Annals of Oncology Advance Access originally published online on April 25, 2008
Annals of Oncology 2008 19(9):1541-1546; doi:10.1093/annonc/mdn165
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breast cancer |
Thymidine phosphorylase expression is associated with time to progression in patients receiving low-dose, docetaxel-modulated capecitabine for metastatic breast cancer
1 Department of Clinical Oncology
2 Department of Pathology
3 Department of Genetics, University Hospital of Udine
4 Division of Oncology ‘C’
5 Division of Pathology, National Cancer Institute, Aviano, Italy
* Correspondence to: Dr F. Puglisi, Department of Clinical Oncology, University Hospital of Udine, Piazzale S.M. Misericordia, 33100 Udine, Italy. Tel:+39-0-432-559304; Fax: +39-0-432-559305; E-mail: puglisi.fabio{at}aoud.sanita.fvg.it
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Background: Preclinical data have indicated a synergistic interaction between docetaxel and capecitabine by means of taxane-induced up-regulation of thymidine phosphorylase (TP). On the basis of such premises, we conducted a phase II trial to determine the activity and tolerability of weekly docetaxel plus capecitabine in patients with metastatic breast cancer (MBC). Furthermore, we explored the relationship between TP tumor expression and benefit from this regimen.
Patients and methods: Patients received docetaxel 36 mg/m2 i.v. on days 1, 8, and 15 and capecitabine orally 625 mg/m2 b.i.d. from days 8 to 21. Cycles were repeated every 4 weeks. In the correlative study, we evaluated the TP expression by immunohistochemistry and the TP messenger RNA expression by real-time RT–PCR in the primary tumor.
Results: Forty-seven women were enrolled. In the intention-to-treat analysis, objective responses were achieved in 24 patients (51%). Fourteen additional patients (30%) had stable disease. The median time to progression (TTP) was 6 months (range 1–44 months). Median survival was 17 months (range 1–48 months). Overall, the treatment was well tolerated. The most common clinical adverse events (all grades) were alopecia (55%), nail changes (53%), fatigue/asthenia (51%), nausea/vomiting (51%), neutropenia (49%), and neuropathy (49%). A significantly higher TTP was observed in patients with TP-positive tumors (log-rank test, P = 0.009). Interestingly, a subgroup analysis confirmed this TTP benefit in patients with TP-positive tumors obtaining a tumor response (log-rank test, P = 0.03), whereas the statistical significance was lost in nonresponders (log-rank test, P = 0.3).
Conclusions: This study indicates that a regimen with low doses of capecitabine plus weekly docetaxel is active against MBC. The correlative analysis provides preliminary evidence that TP expression may be a predictive marker for therapeutic benefit.
Key words: capecitabine, docetaxel, metastatic breast cancer, thymidine phosphorylase
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Capecitabine, an oral fluoropyrimidine prodrug, is modified to 5-fluorouracil preferentially in tumor tissue through a three-step enzymatic process [1]. The last step in the enzymatic cascade is mediated by thymidine phosphorylase (TP) which has been observed to be expressed at higher levels in tumor tissue as compared with normal tissue [2].
In addition to its selective tumor activation, capecitabine has demonstrated synergy with a wide range of other anticancer agents, including taxanes. It has been hypothesized that chemotherapeutic drugs could stimulate tumor expression of TP making cancer cells more vulnerable to capecitabine.
In particular, docetaxel has been reported to increase the expression of TP in human cancer xenograph studies resulting in synergistic inhibition of tumor growth in colon and breast cancer models when combined with capecitabine [3]. Furthermore, preoperative treatment with docetaxel has been observed to up-regulate TP expression in tumor samples from breast cancer patients [4–6].
In patients with metastatic breast cancer (MBC) who have received anthracycline therapy, combination of docetaxel with capecitabine represents a reasonable therapeutic option.
In a phase III trial, 3-weekly capecitabine (1250 mg/m2 twice daily days 1–14) plus docetaxel (75 mg/m2 day 1) demonstrated significantly superior overall survival (OS) when compared with docetaxel alone (3-weekly 100 mg/m2 day 1) [7]. More recently, a retrospective analysis of data from the phase III trial was conducted to investigate if the application of dose reduction could alter the benefit from the capecitabine/docetaxel combination [8]. The authors reported that early capecitabine and docetaxel dose reduction was associated with improved tolerability and fewer treatment interruptions, with no evidence of loss of the efficacy advantage over single-agent docetaxel.
