxylin. The EGF-R levels were evaluated as follows: positive (>= 20% tumor cells showed positive membrane staining), or negative (< 20% tumor cells showed negative membrane staining, or scattered membrane staining was present in a few cells).

Statistical Methods
The primary outcome of interest is OS. We also considered PFS and HPFS as secondary end points. The outcomes were calculated from the date of liver resection to the date of death (for OS) or date of recurrence or progression (for PFS) or date of liver recurrence or progression (for HPFS). The goal is to evaluate the independent prognostic potential of TS, p53, and EGF-R. This was achieved by subjecting the markers, along with 18 baseline characteristics (Table 2Go), to univariate analysis. The results of the univariate analysis were used to determine the variables that were included in the subsequent multivariate analysis.


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  		Table 2. Univariate Overall Survival Analysis (N = 156)
 
All survival probabilities were estimated by using the Kaplan-Meier method. The univariate relationships between OS, PFS, and HPFS with each of the markers and 18 baseline characteristics were evaluated using the log-rank test for categorical variables and the Wald test for continuous variables. Potential treatment-marker interactions were also evaluated using survival probabilities and relative risk estimates.

Cox proportional hazards models were used for multivariate analysis. All three markers, regardless of the univariate results, and significant baseline variables from univariate analysis (P < .10) as well as treatment-marker interactions were included. Model choice was performed using backward selection with P < .10 as the exit criterion. The final model was determined using various likelihood-based criteria (Likelihood Ratio, Akaike’s Information Criterion, and Schwartz’s Bayesian Criterion). All statistical analyses were performed using SAS software (SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Univariate OS Analysis
Among the categorical variables, sex, primary site, resection margin, and number of metastases were univariately significant in relation to OS (Table 2aGo). Of the continuous variables, serum alkaline phosphatase was the only univariately significant factor (Table 2bGo).

Univariate analyses for each molecular marker showed that patients with overexpression had shortened survival (median survivals: 64 v 37 months for TS, 83 v 48 months for p53, and 63 v 42 months for EGF-R). The difference was marginally significant for TS (P = .06) and p53 (P = .07), but it was not significant for EGF-R (P = .30; Table 3Go).


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  		Table 3. Univariate Overall Survival Analysis for Markers (N = 144)*
 
Evaluation by Treatment
To evaluate potential treatment-marker interactions, we investigated the effect of markers within each treatment group separately. Table 4Go presents the median survival times for TS-negative (TS-) and TS-positive (TS+) patients for each treatment group along with the corresponding relative risks of death. Survival profiles of TS- patients are similar for both treatments (median survival of 63 and 67 months for SYS and HAI+SYS groups, respectively; relative risk = 1.01), but risk of death more than quadruples for patients who are TS+ and who received SYS when compared with TS+ patients who received HAI+SYS (median survival of 21 v 64 months, RR = 4.26). Figure 1Go displays the survival curves for these four groups from Table 4Go. It is evident that TS+ patients in the SYS group have poor survival when compared with the three other groups, and in particular with the TS+ patients who received HAI+SYS. This suggests that there can be a significant interaction between TS and treatment.


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  		Table 4. TS by Treatment
 


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  		Fig 1. Overall survival (OS) curve for thymidylate synthase (TS) by treatment. Tick marks indicate last follow-up. HAI, hepatic arterial infusion; SYS, system chemotherapy.

 
Table 5Go presents the corresponding results for p53. Although the median survival is not reached for p53-negative (p53-) patients who received HAI+SYS, the relative risks suggest that the influence of treatment is similar in p53- and p53-positive (p53+) patients. An interaction is not indicated, but an effect of p53 on OS cannot be ruled out because p53- patients seem to do better in both treatment groups. There were no signs of interaction between EGF-R and treatment (data not shown).


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  		Table 5. p53 by Treatment
 
Multivariate Results
The following factors were included in the multivariate analysis for OS: TS, p53, EGF-R, treatment, treatment-TS interaction, resection margin, primary site, number of metastases, and sex. Multivariate analysis revealed TS, TS-treatment interaction, and resection margin as independent risks for survival. Treatment main effect was kept in the model because the interaction was significant. Regarding PFS, TS, p53, EGF-R, treatment, resection margin, primary site, type of surgery, tumor distribution, and serum alkaline phosphatase were included in the multivariate analysis. The factors TS, treatment, number of metastases, and resection margin were found to be independent predictors of PFS. Finally, for HPFS, TS, p53, EGF-R, treatment, resection margin, primary site, number of metastases, type of surgery, tumor distribution, and serum alkaline phosphate were used in the multivariate analysis. The factors that were included in the final model were treatment, TS, resection margin, and serum alkaline phosphatase. Findings of the multivariate analysis for each end point are summarized in Table 6Go.


