Neoadjuvant Docetaxel and Capecitabine in Patients With High Risk Prostate Cancer

Article Outline

• Abstract
• Materials and Methods
  • Patient Eligibility
  • Study Design
  • Monitoring
  • Pathological Evaluation and Immunohistochemistry
  • Apoptosis Assay
  • Statistical Considerations
• Results
  • Patient Characteristics
  • Efficacy
  • Toxicity
  • Local Therapy and Followup
  • Chemotherapy Effect, Immunohistochemistry and Apoptosis Assay
• Discussion
• Conclusions
• Acknowledgments
• References
• Copyright

Purpose

Docetaxel is the most active cytotoxic agent in hormone refractory prostate cancer. Preclinically docetaxel increases expression of thymidine phosphorylase, an enzyme responsible for activation of capecitabine to 5-fluorouracil resulting in increased antitumor activity. We assessed activity and safety of neoadjuvant docetaxel and capecitabine in patients with high risk prostate cancer.

Materials and Methods

Patients with either clinical stage greater than T2, prostate specific antigen 15 ng/ml or more, or Gleason 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 end point was rate of 50% or greater prostate specific antigen decrease. Correlative studies included qualitative changes in histology, 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 specific antigen with infrequent diarrhea or hand-foot syndrome. Eleven patients underwent radical prostatectomy. There were no pathological complete responses and 4 patients demonstrated mild histological changes, including focal necrosis and vacuolated cytoplasm. While there was no discernable pattern of increased thymidine phosphorylase expression, 4 specimens showed decreased survivin expression, suggesting a possible mechanism for chemotherapy induced apoptosis. There was no correlation 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 pathological and prostate specific antigen responses.

Key Words: drug therapy, prostatic neoplasms

Abbreviations and Acronyms: 5-FU, 5-fluorouracil, ADT, androgen deprivation therapy, DPD, dihydropyrimidine dehydrogenase, PSA, prostate specific antigen, TP, thymidine phosphorylase

Patients with high risk prostate cancer (cT3, N1, PSA greater than 20 ng/ml and/or Gleason score 8 or greater) have a 5-year biochemical failure rate after surgery or radiation of 50% or greater.¹ Systemic failure accounts for a significant proportion of these clinical relapses. Adjuvant androgen deprivation therapy is currently the only systemic treatment that impacts survival in selected patients.², ³ Because of heterogeneity of prostate cancer cells and desire to improve on outcome with ADT, chemotherapy in localized, high risk prostate cancer is being explored. Neoadjuvant treatment has the advantage of rapid assessment of pathological and molecular treatment effect.

Docetaxel has demonstrated significant antitumor effect and impact on survival in hormone refractory prostate cancer.⁴, ⁵ This has led to its evaluation in the neoadjuvant setting either as a single agent, or in combination with hormones or estramustine.⁶, ⁷, ⁸ While these trials report PSA decreases of more than 50% in up to 60% of patients, significant pathological responses are rare. Furthermore, because many of these studies incorporated ADT or estramustine, it is difficult to assess the contribution of chemotherapy on pathological and PSA decreases because of the welldescribed effect of hormones on prostate cancer.

Prostate cancer and other solid tumors express high levels of TP, an enzyme responsible for activation of capecitabine to the active drug, 5-fluorouracil.⁹ 5-FU is then catabolized by DPD. 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 models and is synergistic with capecitabine.¹¹ In a phase III trial the combination capecitabine and docetaxel improved overall response rates and survival in patients with advanced breast cancer as compared with docetaxel alone.¹² Because of antitumor activity of docetaxel in prostate cancer, ability to increase TP in preclinical studies and enhanced clinical activity with capecitabine in breast cancer, we developed a phase II trial combining neoadjuvant capecitabine and docetaxel in patients with high risk prostate cancer. A weekly schedule of docetaxel was chosen for the promising rates of PSA decreases in neoadjuvant phase II trials,⁷, ⁸ and because weekly docetaxel, rather than every 3 weeks, could induce further sustained increases in TP, thus enhancing the antitumor activity of the combination.¹¹