The results of this analysis, in turn, provided a further ‘clinical’ support to the hypothesis of a synergy between capecitabine and docetaxel.
In particular, it is tempting to hypothesize that the combination of TP-inducing (i.e. docetaxel) with TP-targeting (i.e. capecitabine) agents could translate in a better therapeutic index.
Of note, preclinical observation indicated that TP up-regulation by docetaxel is transient, with maximal enzymatic induction observed between 6 and 10 days after treatment [3]. Accordingly, an innovative schedule was tested in a phase I trial where docetaxel was given weekly for 3 weeks (days 1, 8, and 15) every 4 weeks, whereas capecitabine was started on day 5 of every course and continued for 14 days (days 5–18) [9].
The present paper reports the results of a phase II trial in patients with MBC who received docetaxel in combination with capecitabine with a schedule aimed at improving synergism between the two drugs by TP up-regulation. In addition, a translational study was designed to evaluate whether the tumor expression of TP could predict therapeutic benefit.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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This phase II, open-label, multicenter study was conducted at the Department of Clinical Oncology, University Hospital of Udine and Division of Oncology ‘C’, National Cancer Institute, Aviano, Italy. The protocol was approved by the institutional review boards of both institutions. All patients provided written informed consent.
Patients with cytologically or histologically confirmed breast cancer and evidence of measurable metastatic disease using Response Evaluation Criteria in Solid Tumors (RECIST) [10] were eligible for the study. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status zero to two and normal renal, hepatic, and hematological function.
Previous treatment should have contained an anthracycline, unless contraindicated in either the adjuvant or the metastatic setting. Patients were ineligible if they had prior therapy with oral capecitabine, infusional fluorouracil or docetaxel, or had received more than one prior chemotherapy for MBC. Also patients with peripheral neuropathy grade 2 or more [National Cancer Institute–Common Toxicity Criteria (NCI-CTC), version 2], central nervous system metastases or with a history of significant cardiac disease were not eligible.
Patients received docetaxel 36 mg/m2 administered i.v. over 60 minutes weekly for 3 weeks and oral capecitabine 625 mg/m2 b.i.d. for 14 days followed by 1 week off, on days 8–21 of every cycle. Cycles were repeated every 28 days. Patients who experienced objective (complete or partial) response, or those with stable disease (SD), were treated until disease progression or intolerable toxicity. All treatments were administered in outpatient setting.
Premedication before docetaxel was mandatory. Prednisone 50 mg was administered orally 12 h before docetaxel, immediately before docetaxel, and 12 h after docetaxel. Antiemetics were used at the investigator's discretion. Prophylactic use of granulocyte colony-stimulating factor and erythropoietin was not allowed; however, these agents could be used for therapeutic intervention at the investigator's discretion.
Toxicity was evaluated according to version 2 of NCI-CTC and was recorded per patient as the worst episode that appeared during a cycle of treatment.
Dosage modifications were applied according to suggestions from the phase I study [9].
Treatment was withheld for grade 2–4 toxicity (except alopecia), and resumed on resolution to grade 0–1, with specified dose modifications. Before starting a new cycle of treatment, an absolute neutrophil count of >1500/mm3 and platelet count >100 000/mm3 were required. For toxicity reasons, treatment was withheld for up to a maximum of 2 weeks. If the toxicity had not resolved to grade 0–1 at the end of this time frame, the patient was withdrawn from the study.
Treatment with capecitabine was resumed at either the original dose level for grade 2 non-hematologic toxicity and grade 3 hematologic toxicity, whereas the dose was reduced by 25% for patients who experienced grade >3 non-hematologic or grade 4 hematologic toxicity. For grade 2–3 hand–foot syndrome (HFS), capecitabine treatment was withheld until resolution to 
grade 1 and then restarted at the same dose.