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  		Table 6. Summary of Multivariate Analysis
 
Interaction between TS and treatment assignment remained significant for OS after adjusting for the presence of other factors. The presence of an interaction term requires some adjustments in reporting relative risks. Separate relative risks should be reported for each TS group. The relative risk of death between the two treatment groups is 4.26 for TS+ patients, but only 1.01 for TS- patients. A significant interaction term also supports our findings from the univariate analysis where TS expression was shown to be a prognostic factor for SYS therapy, but not for HAI+SYS therapy.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
There is an increasing interest in evaluating the role of molecular markers to response and long-term outcome in cancer patients. This article presents the largest group of patients with resectable hepatic metastases from colorectal cancer for whom TS, p53, and EGF-R expressions in hepatic tumors are available. The interaction between TS and treatment assignment has not been reported in the literature before. Although there is evidence that p53 and TS are related to FU resistance, we studied EGF-R only to see whether there is any prognostic information in that marker.

Immunohistochemistry is a semiquantitative assay. However, it has the advantage of assessing expression at the microanatomical detail, where cell-specific levels can be determined at the subcellular level (ie, nucleus v cytoplasm membrane). We made an effort to follow the literature in using the cutoffs for defining positive phenotypes.10,20,22,23 Using different cutoffs may yield different prevalences and also potentially alter the conclusions of any study using immunohistochemistry. The prevalence of TS overexpression in our cohort is about the same as the one reported in one study where the measurements were performed quantitatively using reverse transcription.18 Another study used both immunohistochemistry and direct sequencing of p53 and showed a strong correlation between the two.23 As a result, we feel comfortable that the choice of cutoffs did not unduly influence our conclusions.

There are several well-established prognostic factors for patients with metastatic colorectal cancer.2,3,24–34 Table 7Go summarizes the findings of published articles that report results from univariate analysis. The number of patients in these studies ranged from 100 to 1,568. Some of the factors, such as positive resection margin, number of hepatic metastases, presence of extrahepatic disease, and advanced primary tumor are repeatedly identified as significant predictors of survival in univariate analyses. In addition, size of the largest hepatic tumor, preoperative CEA, and disease-free interval are found to be significant predictors of survival in a smaller group of these studies. The studies that reported multivariate analyses are shown in Table 8Go. It is clear from Table 8Go that three factors are consistently found to be independent predictors of survival in multivariate analysis: positive resection margin, number of hepatic metastases, and stage of the primary tumor.


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  		Table 7. Prognostic Factors From Literature—Univariate Analysis
 

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  		Table 8. Prognostic Factors From Literature—Multivariate Analysis
 
The results of the multivariate analyses reported here indicate that baseline TS expression provides important information about survival and progression independent of the information provided by these clinical factors. Resection margin was also found to be an important factor both for survival and progression in our analysis. Number of metastases was significantly associated with progression, and baseline alkaline phosphatase level was found to be an independent predictor of progression in the liver. Other factors, such as stage of primary disease, tumor size, preoperative CEA, disease-free interval, and extrahepatic disease, which are reported in the literature to be important prognostic factors (as summarized in Tables 7Go and 8Go), were not significantly associated with survival in our data. It is possible that the additional information provided by these factors is not substantially above and beyond the information provided by TS expression. It is also possible that the highly selected nature of our patient population does not lend itself to these prognostic factors. Another explanation is that our series, smaller in size in comparison with some of the retrospective series, lacked the power to detect significant difference for these factors.

Although a significant role of TS is established in predicting survival and progression, no such effect is supported by our data for p53 and EGF-R. There is a marginal univariate significance for p53, but this difference dissipates in a multivariate setting, and it seems that the prognostic information provided by p53 is already embodied in the clinical variables included. A similar phenomenon was noted in earlier studies of the primary colon and rectal tumors.15,16 There are other studies that showed TS expression in primary tumors to be associated with response and survival.5,6,10,11,19 In contrast, a recent report found no relation between TS expression in primary tumor and long-term outcome.20 Previously, another report found no significant relationship between p53 levels in the primary tumor and recurrence.17

Regarding the expression in hepatic tumors, the focus of the literature has been mostly on unresectable patients. TS overexpression was negatively correlated with response, survival, and PFS in a group of 48 unresectable patients who received bolus FU-based therapy alternating with continuous infusion.12 In terms of unresectable patients receiving hepatic arterial infusion, overexpression of TS in hepatic tumors is reported to be a marker of resistance to chemotherapy13 and a negative prognostic factor for survival.14 Another study reported that TS- patients receiving HAI+SYS are four times more likely to respond than TS+ patients.7 Recently, in a cohort of 50 patients with unresectable hepatic metastases, TS was found to correlate with survival and recurrence.18 There is only one study that included resectable patients, along with unresectable ones, that found a significant relationship between p53 and EGF-R with disease-free survival.9 All the 68 patients in that study had synchronous disease.

