Neoadjuvant Docetaxel and Capecitabinein Patients With High Risk Prostate CancerJudah Friedman, Rodney L. Dunn, David Wood, Ulka Vaishampayan, Angela Wu,Deborah Bradley, James Montie, Fazlul H. Sarkar, Rajal B. Shah and Maha HussainFrom the Division of Hematology and Oncology, Department of Medicine (JF, RLD, DB, MH), Department of Pathology (AW, RBS) andDepartment of Urology (DW, JM, RBS), University of Michigan School of Medicine and University of Michigan Comprehensive CancerCenter, Ann Arbor, and Departments of Medicine (UV) and Pathology (FHS), Wayne State University, Detroit, Michigan
Purpose: Docetaxel is the most active cytotoxic agent in hormone refractory prostate cancer. Preclinically docetaxelincreases expression of thymidine phosphorylase, an enzyme responsible for activation of capecitabine to 5-fluorouracilresulting in increased antitumor activity. We assessed activity and safety of neoadjuvant docetaxel and capecitabine inpatients with high risk prostate cancer.Materials and Methods: Patients with either clinical stage greater than T2, prostate specific antigen 15 ng/ml or more, orGleason sum 8 or greater received 3 to 6 cycles of docetaxel (36 mg/m2 intravenously on days 1, 8 and 15) and capecitabine(1,250 mg/m2 per day orally divided twice a day on days 5 to 18) every 28 days, followed by local therapy. The primary endpoint was rate of 50% or greater prostate specific antigen decrease. Correlative studies included qualitative changes inhistology, tissue thymidine phosphorylase and survivin expression, and CK18Asp396 (serum apoptosis marker).Results: A total of 15 patients were treated, of whom 6 (40%) experienced a 50% or greater decrease in prostate specificantigen with infrequent diarrhea or hand-foot syndrome. Eleven patients underwent radical prostatectomy. There were nopathological complete responses and 4 patients demonstrated mild histological changes, including focal necrosis andvacuolated cytoplasm. While there was no discernable pattern of increased thymidine phosphorylase expression, 4 specimensshowed decreased survivin expression, suggesting a possible mechanism for chemotherapy induced apoptosis. There was nocorrelation of prostate specific antigen response and survivin expression, and no increase in serum CK18Asp396.Conclusions: Neoadjuvant docetaxel and capecitabine is well tolerated but is not associated with significant pathologicaland prostate specific antigen responses.
Key Words: drug therapy, prostatic neoplasms
Patients with high risk prostate cancer (cT3, N1, PSAgreater than 20 ng/ml and/or Gleason score 8 orgreater) have a 5-year biochemical failure rate after
surgery or radiation of 50% or greater.1 Systemic failureaccounts for a significant proportion of these clinical re-lapses. Adjuvant androgen deprivation therapy is currentlythe only systemic treatment that impacts survival in se-lected patients.2,3 Because of heterogeneity of prostate can-cer cells and desire to improve on outcome with ADT, che-motherapy in localized, high risk prostate cancer is beingexplored. Neoadjuvant treatment has the advantage of rapidassessment of pathological and molecular treatment effect.
Docetaxel has demonstrated significant antitumor effectand impact on survival in hormone refractory prostate can-cer.4,5 This has led to its evaluation in the neoadjuvantsetting either as a single agent, or in combination withhormones or estramustine.6-8 While these trials report PSAdecreases of more than 50% in up to 60% of patients, signif-
Submitted for publication June 25, 2007.Supported by Grant 5 P30 CA46592 from the National Cancer
Institute and a research grant from Sanofi-Aventis.Study received institutional review board approval.Correspondence: 7314 CCGC, University of Michigan Comprehen-
sive Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, Mich-igan 48109-0946 (telephone: 734-936-8906; FAX: 734-615-2719).
icant pathological responses are rare. Furthermore, becausemany of these studies incorporated ADT or estramustine, itis difficult to assess the contribution of chemotherapy onpathological and PSA decreases because of the welldescribedeffect of hormones on prostate cancer.