Simultaneously we initiated a preclinical trial to assess the in vitro antitumor effect, as well as changes in gene expression, of the combination of docetaxel and fluorouracil based therapy to help guide the correlative studies in this trial. Specifically, from our in vitro studies we found that the antiapoptotic protein, survivin, decreases markedly in prostate cancer cell lines when treated with docetaxel and furtulon (capecitabine is the orally administered pro-drug of furtulon).¹³ Survivin is a member of the inhibitor of apoptosis family of proteins and its over expression correlates with androgen independent prostate cancers.¹⁴ Using immunohistochemistry, we evaluated TP expression before and after chemotherapy to determine the validity of the preclinical basis for this combination. Because it is hypothesized that TP would be increased in response to docetaxel, we measured TP alone, and not DPD. We also measured changes in survivin expression by immunohistochemistry.

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Materials and Methods 

Patient Eligibility 

Eligible patients had newly diagnosed prostate cancer with at least 1 of the characteristics of clinical stage greater than T2, PSA 15 ng/ml or greater, or biopsy Gleason sum 8 or greater. A minimum PSA greater than 5 ng/ml, no evidence of distant metastasis as determined by computerized tomography of the abdomen and pelvis, and bone scan within 6 weeks of registration, an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, and no previous or current antiandrogen therapy, chemotherapy or radiotherapy were required. Patients were also required to have an absolute neutrophil count greater than 1,500/ml, platelet count greater than 100,000/ml, serum creatinine less than 2.0 mg/dl, normal total bilirubin and liver enzymes less than 2.5 × the upper limits of normal. Patients with a baseline peripheral neuropathy more than grade 2 were excluded from study. Pre-therapy biopsy materials must have been submitted for pathological review. All patients provided signed, written informed consent for the trial approved by the institutional review board.

Study Design 

Patients were treated with 36 mg/m² docetaxel intravenously on days 1, 8, and 15 every 28 days. Capecitabine was administered orally at 1,250 mg/m² per day divided in 2 equal doses 12 hours apart on days 5 to 18. Patients were pretreated with 8 mg of dexamethasone orally 12 hours and 1 hour before, and 12 hours after docetaxel chemotherapy. The doses and schedule of capecitabine and docetaxel that were used in this study were based on a phase I study by Nadella et al.¹⁵ The sequencing of docetaxel and capecitabine is based on the observed increase in the enzyme activity 4 days after treatment with docetaxel.¹¹ Two dose reductions of docetaxel (30 and 25 mg/m²) were allowed for neutropenia, thrombocytopenia, neuropathy or liver function abnormalities. A maximum of 2 dose reductions (1,000 and 800 mg/m²) were allowed for capecitabine in the event of hand-foot syndrome, mucositis or diarrhea. In the absence of progression or unacceptable toxicities, treatment continued for 3 cycles. Patients with a PSA decrease of less than 50% were withdrawn from the study and treated with local therapy. Responding patients were offered 3 additional cycles to maximize benefit.

Monitoring 

Prior to each cycle patients had a complete physical examination including a digital rectal examination, serum chemistries, testosterone and PSA level measurements. After 3 and 6 courses, computerized tomography of the abdomen and pelvis were performed. Patients who elected definitive radiation therapy were asked to provide a post-therapy prostate biopsy (12 cores).

Pathological Evaluation and Immunohistochemistry 

The morphology and immunostaining profile of all samples were reviewed by a genitourinary pathologist at University of Michigan. Complete eradication of tumor would be considered a complete pathological response. All prechemotherapy needle biopsy samples were evaluated and compared to post-chemotherapy samples. Post-chemotherapy samples were examined for recognized effects of therapy on normal and malignant tissue.¹⁶ Effects of chemotherapy on the tumor were scored (0—none, 1—mild or very focal, 2—moderate or multifocal and 4—strongest or diffuse) for presence of necrosis, pyknosis, cytoplasmic vacuolation, fibrosis, glandular breakdown and extravasated mucin. Immunohistochemical 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) were performed on specimens before and after chemotherapy.