Overall, many previous studies reported that TS and p53 expressions in hepatic tumors correlate with outcome, but none of these studies specifically focused on resectable patients receiving adjuvant chemotherapy (Table 1Go).

Our findings indicate that the prognostic role of TS expression in hepatic tumors established by these findings extends to the resected population undergoing adjuvant therapy as well. In the cohort analyzed here, TS overexpression was a major factor in predicting OS for the patients receiving SYS, but not necessarily for those who receive adjuvant HAI+SYS.

The TS-treatment interaction we identified here has implications for treating future patients. Previous in vitro studies showed that tumor resistance to fluorinated pyrimidines, including FU and FUDR, is related to insufficient inactivation of the TS enzyme. An important finding from this study is that delivery of hepatic arterial infusion FUDR results in increased survival even in the face of TS overexpression. Whether this is because of the higher doses that can be given by the technique or because of the regional application that may produce higher intracellular levels is not clear. Identification of treatment-marker interactions are important because they enable us to predict resistance or sensitivity to certain therapies and prescribe appropriate regimens. Such interactions should be verified prospectively before they can be incorporated into clinical routine.21 We plan to evaluate the tissue specimens from other ongoing studies to further substantiate the role of TS expression in hepatic tumors as a predictor of long-term outcome and to validate our findings.


   NOTES
 
Supported by NCI grant 5R01CA61524-7.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Kemeny N, Huang Y, Cohen AM, et al: Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 341:2039–2048, 1999[Abstract/Free Full Text]

2. Fong Y, Fortner J, Sun RL, et al: Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer. Ann Surg 230:309–321, 1999[CrossRef][Medline]

3. Nordlinger B, Guiguet M, Vaillant JC, et al: Surgical resection of colorectal carcinoma metastases to the liver. Cancer 77:1254–1262, 1996[CrossRef][Medline]

4. Leichman CG: Predictive and prognostic markers in gastrointestinal cancers. Curr Opin Oncol 13:291–299, 2001[CrossRef][Medline]

5. Zeng ZS, Sarkis AS, Zhang ZF, et al: p53 nuclear overexpression: An independent predictor of survival in lymph node–positive colorectal cancer patients. J Clin Oncol 12:2043–2050, 1994[Abstract/Free Full Text]

6. Johnston PG, Fisher ER, Rockette HE, et al: The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer. J Clin Oncol 12:2640–2647, 1994[Abstract/Free Full Text]

7. Kornmann M, Link KH, Lenz HJ, et al: Thymidylate synthase is a predictor for response and resistance in hepatic artery infusion chemotherapy. Cancer Lett 118:29–35, 1997[CrossRef][Medline]

8. Belluco C, Guillem JG, Kemeny N, et al: p53 nuclear protein overexpression in colorectal cancer: A dominant predictor of survival in patients with advanced hepatic metastases. J Clin Oncol 14:2696–2701, 1996[Abstract/Free Full Text]

9. De Jong KP, Stellema R, Karrenbeld A, et al: Clinical relevance of transforming growth factor alpha, epidermal growth factor receptor, p53 and Ki67 in colorectal liver metastases and corresponding primary tumors. Hepatology 28:971–979, 1998[CrossRef][Medline]

10. Lenz HJ, Danenberg KD, Leichman CG, et al: p53 and thymidylate synthase gene expression in untreated stage II colon cancer: Association with recurrence, survival and site. Clin Cancer Res 4:1227–1234, 1998[Abstract]

11. Lenz HJ, Hayashi K, Salonga D, et al: p53 point mutations and thymidylate synthase messenger RNA levels in disseminated colorectal cancer: An analysis of response and survival. Clin Cancer Res 4:1243–1250, 1998[Abstract]

12. Aschele C, Debernardis D, Casazza S, et al: Immunohistochemical quantitation of thymidylate synthase expression in colorectal cancer metastases predicts for clinical outcome to fluorouracil-based chemotherapy. J Clin Oncol 17:1760–1770, 1999[Abstract/Free Full Text]

13. Davies MM, Johnston PG, Kaur S, et al: Colorectal liver metastasis thymidylate synthase staining correlates with response to hepatic arterial floxuridine. Clin Cancer Res 5:325–328, 1999[Abstract/Free Full Text]

14. Link KH, Kornmann M, Butzer U, et al: Thymidylate synthase quantitation and in vitro chemosensitivity testing predicts responses and survival of patients with isolated nonresectable liver tumors receiving hepatic arterial infusion chemotherapy. Cancer 89:288–296, 2000[CrossRef][Medline]