Prostate cancer and other solid tumors express high levelsof TP, an enzyme responsible for activation of capecitabine tothe active drug, 5-fluorouracil.9 5-FU is then catabolized byDPD. In multiple tumor cell lines, including prostate cancer,the activity of capecitabine is related to the ratio of TP/DPD.10
Docetaxel has been shown to enhance TP levels in tumor mod-els and is synergistic with capecitabine.11 In a phase III trialthe combination capecitabine and docetaxel improved overallresponse rates and survival in patients with advanced breastcancer as compared with docetaxel alone.12 Because of an-titumor activity of docetaxel in prostate cancer, ability toincrease TP in preclinical studies and enhanced clinical activ-ity with capecitabine in breast cancer, we developed a phase IItrial combining neoadjuvant capecitabine and docetaxel in pa-tients with high risk prostate cancer. A weekly schedule ofdocetaxel was chosen for the promising rates of PSA decreasesin neoadjuvant phase II trials,7,8 and because weekly do-cetaxel, rather than every 3 weeks, could induce further sus-tained increases in TP, thus enhancing the antitumor activity
of the combination.11
Vol. 179, 911-916, March 2008Printed in U.S.A.
DOI:10.1016/j.juro.2007.10.064
NEOADJUVANT DOCETAXEL AND CAPECITABINE FOR HIGH RISK PROSTATE CANCER912
Simultaneously we initiated a preclinical trial to assessthe in vitro antitumor effect, as well as changes in geneexpression, of the combination of docetaxel and fluorouracilbased therapy to help guide the correlative studies in thistrial. Specifically, from our in vitro studies we found that theantiapoptotic protein, survivin, decreases markedly in pros-tate cancer cell lines when treated with docetaxel and fur-tulon (capecitabine is the orally administered pro-drug offurtulon).13 Survivin is a member of the inhibitor of apopto-sis family of proteins and its over expression correlates withandrogen independent prostate cancers.14 Using immuno-histochemistry, we evaluated TP expression before and afterchemotherapy to determine the validity of the preclinicalbasis for this combination. Because it is hypothesized thatTP would be increased in response to docetaxel, we mea-sured TP alone, and not DPD. We also measured changes insurvivin expression by immunohistochemistry.
MATERIALS AND METHODS
Patient EligibilityEligible patients had newly diagnosed prostate cancer withat least 1 of the characteristics of clinical stage greater thanT2, PSA 15 ng/ml or greater, or biopsy Gleason sum 8 orgreater. A minimum PSA greater than 5 ng/ml, no evidenceof distant metastasis as determined by computerized tomog-raphy of the abdomen and pelvis, and bone scan within 6weeks of registration, an ECOG (Eastern Cooperative On-cology Group) performance status of 0 or 1, and no previousor current antiandrogen therapy, chemotherapy or radio-therapy were required. Patients were also required to havean absolute neutrophil count greater than 1,500/ml, plateletcount greater than 100,000/ml, serum creatinine less than2.0 mg/dl, normal total bilirubin and liver enzymes less than2.5 � the upper limits of normal. Patients with a baselineperipheral neuropathy more than grade 2 were excludedfrom study. Pre-therapy biopsy materials must have beensubmitted for pathological review. All patients providedsigned, written informed consent for the trial approved bythe institutional review board.
Study DesignPatients were treated with 36 mg/m2 docetaxel intrave-nously on days 1, 8, and 15 every 28 days. Capecitabine wasadministered orally at 1,250 mg/m2 per day divided in 2equal doses 12 hours apart on days 5 to 18. Patients werepretreated with 8 mg of dexamethasone orally 12 hours and1 hour before, and 12 hours after docetaxel chemotherapy.The doses and schedule of capecitabine and docetaxel thatwere used in this study were based on a phase I study byNadella et al.15 The sequencing of docetaxel and capecitab-ine is based on the observed increase in the enzyme activity4 days after treatment with docetaxel.11 Two dose reduc-tions of docetaxel (30 and 25 mg/m2) were allowed for neu-tropenia, thrombocytopenia, neuropathy or liver functionabnormalities. A maximum of 2 dose reductions (1,000 and800 mg/m2) were allowed for capecitabine in the event ofhand-foot syndrome, mucositis or diarrhea. In the absence ofprogression or unacceptable toxicities, treatment continuedfor 3 cycles. Patients with a PSA decrease of less than 50%were withdrawn from the study and treated with local ther-apy. Responding patients were offered 3 additional cycles to
maximize benefit.
MonitoringPrior to each cycle patients had a complete physical exami-nation including a digital rectal examination, serum chem-istries, testosterone and PSA level measurements. After 3and 6 courses, computerized tomography of the abdomenand pelvis were performed. Patients who elected definitiveradiation therapy were asked to provide a post-therapy pros-tate biopsy (12 cores).