Docetaxel treatment within a cycle was withheld for the presence of any grade 
2 toxicity (except alopecia) during the scheduled day of docetaxel administration and the patient was reevaluated weekly until resolution to grade 2. Missed doses of docetaxel were not to be made up. Treatment was restarted at the same dose for grade 3 toxicity, except hepatic, and reduced by 25% for grade 4 toxicity. For patients who experienced elevations in hepatic functions tests, the docetaxel dose was reduced by 25% after recovery from grade 2 bilirubin elevations or from grade 3 elevations in alkaline phosphatase or aspartate aminotransferase (AST) (5.1–20x Upper limits of normal (ULN)). Docetaxel dose was reduced by 25% for concurrent grade 2 elevations of alkaline phosphatase (2.5–5x ULN) and AST (1.6–5x ULN) in the presence of normal bilirubin levels. For treatment during subsequent courses, docetaxel was permanently reduced by 25% for patients who experienced grade 4 myelosuppression or febrile neutropenia, or any grade 3 non-hematologic toxicity (except HFS and nausea/vomiting) during the previous course of treatment.
correlative study
Fixed tissues from the primary tumor of 32 patients were used for immunohistochemistry (IHC) and gene expression assessments of TP.
Samples were processed to evaluate TP expression on tumor cells and on stromal cells as previously reported [6]. IHC was carried out at a single central laboratory using a primary mouse anti-TP monoclonal antibody (Roche Diagnostics, Mannheim, Germany).
TP expression was assessed on 5-µm sections of paraffin-embedded tissue samples. Endogenous peroxidase activity was inhibited by incubating the slides in 0.3% H2O2 in absolute methanol for 5 min. Antigen retrieval was done in a water bath at 98°C (40 min in 1 mM EDTA buffer, pH 8.0). The tissues were blocked with 20% goat serum for 20 min and then incubated overnight at 4°C with mouse monoclonal anti-TP antibody diluted 1:100 (Roche Diagnostics). For staining detection, the EnVision+ Detection System (Dako, Denmark, A/S) was used according to the manufacturer's recommendation. In each experiment, a negative control was included in which primary antibody was replaced by mouse ascites. Liver Kupffer cells served as a positive control.
TP expression was evaluated on tumor cells and stromal cells by semiquantitative microscopic analysis. Staining intensity as well as percentage of stained cells was considered in assessment of cytoplasmic staining according to the method described by Tsuda et al. [11]. The intensity of immunoreactivity was scored as 0, 1, 2, or 3 denoting negative, weak, moderate, or strong staining, respectively. Then, the percentages of areas of each category (0–3) of staining were estimated and, regardless of positive or negative staining, the category of the largest area of cancer or stromal tissue was reported as the representative score for each case. Therefore, for statistical analysis, the TP expression level for each case was putatively defined as positive if the predominant intensity was 2 or 3.
For quantitation of TP in tissue samples by RT–PCR, macroscopic dissected 10-µm sections were prepared from the paraffin-embedded material.
RNA was extracted using RNeasy FFPE kit (Qiagen, Milano, Italy). The extraction was carried out following the manufacturing instruction with the exception that the deparaffinizing step was done by incubation in two consecutive baths of xilene for 15 min, centrifuged, and washed in 100% ethanol.
RNA was reverse-transcribed using SuperScript III Revers Transcriptase (Invitrogen, Milan, Italy) according to the manufacturer's protocols.
Real-time PCR reactions were carried out by using standard conditions in the the ABI Prism 7300 thermal cycler (Applied Biosystems, Foster City, CA). Oligonucleotide primers and probes for TP and the endogenous gene, beta-actin (BA), are the following:
- TP forward: 5'-CCTGCGGACGGAATCCT-3'
- TP reverse: 5'-GCTGTGATGAGTGGCAGGCT-3'
- TP probe: 5'-CAGCCAGAGATGTGACAGCCACCGT-3'
- BA forward: 5'-CGAGCGCGGCTACAGCTT-3'
- BA reverse: 5'-TCCTTAATGTCACGCACGATTT-3'
- BA probe: 5'-ACCACCACGGCCGAGCGG-3'
- TP reverse: 5'-GCTGTGATGAGTGGCAGGCT-3'
The 
CT method, by means of the SDS software (Applied Biosystems), was used to calculate the messenger RNA (mRNA) levels, by using the cell line MDA 468 as calibrator.
evaluation criteria and statistical analysis
The primary end point of the study was response rate (RR). Tumor lesions were measured using RECIST [10] at baseline and at the end of every other chemotherapy cycle.
The RR and its 95% exact binomial confidence interval (CI) were assessed. A one-sample two-sided binomial exact test was conducted to test whether the null hypothesis of RR was equal to 0.3 against the alternative hypothesis that the RR was not equal to 0.5; the preplanned sample size and power for this test was 46 patients with 80% power (
= 0.05, two-tailed).
