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Journal of Clinical Oncology, Vol 24, No 25 (September 1), 2006: pp. 4069-4077 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.2084 Thymidine Phosphorylase Expression Is Associated With Response to Capecitabine Plus Irinotecan in Patients With Metastatic Colorectal Cancer
From the Fox Chase Cancer Center; Thomas Jefferson University, Philadelphia; MDR Global Systems, Windber, PA; Swedish Cancer Institute, Seattle; Rockwood Clinic-Oncology Department, Spokane, WA; University of Alabama, Birmingham, AL; Roche Laboratories Inc, Nutley, NJ; Eastern Connecticut Hematology & Oncology, Norwich, CT; and Loma Linda University Cancer Institute, Loma Linda, CA. Address reprint requests to Neal J. Meropol, MD, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111; e-mail: Neal.Meropol{at}fccc.edu
Purpose: To evaluate the clinical activity and toxicity of capecitabine plus irinotecan as first-line therapy for patients with metastatic colorectal cancer (mCRC), and to describe the association of expression of thymidine phosphorylase (TP), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) with antitumor activity. Patients and Methods: Patients with previously untreated mCRC received irinotecan days 1 and 8 intravenously, and capecitabine days 2 to 15 orally in 21-day cycles. Doses were irinotecan 125 mg/m2 and capecitabine 1,000 mg/m2 bid (n = 15; cohort 1), or irinotecan 100 mg/m2 and capecitabine 900 mg/m2 bid (n = 52; cohort 2). Tissues from primary and metastatic sites were assessed for TP, TS, and DPD gene and protein expression. Results: An unacceptable level of GI toxicity in the first 15 patients led to a protocol modification in starting doses. The response rate was 45% (30 of 67 patients). Overall survival was associated with TP expression assessed by immunohistochemistry in both primary tumors (P = .045) and metastases (P = .001). Objective tumor response was associated with TP expression in primary tumors (odds ratio, 4.77; 95% CI, 1.25 to 18.18), with a similar trend in metastases (odds ratio, 8.67; 95% CI, 0.95 to 79.1). TP gene expression in primary tumors was also associated with response. Conclusion: These data indicate that capecitabine plus irinotecan is an active regimen against mCRC. The biomarker analysis (including metastatic tissue) was feasible in a multicenter setting, and provides preliminary evidence that TP expression may be a predictive marker for response.
Colorectal cancer is the second leading cause of cancer death in the United States.1 Several agents are now available for the systemic therapy of patients with colorectal cancer, including fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab, and cetuximab.2-12 In patients with metastatic disease4-6,8,10 and in the adjuvant setting,13 the addition of other agents to a fluorouracil (FU) backbone results in improved overall or disease-free survival. Capecitabine is an oral fluoropyrimidine carbamate that was developed initially in an effort to achieve improved tumor selectivity. After oral administration, capecitabine is metabolized to FU through three enzymatic steps.14 The final step involves the conversion of 5'-deoxy-5-fluorouridine to FU by the tumor-associated angiogenic factor thymidine phosphorylase (TP). Because TP has high levels of expression in colorectal tumor tissues, capecitabine metabolism results in the preferential activation of FU at tumor sites.15 As a single agent, capecitabine is at least as effective as and more convenient than intravenous FU in patients with colorectal cancer.7,11,16 A commonly used regimen for patients with metastatic colorectal cancer is a combination of FU plus irinotecan. Response rates with this regimen as first-line therapy for metastatic colorectal cancer have ranged from approximately 40% to 55%.6,10,17 In an effort to develop a more convenient, well-tolerated, and active fluoropyrimidine-based regimen for patients with colorectal cancer, we undertook a phase II trial of capecitabine plus irinotecan. A key component of this study was an assessment of TP in both primary and metastatic tumors; on the basis of mechanism of action, we hypothesized that those tumors with the greatest TP expression would be most likely to respond to capecitabine, in contrast with previous studies demonstrating an association of TP expression with FU resistance.18,19 In addition, we hypothesized that as with intravenous FU, tumors expressing high levels of dihydropyrimidine dehydrogenase (DPD; a key enzyme responsible for FU inactivation) or high levels of thymidylate synthase (TS; a key target of FU) would be resistant to capecitabine.19-22
Patient Selection Patients age  18 years with histologically confirmed metastatic colorectal adenocarcinoma and at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST)23 were considered eligible for study. All patients were required to have both primary and metastatic tissue (paraffin embedded) available for correlative studies. No prior chemotherapy was permitted except adjuvant FU completed at least 12 months before enrollment. Details of eligibility criteria have been reported previously.24 The study was approved by the institutional review boards at all participating sites, and written informed consent was required for all patients.