Pathological Evaluation and ImmunohistochemistryThe morphology and immunostaining profile of all sampleswere reviewed by a genitourinary pathologist at Universityof Michigan. Complete eradication of tumor would be con-sidered a complete pathological response. All prechemo-therapy needle biopsy samples were evaluated and com-pared to post-chemotherapy samples. Post-chemotherapysamples were examined for recognized effects of therapy onnormal and malignant tissue.16 Effects of chemotherapy onthe tumor were scored (0—none, 1—mild or very focal,2—moderate or multifocal and 4—strongest or diffuse) forpresence of necrosis, pyknosis, cytoplasmic vacuolation, fi-brosis, glandular breakdown and extravasated mucin. Im-munohistochemical stains for thymidine phosphorylase(Neomarker clone PGF.44C, pH6 antigen pretreatment,1:200 for 60 minutes) and Survivin (Novus Cat #NB 500-201, Citrate Buffer pretreatment, 1:150 for 30 minutes) wereperformed on specimens before and after chemotherapy.
Apoptosis AssayAn assay of apoptosis was evaluated to explore its useful-ness in this setting. Cleavage of cytokeratin 18 (CK 18) bycaspases after the aspartic acid residue 396 during apoptosisresults in exposure of a neoepitope (CK18Asp396), which isbelieved to be a surrogate marker for apoptosis. Plasma wascollected and stored at �80C. Levels of CK18Asp396 weremeasured using a commercially available enzyme linkedimmunosorbent assay, M30-Apoptosense® (PEVIVA AB).17
Statistical ConsiderationsThe primary end point was the response rate of the combi-nation of capecitabine and docetaxel defined as a reductionin the PSA by at least 50%. Using a 2-stage Simon’s mini-max design, if 7 or less responses were seen in the first 14patients, the study was stopped and the regimen deemed notworthy of continued study. Otherwise, a total of 23 patientswere to be accrued. If 15 or less responses were observed inthe final set of 23 patients at the end of the study, theregimen would be deemed ineffective. If 16 or more re-sponses are observed, the regimen would be consideredpromising. This 2-stage design allowed for a 5% type I errorand 80% power. Secondary end points included assessmentof feasibility and toxicity of neoadjuvant chemotherapy,evaluation of intratumor changes in 5-FU metabolism, andmolecular responses to chemotherapy.
RESULTS
Patient CharacteristicsFrom June 2003 until June 2005, 15 patients were enrolledin the study. Patient characteristics are outlined in table 1.Most patients (73%) had 2 or more high risk features. The
high risk features that most commonly qualified patients for
NEOADJUVANT DOCETAXEL AND CAPECITABINE FOR HIGH RISK PROSTATE CANCER 913
the study were a Gleason score of 8 or more in 14 of 15 (93%)and/or PSA 15 ng/ml or greater in 12 of 15 (80%).
EfficacyOf the 15 patients 9 completed 3 cycles, 2 completed 2 cyclesand 4 completed more than 3 cycles of chemotherapy.Weekly docetaxel and capecitabine had a significant effecton the median serum PSA, decreasing from a median of 23.2ng/ml before therapy to a median of 12.2 ng/ml after therapy(p �0.001, fig. 1). All but 1 patient had a decrease in PSA ontherapy. Median testosterone did not change before andafter chemotherapy (3.58 vs 3.63 ng/ml). Only 6 of 15 (40%)experienced a 50% or greater decrease in serum PSA, theprimary end point of the study. Because the protocol calledfor at least 8 patients with a 50% or greater decrease, ac-crual to the second stage was not pursued.
ToxicityGrade 1 or 2 fatigue was experienced by 66% of patients, aswell as gastrointestinal side effects such as nausea in 46%,
TABLE 1. Baseline characteristics
No. pts 15Median pt age (range) 58 (40–71)No. race:
Median Gleason score (range) 8 (7–10)Median PSA (range) 23.2 (8.1–282.2)Median No. qualifying criteria (range) 2 (1–3)
FIG. 1. Box plots of serum PSA and testo
changes in taste in 40%, nail changes in 40% and tearing in40%. Six patients (40%) experienced grade 1 or 2 hand-footsyndrome. Three and 2 patients experienced grade 3 diar-rhea and mucositis, respectively. Only 1 patient experiencedgrade 4 neutropenia. However, 11 of the 15 patients experi-enced grade 1 or 2 decrease in hemoglobin. There was noepisode of neutropenic fever. However, 1 patient experienceda peri-rectal abscess and facial cellulitis in the absence ofneutropenia.