Time to progression (TTP) was defined as the interval from the date of the first docetaxel infusion until tumor progression, and OS as the interval from the first day of treatment until death for any cause. Data were analyzed as of May 2007. TTP and OS were estimated using the Kaplan–Meier product-limit method. To test the difference between TTP curves according to TP expression, the log-rank test was used. P values <0.05 were considered to indicate statistical significance.
All statistics were calculated using StatView for Windows, SAS Institute Inc. Copyright® 1992–1998, version 5.0.
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patients' characteristics
A total of 47 patients were enrolled between July 2002 and November 2006. All patients received capecitabine and docetaxel and comprised the intention-to-treat population. As of May 2007, they were assessable for efficacy and safety analysis.
Baseline patient characteristics are listed in Table 1.
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The median age was 59 years (range 33–74), and most of the patients (98%) had a good performance status (ECOG 0 or 1). The tumor estrogen receptor status was positive in 70% of women and progesterone receptor status was positive in 60%.
Forty patients (85%) had multiple metastases involving two or more organ systems. Liver was the most common metastatic site. Among the 47 women treated in this study, 32 (68%) had received prior chemotherapy, whereas 15 patients (32%) were chemotherapy naive.
efficacy
Median TTP was 6 months (range 1–44 months; mean 10.2; 95% CI 7.1–13.2). Median OS was 15 months (range 1–48 months; mean 19.1; 95% CI 15.4–22.7). One patient died after 36 days from the start of treatment because of early disease progression.
Four patients experienced complete response (8%; 95% CI 0.5% to 16%). Partial response was observed in 20 patients (42%; 95% CI 28% to 57%), translating into an overall response rate (ORR) of 51% (95% CI 37% to 65%). Of note, ORR was 73% and 40% in chemotherapy naive patients and in pretreated patients, respectively. SD was seen in 14 patients (30%; 95% CI 17% to 43%) and progressive disease (PD) in nine patients (19%; 95% CI 8% to 30%).
drug delivery and safety
Overall, capecitabine plus docetaxel combination was well tolerated, and no treatment-related deaths were observed. Forty-seven patients received a total of 239 cycles. The median number of cycles received was 6 (range 1–10). Average delivered dose intensity, defined as actual dose/planned dose, was 89.61% for docetaxel and 86.42 % for capecitabine. Dose modifications and/or discontinuation of therapy were observed in 21 women (45.65%); 20 patients required dose reductions [17 patients (36%) in the docetaxel dose and 16 patients (34%) in the capecitabine dose]; treatment was discontinued in one patient (2%) and no patients had dose modifications before discontinuation.
Main causes of dose modifications and/or discontinuation of therapy were neutropenia, mucositis, fatigue/asthenia, HFS, and nail changes.
Hematological and non-hematological adverse effects are depicted in Table 2. The most common clinical adverse events (all grades) were alopecia (55%), nail changes (53%), fatigue/asthenia (51%), nausea/vomiting (51%), neutropenia (49%), and neuropathy (49%). Among peculiar events associated with the use of docetaxel, hyperlacrimation occurred in 47% of patients. Of note, with the exception of neutropenia and nail changes, grade 3/4 toxic effects were rare. No episodes of febrile neutropenia were observed.
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TP expression evaluation and association with outcome measures
Tumor samples from 32 patients were used to test the association between clinical outcomes (TTP and best response to therapy) and TP expression, as measured by IHC (n = 32) or RT–PCR (n = 28) in primary tumors.
TP was primarily expressed in tumor cells and tumor-associated stromal cells. The usual pattern of TP IHC staining was cytoplasmic, although occasionally both cytoplasmic and nuclear staining was seen. In tumor cells, high TP expression was seen in 13 of 32 cases (41%), whereas in the stroma, TP expression was categorized as positive in 23 of 32 cases (72%).
When the TTP curves were plotted by TP as measured by IHC and compared by log-rank test, a significantly higher TTP was observed in patients with TP-positive tumors (log-rank test, P = 0.009) (Figure 1). Median TTP among patients with TP-positive primary tumors was 10.5 months (mean 16.5; 95% CI 9.4–23.5 months) compared with 4.2 months (mean 5.8; 95% CI 4.0–7.7 months) among patients with TP-negative tumors.
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A subgroup analysis confirmed TTP benefit in patients with TP-positive tumors obtaining a tumor response (log-rank test, P = 0.03), whereas the statistical significance was lost in nonresponders (log-rank test, P = 0.3). No association was found between TP mRNA expression and TTP.