Apoptosis Assay 

An assay of apoptosis was evaluated to explore its usefulness in this setting. Cleavage of cytokeratin 18 (CK 18) by caspases after the aspartic acid residue 396 during apoptosis results in exposure of a neoepitope (CK18Asp396), which is believed to be a surrogate marker for apoptosis. Plasma was collected and stored at −80C. Levels of CK18Asp396 were measured using a commercially available enzyme linked immunosorbent assay, M30-Apoptosense^® (PEVIVA AB).¹⁷

Statistical Considerations 

The primary end point was the response rate of the combination of capecitabine and docetaxel defined as a reduction in the PSA by at least 50%. Using a 2-stage Simon’s minimax design, if 7 or less responses were seen in the first 14 patients, the study was stopped and the regimen deemed not worthy of continued study. Otherwise, a total of 23 patients were to be accrued. If 15 or less responses were observed in the final set of 23 patients at the end of the study, the regimen would be deemed ineffective. If 16 or more responses are observed, the regimen would be considered promising. This 2-stage design allowed for a 5% type I error and 80% power. Secondary end points included assessment of feasibility and toxicity of neoadjuvant chemotherapy, evaluation of intratumor changes in 5-FU metabolism, and molecular responses to chemotherapy.

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Results 

Patient Characteristics 

From June 2003 until June 2005, 15 patients were enrolled in 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 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%).

Table 1. Baseline characteristics

No. pts	15
Median pt age (range)	58 (40–71)
No. race:
White	11
Black	4
No. clinical stage:
T1c	1
T2a	2
T2b	3
T2c	4
T3	2
T4	1
Pos nodes	1
Median Gleason score (range)	8 (7–10)
Median PSA (range)	23.2 (8.1–282.2)
Median No. qualifying criteria (range)	2 (1–3)

Efficacy 

Of the 15 patients 9 completed 3 cycles, 2 completed 2 cycles and 4 completed more than 3 cycles of chemotherapy. Weekly docetaxel and capecitabine had a significant effect on the median serum PSA, decreasing from a median of 23.2 ng/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 on therapy. Median testosterone did not change before and after chemotherapy (3.58 vs 3.63 ng/ml). Only 6 of 15 (40%) experienced a 50% or greater decrease in serum PSA, the primary end point of the study. Because the protocol called for at least 8 patients with a 50% or greater decrease, accrual to the second stage was not pursued.

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• Fig. 1. 

  Box plots of serum PSA and testosterone before and after treatment

Toxicity 

Grade 1 or 2 fatigue was experienced by 66% of patients, as well as gastrointestinal side effects such as nausea in 46%, changes in taste in 40%, nail changes in 40% and tearing in 40%. Six patients (40%) experienced grade 1 or 2 hand-foot syndrome. Three and 2 patients experienced grade 3 diarrhea and mucositis, respectively. Only 1 patient experienced grade 4 neutropenia. However, 11 of the 15 patients experienced grade 1 or 2 decrease in hemoglobin. There was no episode of neutropenic fever. However, 1 patient experienced a peri-rectal abscess and facial cellulitis in the absence of neutropenia.

Local Therapy and Followup 

Thus far median followup is 17.5 months (range 9 to 34). Eleven patients underwent radical prostatectomy, 6 of 11 had positive margins and 2 of 11 had involved lymph nodes. Of the 8 patients who were treated with radical prostatectomy alone (no adjuvant radiotherapy or antiandrogen therapy) 5 had a biochemical recurrence in a median 11 months. Of the 6 patients who achieved at least a 50% decrease in PSA 5 had either involved surgical margins and/or lymph nodes with prostate cancer. Gleason sum and pathological stage after chemotherapy is shown in table 2. Three patients elected definitive radiotherapy (2 with concurrent androgen blockade). One patient never underwent definitive therapy as he was diagnosed with locally advanced gall bladder carcinoma while on trial.