Local Therapy and FollowupThus far median followup is 17.5 months (range 9 to 34).Eleven patients underwent radical prostatectomy, 6 of 11had positive margins and 2 of 11 had involved lymph nodes.Of the 8 patients who were treated with radical prostatec-tomy alone (no adjuvant radiotherapy or antiandrogen ther-apy) 5 had a biochemical recurrence in a median 11 months.Of the 6 patients who achieved at least a 50% decrease inPSA 5 had either involved surgical margins and/or lymphnodes with prostate cancer. Gleason sum and pathologicalstage after chemotherapy is shown in table 2. Three patientselected definitive radiotherapy (2 with concurrent androgenblockade). One patient never underwent definitive therapyas he was diagnosed with locally advanced gall bladdercarcinoma while on trial.
Chemotherapy Effect,Immunohistochemistry and Apoptosis AssayBiopsy specimens before and after chemotherapy were avail-able for 7 of the 11 patients who underwent radical prosta-tectomy. For the remaining 4 patients samples from outsideinstitutions were not available for review. Of the 3 patientswho underwent definitive radiation therapy 1 underwent apost-chemotherapy transrectal biopsy but it was of insuffi-cient quality for interpretation. The other 2 patients were
sterone before and after treatment
12.2
NEOADJUVANT DOCETAXEL AND CAPECITABINE FOR HIGH RISK PROSTATE CANCER914
not offered biopsy due to poor response and need for defini-tive radiation with androgen blockade. Of the 7 post-chemo-therapy, prostatectomy specimens 4 showed overall mildchemotherapy response. The most common features werefocal cytoplasmic clearing or vacuolization (6 with score 1 to2) and glandular breakdown (5 with score 1 to 3). Fourspecimens showed focal apoptosis/pyknosis (score 1 to 2) anda few (1 to 2) showed focal (score of 1) necrosis of the tumorcells. Only 1 of the 3 PSA responders (greater than 50%decrease in PSA) showed mild chemotherapy response.There was no discernable pattern of increased TP expressionin prostatectomy specimens compared to pre-chemotherapybiopsies (3 increased, 3 decreased, 1 with unchanged TPexpression). Four prostatectomy specimens showed de-creased survivin expression in the tumor cells. TP and sur-vivin expression did not correlate with PSA response. Figure2 shows a representative case of decreased survivin expres-sion after chemotherapy as well as the observed chemother-apy effects.
Plasma samples for apoptosis assays were available for 11patients at baseline and after cycle 1 of neoadjuvant chemo-therapy. No significant difference in levels of apoptosis associ-ated neo-epitope, CK18Asp396, was found before (mean value
10 T2c 8 21.2 T2b11 T2a 9 23.2 Not available12 T4 8 15.2 T413 T2a 6 26.8 T314 T3 10 78.7 Not available15 T2N1 9 24.7 Not available
FIG. 2. Morphological features of chemotherapy effects includedapoptosis/pyknosis (A) and cytoplasmic vacuolization (B). Compared
to prechemotherapy specimens (C), survivin expression was de-creased in postchemotherapy specimens (D) in 4 patients.
of 109.6 U/l) vs after (mean value of 112.3 U/l) chemotherapy,or in PSA responders vs nonresponders.
DISCUSSION
Neoadjuvant docetaxel and capecitabine in men with highrisk localized prostate cancer resulted in a significant de-crease in serum PSA, but did not reach the threshold setprospectively by the study for continuation of the study, norwas it associated with significant pathological response.Overall, the regimen was well tolerated, with infrequentgrade 3 or 4 adverse events. The clinical outcome for thesemen appears to be consistent with what is expected for theextent of local disease.
To fully evaluate effects of neoadjuvant chemotherapyindependent of clinical variables (PSA) it was essential toevaluate pathological samples before and after chemother-apy. By not using ADT we were able to evaluate the effect ofchemotherapy alone. Only focal and mild effects were ob-served in 4 of the 7 patient samples. Even with relativelymore significant pathological changes seen with the use ofneoadjuvant hormone based therapy, pathological completeresponses are rare.18 In contrast, in neoadjuvant studieswith breast cancer pathological complete response rates upto 30% were reported with impressive increase in disease-free survival.19 The lack of significant pathological completeresponses with neoadjuvant therapy for prostate cancer doesnot necessarily mean lack of benefit. However, until betterclinical or molecular response surrogates are identified, it isreasonable to use pathological complete response rates as ametric for screening agents in this setting in the context ofuncontrolled clinical trials. Alternatively, randomized phaseII designs can be implemented to evaluate several indicatorsof potential clinical activity including progression free sur-vival (clinical/biochemical) and tissue based indicators.