Although best tumor response evaluated according to RECIST guidelines was higher in TP-positive than in TP-negative tumors, the difference was not statistically significant. Nine out of 13 patients (69%) with TP-positive and eight out of 19 (42%) TP-negative tumors experienced objective tumor response, respectively. Notably, among six patients who experienced PD, five had TP-negative primary tumors (chi-square test, P value = 0.18).
There were no significant associations between stromal TP-expression by IHC and outcome measures (data not shown).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Despite advances in the diagnosis and treatment of breast cancer, metastatic disease remains largely incurable with little incremental progress in median survival rates, with the exception of patients receiving new target therapies [12, 13]. While the treatment of metastatic disease is essentially palliative, it provides the opportunity to explore new approaches which are eventually transferred to the adjuvant setting [14]. Research for MBC should therefore attempt at studying treatment strategies designed on findings obtained from basic research. In view of preclinical studies reporting transient and time-dependent docetaxel-mediated up-regulation of TP [3], a phase I was carried out to test the combination of weekly docetaxel and twice-daily capecitabine [9]. The treatment schedule was on the basis of the hypothesis that, through a more sustained up-regulation of TP, lower doses of capecitabine could be used without compromising therapeutic benefit. In turn, therapeutic index for the combination could increase. Of note, given that up-regulation was maximal at days 6–10, capecitabine was started on day 5.
The present phase II study, designed on the same background of the abovementioned phase I study, indicates that the combination of low doses of capecitabine plus weekly docetaxel is an active regimen in the treatment of anthracycline-pretreated patients with MBC. At doses of docetaxel 36 mg/m2 on days 1, 8, 15 and capecitabine 625 mg/m2 b.i.d. on days 8–21, the regimen has an acceptable safety profile. As in other studies with similar schedule, the incidence of hematological and other grade 3/4 toxic effects was low representing an important patient advantage over more intensive chemotherapy schedules. Nail changes, however, were of discomfort to several patients.
Furthermore, the observed results on ORR (51%) and TTP (6 months) are consistent and compare favorably with those of historical reports of trials that tested weekly docetaxel in combination with capecitabine [15–17].
Notably, a recent retrospective analysis of the landmark phase III study [8], as well as multiple phase II studies of taxanes with reduced-dose capecitabine [17–21], indicates that reducing the dose of capecitabine is a reasonable strategy when the agent is combined with docetaxel or paclitaxel. The present study provides further evidence in favor of this therapeutic approach. In addition, the correlative analysis of TP corroborates the hypothesis that, at least in breast cancer, the tumor expression of this enzyme may represent a useful predictor of response to capecitabine and/or taxane-modulated capecitabine regimens.
In particular, when outcomes were compared according to IHC-detected TP status, patients with TP-positive tumors experienced a more than doubled TTP (10.5 versus 4.2 months, log-rank test, P = 0.009).
Interestingly, TTP benefit was observed in patients with TP-positive tumors who obtained a tumor response (log-rank test, P = 0.03), whereas the statistical significance was lost in nonresponders (log-rank test, P = 0.3). The lack of benefit in cases with TP-positive tumors that did not obtain a tumor shrinkage after chemotherapy could be the result of primary resistance to capecitabine that deserves to be elucidated.
When TP expression was evaluated by RT–PCR, no predictive value was observed. A possible explanation of the discordance between the IHC and RT–PCR methods in predicting outcome is that the RT–PCR assessment was carried out on a macroscopically dissected portion of the tumor. As result, the analysis could include also tumor stroma, being less representative of the tumor cells.
Overall, the results of the present correlative study must be viewed as hypothesis generating and interpreted with caution because of the small sample sizes.
In conclusion, IHC evaluation of TP expression is a promising predictor of therapeutic benefit from docetaxel-modulated capecitabine for MBC. The validity of these preliminary findings deserve to be prospectively studied in appropriately powered translational trials.
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Acknowledgements |
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This work was presented in part at the 2007 San Antonio Breast Cancer Symposium. We wish to thank Roberta Sottile and Antonella Spada for the their precious work of data management. In addition, we wish to thank Maura Pandolfi for her significant technical support. The work was performed under the auspices of Associazione Ricerca Traslazionale in Senologia.
Received for publication March 14, 2008. Accepted for publication March 18, 2008.
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References |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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