15. Edler D, Kressner U, Ragnhammar P, et al: Thymidylate synthase expression: An independent prognostic factor for local recurrence, distant metastasis, disease-free and overall survival in rectal cancer. Clin Cancer Res 6:1378–1384, 2000[Abstract/Free Full Text]

16. Edler D, Kressner U, Ragnhammar P, et al: Immunohistochemicaly detected thymidylate synthase in colorectal cancer: An independent prognostic factor of survival. Clin Cancer Res 6:488–492, 2000[Abstract/Free Full Text]

17. Cascinu S, Catalano V, Aschele C, et al: Immunohistochemical determination of p53 protein does not predict clinical response in advanced colorectal cancer with low thymidylate synthase expression receiving a bolus 5-fluorouracil-leucovorin combination. Ann Oncol 11:1053–1056, 2000[Abstract/Free Full Text]

18. Shirota Y, Stoehlmacher J, Brabender J, et al: ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol 19:4298–4304, 2001[Abstract/Free Full Text]

19. Edler D, Glimelius B, Hallstrom M, et al: Thymidylate synthase expression in colorectal cancer: A prognostic and predictive marker of benefit from adjuvant fluorouracil-based chemotherapy. J Clin Oncol 20:1721–1728, 2002[Abstract/Free Full Text]

20. Allegra CJ, Parr AL, Wold LE, et al: Investigation of the prognostic and predictive value of thymidylate synthase, p53 and ki-67 in patients with locally advanced colon cancer. J Clin Oncol 20:1735–1743, 2002[Abstract/Free Full Text]

21. Allegra CJ: Thymidylate synthase levels: Prognostic, predictor or both? J Clin Oncol 20:1711–1713, 2002[Free Full Text]

22. Scher HI, Sarkis A, Reuter V, et al: Changing pattern of expression of the epidermal growth factor receptor and transforming growth factor alpha in the progression of prostatic neoplasms. Clin Cancer Res 1:545–550, 1995[Abstract]

23. Soong R, Grieu F, Robbins P, et al: p53 alterations are associated with improved prognosis in distal colonic carcinomas. Clin Cancer Res 3:1405–1411, 1997[Abstract]

24. Doci R, Gennari L, Bignami P, et al: One hundred patients with hepatic metastases from colorectal cancer treated by resection: analysis of prognostic determinants. Br J Surg 78:797–801, 1991[Medline]

25. Gayowski TJ, Iwatsuki S, Madariaga JR, et al: Experience in hepatic resection for metastatic colorectal cancer: Analysis of clinical and pathologic risk factors. Surgery 116:703–711, 1994[Medline]

26. Jamison RL, Donohue JH, Nagorney DM, et al: Hepatic resection for metastatic colorectal cancer results in cure for some patients. Arch Surg 32:505–510, 1997

27. Jenkins LT, Millikan KW, Bines SD, et al: Hepatic resection for metastatic colorectal cancer. Am Surg 63:605–610, 1997[Medline]

28. Bakalakos EA, Kim JA, Young DC, et al: Determinants of survival following hepatic resection for metastatic colorectal cancer. World J Surg 22:399–404, 1998[CrossRef][Medline]

29. Cady B, Jenkins RL, Steele GD Jr, et al: Surgical margin in hepatic resection for colorectal metastasis. Ann Surg 227:566–571, 1998[CrossRef][Medline]

30. Ohlsson B, Stenram U, Tranberg KG: Resection of colorectal metastases: 25-year experience. World J Surg 22:268–276, 1998[CrossRef][Medline]

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33. Minagawa M, Makuuchi M, Torzilli G, et al: Extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer. Ann Surg 31:487–499, 2000

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Submitted June 11, 2002; accepted October 14, 2002.


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M. A. Shah, N. Kemeny, A. Hummer, M. Drobnjak, M. Motwani, C. Cordon-Cardo, M. Gonen, and G. K. Schwartz
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N. E. Kemeny
In Reply:
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Fractional Genomic Alteration Detected by Array-Based Comparative Genomic Hybridization Independently Predicts Survival after Hepatic Resection for Metastatic Colorectal Cancer
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The Clinical Risk Score: Emerging as a Reliable Preoperative Prognostic Index in Hepatectomy for Colorectal Metastases
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S. Popat, A. Matakidou, and R. S. Houlston
Thymidylate Synthase Expression and Prognosis in Colorectal Cancer: A Systematic Review and Meta-Analysis
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A. Alimonti, G. Ferretti, S. Di Cosimo, F. Cognetti, and A. Vecchione
Can Colorectal Cancer Patients With Thymidylate Synthase-Overexpressing Liver Metastases Have an Overall Survival Advantage With Hepatic Arterial Infusion Alone?
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J. R. Bertino and D. Banerjee
Is the Measurement of Thymidylate Synthase to Determine Suitability for Treatment with 5-Fluoropyrimidines Ready for Prime Time?
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