Table 2. Pathological and PSA responses

Before Chemotherapy				After Chemotherapy
Pt	Stage	Gleason	PSA	Stage	PSA (% change)	Gleason	Margin	Nodes
1	T2c	8	12.1	Not available	12.6(+4)	Not available	Not available	Not available
2	T1c	7	33.8	T2a	22.1(−34)	7	−
3	T2c	8	8.1	T3a	4.7(−42)	7	−	−
4	T2a	9	19.5	T3a	9.4(−52)	9	+	−
5	T2c	8	15.1	T3b	9.7(−36)	7	+	−
6	T2b	8	282.1	T3b	64.3(−77)	7	+	+
7	T2b	9	30.1	T3b	19.9(−34)	9	+	+
8	T2b	8	10.2	T3a	6.6(−35)	7	−	−
9	T2c	8	198	T2b	27.3(−86)	8	−	−
10	T2c	8	21.2	T2b	19.4(−8.4)	8	−	−
11	T2a	9	23.2	Not available	12.2(−47)	Not available	Not available	Not available
12	T4	8	15.2	T4	3.3(−78)	8	+	−
13	T2a	6	26.8	T3	7.2(−73)	7	+	−
14	T3	10	78.7	Not available	60.2(−24)	Not available	Not available	Not available
15	T2N1	9	24.7	Not available	12.2(−51)	Not available	Not available	Not available

Chemotherapy Effect, Immunohistochemistry and Apoptosis Assay 

Biopsy specimens before and after chemotherapy were available for 7 of the 11 patients who underwent radical prostatectomy. For the remaining 4 patients samples from outside institutions were not available for review. Of the 3 patients who underwent definitive radiation therapy 1 underwent a post-chemotherapy transrectal biopsy but it was of insufficient quality for interpretation. The other 2 patients were not offered biopsy due to poor response and need for definitive radiation with androgen blockade. Of the 7 post-chemotherapy, prostatectomy specimens 4 showed overall mild chemotherapy response. The most common features were focal cytoplasmic clearing or vacuolization (6 with score 1 to 2) and glandular breakdown (5 with score 1 to 3). Four specimens showed focal apoptosis/pyknosis (score 1 to 2) and a few (1 to 2) showed focal (score of 1) necrosis of the tumor cells. 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 expression in prostatectomy specimens compared to pre-chemotherapy biopsies (3 increased, 3 decreased, 1 with unchanged TP expression). Four prostatectomy specimens showed decreased survivin expression in the tumor cells. TP and survivin expression did not correlate with PSA response. Figure 2 shows a representative case of decreased survivin expression after chemotherapy as well as the observed chemotherapy effects.

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• Fig. 2. 

  Morphological features of chemotherapy effects included apoptosis/pyknosis (A) and cytoplasmic vacuolization (B). Compared to prechemotherapy specimens (C), survivin expression was decreased in postchemotherapy specimens (D) in 4 patients.

Plasma samples for apoptosis assays were available for 11 patients at baseline and after cycle 1 of neoadjuvant chemotherapy. No significant difference in levels of apoptosis associated neo-epitope, CK18Asp396, was found before (mean value of 109.6 U/l) vs after (mean value of 112.3 U/l) chemotherapy, or in PSA responders vs nonresponders.

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Discussion 

Neoadjuvant docetaxel and capecitabine in men with high risk localized prostate cancer resulted in a significant decrease in serum PSA, but did not reach the threshold set prospectively by the study for continuation of the study, nor was it associated with significant pathological response. Overall, the regimen was well tolerated, with infrequent grade 3 or 4 adverse events. The clinical outcome for these men appears to be consistent with what is expected for the extent of local disease.

To fully evaluate effects of neoadjuvant chemotherapy independent of clinical variables (PSA) it was essential to evaluate pathological samples before and after chemotherapy. By not using ADT we were able to evaluate the effect of chemotherapy alone. Only focal and mild effects were observed in 4 of the 7 patient samples. Even with relatively more significant pathological changes seen with the use of neoadjuvant hormone based therapy, pathological complete responses are rare.¹⁸ In contrast, in neoadjuvant studies with breast cancer pathological complete response rates up to 30% were reported with impressive increase in disease-free survival.¹⁹ The lack of significant pathological complete responses with neoadjuvant therapy for prostate cancer does not necessarily mean lack of benefit. However, until better clinical or molecular response surrogates are identified, it is reasonable to use pathological complete response rates as a metric for screening agents in this setting in the context of uncontrolled clinical trials. Alternatively, randomized phase II designs can be implemented to evaluate several indicators of potential clinical activity including progression free survival (clinical/biochemical) and tissue based indicators.