Treatment Protocol
Toxicity Assessments and Dose Modification
Response and Survival Assessments
Correlative Studies For quantitation of TP, DPD, and TS in tissue samples by reverse transcriptase polymerase chain reaction (RT-PCR), macroscopic dissected sections were prepared from the paraffin-embedded material. Quantitative RT-PCR was performed using the LightCycler instrument (Roche Diagnostics, Mannheim, Germany) according to the manufacturer's instructions with Roche Diagnostics Quantification Kits.26 Detail regarding correlative study methodology is provided in the online-only appendix.
Statistical Analyses The study was conducted with a two-stage design to detect a response rate of 50% from a null response rate of 30% (one-sided 5% level of significance) with at least 80% power. The first stage would accrue 14 assessable patients. If three or more responses were observed in the first stage, an additional 31 assessable patients were to be accrued in the second phase, for a total of 45 assessable patients. The null hypothesis would be rejected if 20 or more responses were observed in the 45 assessable patients. A total of at least 50 patients were to be recruited to allow for an estimated 10% dropout or nonassessable rate. This two-stage design was implemented for patients enrolled after the protocol amendment described above became effective (cohort 2). Primary and secondary efficacy end point data were summarized by cohort. The efficacy analyses included all patients who received at least one dose of both capecitabine and irinotecan. Safety analyses included all patients who received at least one dose of any study medication and had postbaseline safety measurements. An exact 90% CI was calculated for the primary efficacy parameter, using the Clopper-Pearson formula. The Kaplan-Meier product limit method was applied for all time-to-event/duration variables (ie, TTP, survival, and duration of overall response). The association between biomarker parameters and efficacy end points was evaluated in all enrolled patients who completed at least two cycles of study treatment. Results were adjusted for starting dose. The TTP and survival curves were plotted by TP protein expression and compared by the log-rank test. Summary statistics were derived for TP, TS, and DPD, including mean, median, and range.27,28 Logistic regression analysis with cohort and biomarker parameters as independent variables was used to assess the association between the binary tumor response and the biomarker parameters. Cox regression with cohort and biomarker parameters as independent variables was performed to assess the association between the biomarkers and the time-to-event efficacy end points. Given that study power and sample size were not based on biomarker end points, these analyses are exploratory. Log-rank test and Cochran-Mantel-Haenszel test were applied in the exploratory analyses.
Patient Demographics Sixty-seven patients from 13 study sites were enrolled. Fifteen patients initially were treated with irinotecan 125 mg/m2 and capecitabine 2,000 mg/m2 per day (cohort 1). Real-time safety monitoring demonstrated an unacceptable level of toxicity at these doses, and 52 patients subsequently were enrolled at reduced doses of irinotecan 100 mg/m2 and capecitabine 1,800 mg/m2 per day (cohort 2). Demographics are summarized in Table 1. All patients in each cohort were assessable for safety and efficacy.
Adverse Events Adverse events are summarized in Table 2. The most common reported events were diarrhea, nausea or vomiting, fatigue, and hand-foot syndrome. The toxicity pattern in cohort 2 was similar to that in cohort 1, but the severity was reduced. Five patients (33%) in cohort 1 and seven patients (13%) in cohort 2 withdrew from the study because of treatment-related adverse events (four with diarrhea; two each with deep venous thrombosis and dehydration; and one each with colitis, hand-foot syndrome, pneumonia, and small bowel obstruction). One treatment-related death (pulmonary embolism) was considered possibly related to treatment.
Response to Treatment Response and survival estimates were similar for patients in cohorts 1 and 2 (Table 3). The objective response rate was 47% (90% CI, 24.4% to 70.0%) in cohort 1, and 44% (90% CI, 32.4% to 56.5%) in cohort 2. Median time to objective response was 5.5 months (95% CI, 2.7 to 8.6 months) for patients in cohort 1, and 4.3 months (95% CI, 2.6 to 9.6 months) for patients in cohort 2. Kaplan-Meier estimates of TTP and overall survival are shown in Figures 1 and 2, respectively. The median number of treatment cycles was 11 in cohort 1 and 8.5 in cohort 2.