The choice to combine capecitabine with docetaxel wasbased on the preclinical knowledge that docetaxel increasedTP levels in tumor samples, and that higher TP levels wouldtranslate into greater conversion of capecitabine to activedrug. We found that TP expression increased only mildly in3 of the 7 samples and did not correlate to PSA response. Itis not clear why we did not detect an increase in TP expres-sion in our study. It is possible that increased TP expressionin response to docetaxel may only be transient and, thus, not
nd PSA responses
After Chemotherapy
% change) Gleason Margin Nodes
(�4) Not available Not available Not available(�34) 7 �(�42) 7 � �(�52) 9 � �(�36) 7 � �(�77) 7 � �(�34) 9 � �(�35) 7 � �(�86) 8 � �
(�8.4) 8 � �(�47) Not available Not available Not available(�78) 8 � �(�73) 7 � �(�24) Not available Not available Not available(�51) Not available Not available Not available
cal a
PSA (
12.622.14.79.49.7
64.319.96.6
27.319.412.23.37.2
60.2
detected at the time of radical prostatectomy. Alternatively,
NEOADJUVANT DOCETAXEL AND CAPECITABINE FOR HIGH RISK PROSTATE CANCER 915
docetaxel given every 3 weeks may have had a more pro-found effect on TP expression in vivo despite the in vitrodata in support of weekly docetaxel. In fact, schedule may bevery important given the knowledge that docetaxel’s great-est impact on hormone refractory prostate cancer survivaloccurs when administered every 3 weeks, rather thanweekly.
Our neoadjuvant study was unique in that we investi-gated the regimen in cell line experiments and used the datato prospectively evaluate expressed genes that potentiallycould be altered by the chemotherapy used in this trial. Inour preclinical studies we observed a marked decrease insurvivin expression after treating a prostate cancer cell linewith docetaxel and furtulon.13 In this study we found that 4 ofthe 7 samples showed decreases in survivin expression byimmunohistochemistry, suggesting that in vivo, docetaxel maydecrease survivin expression. Evaluation of survivin expres-sion after chemotherapy in a larger sample size may help tofurther characterize the effects of docetaxel in vivo. Combiningdocetaxel with drugs that further lower the apoptotic thresh-old by decreasing the activity or expression of antiapoptoticproteins such as survivin would be an important new hy-pothesis to explore in future neoadjuvant trials.
CONCLUSIONS
With only modest PSA decreases and subtle pathologicalchanges, this treatment failed to meet the per protocol effi-cacy parameters.
ACKNOWLEDGMENTS
Daffyd Thomas performed the thymidine phosphorylase stainand provided guidance on immunohistochemistry stainingtechniques.
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EDITORIAL COMMENT
The rationale for combining docetaxel and capecitabine
stems from laboratory observations that docetaxel increases
NEOADJUVANT DOCETAXEL AND CAPECITABINE FOR HIGH RISK PROSTATE CANCER916
expression of TP, which metabolizes capecitabine to 5-flu-orouracil. Why did this study not meet its end points, then?TP was not significantly upregulated, and even if it was,5-FU has historically had modest antitumor effects in pros-tate cancer. Also, docetaxel might have been suboptimallydosed, using a weekly schedule (reference 4 in article). How-ever, this regimen has been tested using a 3-week schedule,but those results would also lead to abandoning the regimenif this study’s stopping rules were applied.1
These results notwithstanding, the rationale for applyingdocetaxel as neoadjuvant therapy is compelling. The endpoints of such studies should be clinical, and not the patho-
logical complete response rate (which was disappointing in
this study), as the target of chemotherapy is not the primarycancer, but micrometastatic disease. Phase III trials areunder way and warrant the support of the urological com-munity.
Michael J. MorrisGenitourinary Oncology Service
Memorial Sloan-Kettering Cancer CenterNew York, New York
1. Kolodziej M, Neubauer MA, Rousey SR, Pluenneke RE, PerrineG, Mull S et al: Phase II trial of docetaxel/capecitabine inhormone-refractory prostate cancer. Clin Genitourin Cancer