Predictive Biomarkers A total of 58 (87%) patients completed two cycles of treatment and were assessable for biomarker analysis: 12 (80%) in cohort 1 and 46 (88%) in cohort 2. All patients provided tumor samples from primary and metastatic sites for comparison of biomarker expression. Figure 3 compares the expression of DPD, TS, and TP in primary tumors and metastases.
When grading protein expression by IHC, there was at least 1 unit of discordance in 47% of samples for DPD (n = 47), 54% for TS (n = 46), and 59% for TP (n = 46). In pairs where at least one sample (primary or metastasis) was negative for staining, there was discordance in 47% of DPD samples (n = 36), 71% of TS samples (n = 7), and 75% of TP samples (n = 16). The association between the putative fluoropyrimidine biomarkers TP, TS, and DPD and response to capecitabine plus irinotecan, as measured by IHC, is listed in Table 4. TP expression in primary tumors, as measured by IHC, was significantly associated with response to therapy. A similar trend was observed with TP expression in metastases, although this was not statistically significant. TS and DPD expression by IHC were not associated with response to capecitabine plus irinotecan. The sensitivity, specificity, positive predictive value, and negative predictive value for TP expression by IHC were 85% and 96%, 48% and 30%, 65% and 61%, and 73% and 86% in primary and metastatic tumors, respectively.
TP as measured by IHC was associated with TTP and overall survival. As shown in Figure 4, TTP was superior in patients with tumors that expressed TP. Median TTP among patients expressing TP in primary tumors was 8.7 months (95% CI, 6.2 to 10.8 months) compared with 6.0 months (95% CI, 2.6 to 8.7 months) among patients not expressing TP (P = .039, log-rank test), and 8.7 months (95% CI, 7.4 to 10.2 months) compared with 5.4 months (95% CI, 2.5 to 7.6 months) in metastatic tumors (P = .002, log-rank test).
Figure 5 shows overall survival based on TP expression. In patients with TP-expressing primary tumors, median survival was 28.2 months (95% CI, 15.5 to 39.8 months) compared with 14.9 months (95% CI, 9.0 to 20.5) in patients with TP-negative primary tumors (P = .045, log-rank test; Fig 5A). TP expression in metastases was also associated with improved median survival (TP-positive tumors, 26.6 months; 95% CI, 16.8 to 30.0 months, and TP-negative tumors, 9.8 months; 95% CI, 2.6 to 21.2 months; P =.001, log-rank test; Fig 5B).
The results of mRNA quantification in primary tumors, any metastatic tumor, and metastatic tumors taken exclusively from the liver are listed in Table 5. The median and mean ± standard deviation values in primary tumors (n = 46) were 23.8 and 31.8 ± 37.1 for TP, 1.6 and 2.2 ± 1.7 for TS, and 4.6 and 8.9 ± 18.4 for DPD, respectively. In metastatic tumors from any source (n = 42), the values were 30.8 and 95.7 ± 283.2 for TP, 1.6 and 2.0 ± 2.7 for TS, and 7.6 and 103.2 ± 530.0 for DPD, respectively. Consistent with the results obtained by IHC, there was no association of TS or DPD gene expression in either primary or metastatic tumors, whether taken from any source or exclusively from the liver, and response to therapy. TP gene expression in primary tumors was associated with response, but this was not observed for metastatic tumors from any source or only from the liver. The ratio of TP/DPD gene expression was not associated with response.
Gene and protein expression of TP, TS, or DPD in primary or metastatic tumors was not associated with grade 3 or 4 diarrhea or neutropenia in the first two cycles of treatment (data not shown).
This study indicates that the combination of capecitabine plus irinotecan is an active regimen in the initial management of patients with metastatic colorectal cancer. At starting doses of irinotecan 100 mg/m2 on days 1 and 8, and capecitabine 900 mg/m2 bid on days 2 to 15, the regimen has an acceptable adverse effect profile. The response rate (45%), TTP (7.6 months), and survival (20.5 months) data that we present compare favorably with other reports of capecitabine plus irinotecan,29-35 as well as intravenous irinotecan, FU, and leucovorin.4,10,17 Given the availability of a variety of agents with activity against metastatic colorectal cancer in the first-line setting (eg, FU, capecitabine, irinotecan, oxaliplatin, cetuximab, and bevacizumab), there is heightened urgency to identify biomarkers that are predictive of response, such that treatment can be selected rationally for individual patients. We hypothesized that a key enzyme in the activation pathway of capecitabine, TP, might contribute to the sensitivity of tumors to this agent. In fact, whereas thymidine phosphorylase has been associated with resistance to FU,18,19 we postulated that the converse would be true of capecitabine, thus potentially describing a biochemical rationale for the selection of a particular fluoropyrimidine. In this phase II study, TP expression by IHC was associated with improved response rates, TTP, and overall survival. We observed substantial discordance between primary and metastatic tumors (including both hepatic and nonhepatic) in TP expression (as well as expression of TS and DPD), which could reflect sampling variation, or perhaps a true difference in the biology of primary and metastatic colorectal tumors.36,37 Biologic differences in gene expression between primaries and metastases could be further compounded by the fact that metastases in colorectal cancer frequently are not synchronous, thus allowing for additional genetic mutation over time at distant sites. To our knowledge, this study is the first systematic comparison of TP expression in primary and metastatic colorectal cancers from the same patients, and illustrates the feasibility of a clinical trial in which accessible tumor from a metastatic site is an entry criterion. In this study, although the association of TP expression and clinical activity was most pronounced in metastases, similar findings were obtained using primary tumors. Thus, availability of a biopsy specimen from a metastatic site may not be required. When we explored the potential predictive value of TP gene expression by RT-PCR, the results were less consistent than with IHC. Although TP expression in primary tumors was associated with response, this finding was influenced by how the populations with high and low expression were defined. Furthermore, TP gene expression in metastases, whether considering only liver metastases or all sites, was not associated with response. These findings may reflect the small sample sizes available for these analyses. Another possibility is that the IHC assessment of the specific tumor specimen was a more representative global assessment of the entire tumor field, whereas the RT-PCR assessment was based on a much smaller portion of the tumor field that had been dissected macroscopically and was thus perhaps inherently less representative of the tumor specimen as a whole, possibly leading to misinterpretation and, at the least, discordance from the IHC interpretation. Future studies with quantitative RT-PCR approaches may need to use multiple sampling to provide a more representative sampling of the entire tumor field. This concern, although relevant for macroscopically dissected samples, may also be important for laser-capture microdissected samples. These considerations are particularly important in the planning of correlative studies using IHC and quantitative RT-PCR in upcoming larger phase III cooperative group protocols in patients with colorectal cancer. In summary, TP expression in primary or metastatic tumors, measured by IHC, may be useful for predicting response to first-line treatment of metastatic colorectal cancer with capecitabine plus irinotecan. This finding must be viewed as preliminary, given that the study was not powered to address this hypothesis definitively. We previously described that germline variation in UGT1A7 and UGT1A9, enzymes possibly involved in SN-38 glucuronidation, influenced the response and toxicity of patients treated in this clinical trial.24 It is clear that the identification and validation of predictive markers for clinical use must take into account multiple pathways that affect the pharmacodynamics of multiple drugs commonly administered in combination. Variability in tumors as well as patient germline polymorphisms must be considered. Additional prospective studies will be required to determine whether TP expression can be used to predict clinical outcome in patients treated with capecitabine, or in the rational selection of capecitabine versus intravenous FU. Such studies must include standardized, well-validated assay methodology. Furthermore, sample size must be sufficient to achieve adequate statistical power for specific biomarker end points. The era in which we can design studies with biomarker validation as a primary end point has arrived.
Toxicity assessments and dose modification. All patients underwent clinical evaluations on days 1, 8, and 15 of cycles 1 and 2. Toxicity was assessed using the National Cancer Institute Common Toxicity Criteria version 2.25 Treatment was withheld for grade 2 to 4 toxicity, and resumed on resolution to grade 0 to 1. For grade 1 hyperbilirubinemia, treatment was also withheld until resolution. Irinotecan was reduced by one dose level for grade 3 to 4 hematologic toxicities or diarrhea, and for other grade 2 to 4 nonhematologic toxicities. Irinotecan dose levels were 125, 100, 75 mg/m2 for cohort 1 and 100, 80, 60 mg/m2 for cohort 2. Capecitabine was reduced by one dose level for the first appearance of grade 2 to 3 nonhematologic toxicities, and by two dose levels for grade 4 toxicity. Capecitabine was reduced two dose levels from the starting dose for the second appearance of a specific nonhematologic toxicity, and was discontinued for the second appearance of a grade 4 toxicity, or the third appearance of a grade 2 to 3 toxicity. Capecitabine dose levels were 1,000 (900), 750, 600 mg/m2 bid. Protocol therapy was discontinued if a dosing delay of more than 21 days was required. Correlative studies. Fixed tissues in paraffin from the primary tumor and at least one metastatic site were used for IHC and gene expression assessments of TP, DPD, and TS. IHC was performed using test kits (Roche Diagnostics GmbH) per the manufacturer's instructions, with Anti-TP (Roche catalog 3 183 653, year 2003), Anti-TS antiserum (Roche catalog 1 186 008, year 2003), and Anti-DPD antibody (Roche catalog 3 183 645, year 2003). Controls were liver and tonsil macrophages (TP), liver parenchyma and tonsil (DPD), and tonsil (TS). Semiquantitative microscopic analyses of protein expression were performed, providing either a negative rating or positive rating of 1+ (weak), 2+ (strong), or 3+ (very strong). Two IHC-experienced reviewers (R.S. and A.J.K.) scored the tumor and stromal elements according to the scoring guidelines for intensity and percentage found in the Roche antibody kit package inserts. The intensity, percentage of positive tumor cells, and subcellular location (ie, cytoplasmic, nuclear) for both the primary tumor and metastasis were also noted for each case. Reviewed concordance on selected areas for evaluation was made before scoring. For quantitation of TP, DPD, and TS in tissue samples by RT-PCR, macroscopic dissected sections were prepared from the paraffin-embedded material. Paraffin tissue sections were deparaffinized by incubation with 800 µL of xylene and 400 µL of 100% ethanol, after which the samples were centrifuged with the supernatant removed. Tissue pellets were washed with 1 mL of 100% ethanol and dried for 10 minutes at 55°C. RNA isolation that followed was performed using the Roche High Pure RNA Isolation Kit (Roche Diagnostics, Mannheim, Germany) per the manufacturer's instructions. Quantitative RT-PCR was performed using the LightCycler instrument according to manufacturer's instructions with the following Quantification Kits (Roche Diagnostics): LightCycler TP mRNA Quantification KitPLUS (catalog No. 03302946001), LightCycler DPD mRNA Quantification KitPLUS (catalog No. 03302938001), and LightCycler TS mRNA Quantification KitPLUS (catalog No. 03302954001). To normalize the values, gene levels from each sample were divided by S9 levels in the same sample.26 The following principal investigators and institutions enrolled patients onto this study: Fakniuddin Ahmed, HemOnCare, PC Research, New York, NY; Miklos Auber, Robert Byrd Health Science Center, Morgantown, WV; Hoo Chun, New York Medical College, Valhalla, NY; Philip Desimone, University of Kentucky, Lexington, KY; Mandeep Dhami, Eastern CT Hematology & Oncology, Norwich, CT; George Giels, Charleston Hematology and Oncology, Charleston, SC; Thomas Godfrey, Loma Linda University Cancer Institute, Loma Linda, CA; Philip J. Gold, Swedish Cancer Institute, Seattle, WA; Stephen Kahanic, Siouxland Hematology/Oncology, Sioux City, IA; Kirk Lund, Rockwood Clinic-Oncology Department, Spokane, WA; John Marshall, Georgetown University Medical Center, Washington, DC; Neal J. Meropol, Fox Chase Cancer Center, Philadelphia, PA; Edith Mitchell, Thomas Jefferson University, Philadelphia, PA; Muhammad Saif, Wallace Tumor Institute, Birmingham, AL; Robert Shepard, University of Virginia Health System, Charlottesville, VA.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-$99,900 (C)
We thank Todd Hill for study management, Teng-Chaio Chu for statistical assistance, and Nelson Erlick for editorial support. We also thank the site Principal Investigators (listed in the online-only appendix), without whom this study would not have been possible.
Supported by Roche Laboratories Inc. Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