The choice to combine capecitabine with docetaxel was based on the preclinical knowledge that docetaxel increased TP levels in tumor samples, and that higher TP levels would translate into greater conversion of capecitabine to active drug. We found that TP expression increased only mildly in 3 of the 7 samples and did not correlate to PSA response. It is not clear why we did not detect an increase in TP expression in our study. It is possible that increased TP expression in response to docetaxel may only be transient and, thus, not detected at the time of radical prostatectomy. Alternatively, docetaxel given every 3 weeks may have had a more profound effect on TP expression in vivo despite the in vitro data in support of weekly docetaxel. In fact, schedule may be very important given the knowledge that docetaxel’s greatest impact on hormone refractory prostate cancer survival occurs when administered every 3 weeks, rather than weekly.

Our neoadjuvant study was unique in that we investigated the regimen in cell line experiments and used the data to prospectively evaluate expressed genes that potentially could be altered by the chemotherapy used in this trial. In our preclinical studies we observed a marked decrease in survivin expression after treating a prostate cancer cell line with docetaxel and furtulon.¹³ In this study we found that 4 of the 7 samples showed decreases in survivin expression by immunohistochemistry, suggesting that in vivo, docetaxel may decrease survivin expression. Evaluation of survivin expression after chemotherapy in a larger sample size may help to further characterize the effects of docetaxel in vivo. Combining docetaxel with drugs that further lower the apoptotic threshold by decreasing the activity or expression of antiapoptotic proteins such as survivin would be an important new hypothesis to explore in future neoadjuvant trials.

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Conclusions 

With only modest PSA decreases and subtle pathological changes, this treatment failed to meet the per protocol efficacy parameters.

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Acknowledgments 

Daffyd Thomas performed the thymidine phosphorylase stain and provided guidance on immunohistochemistry staining techniques.

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References 

1. Partin AW, Yoo J, Carter HB, Pearson JD, Chan DW, Epstein JL, et al. The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol. 1993;150:110
   • View In Article
   • MEDLINE
2. Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med. 1999;341:1781
   • View In Article
   • MEDLINE
   • CrossRef
3. Bola M, Gonzalez D, Warde P, Dubois JB, Mirimanoff RO, Storme G, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med. 1997;337:295
   • View In Article
   • MEDLINE
   • CrossRef
4. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502
   • View In Article
   • CrossRef
5. Petrylak DP, Tangen CM, Hussain MH, Laura PN, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513
   • View In Article
   • CrossRef
6. Hussain M, Smith DC, El-Rayes BF, Du W, Vaishampayan U, Fontana J, et al. Neoadjuvant docetaxel and estramustine chemotherapy in high-risk/locally advanced prostate cancer. Urology. 2003;61:774
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (128 KB)
   • CrossRef
7. Dreicer R, Magi-Galluzzi C, Zhou M, Rothaermel J, Reuther A, Ulchaker J, et al. Phase II trial of neoadjuvant docetaxel before radical prostatectomy for locally advanced prostate cancer. Urology. 2004;63:1138
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (109 KB)
   • CrossRef
8. Febbo PG, Richie JP, George DJ, Manola J, Shankar S, Barnes AS, et al. Neoadjuvant docetaxel before radical prostatectomy in patients with high-risk localized prostate cancer. Clin Cancer Res. 2005;11:5233
   • View In Article
   • MEDLINE
   • CrossRef
9. Takebayashi Y, Yamada K, Miyadera K, Sumizawa T, Furukawa T, Kinoshita F, et al. The activity and expression of thymidine phosphorylase in human solid tumours. Eur J Cancer. 1996;32A:1227
   • View In Article
   • MEDLINE
10. Ishikawa T, Sekiguchi F, Fukase Y, Sawada N, Ishitsuka H. Positive correlation between the efficacy of capecitabine and doxifluridine and the ratio of thymidine phosphorylase to dihydropyrimidine dehydrogenase activities in tumors in human cancer xenografts. Cancer Res. 1998;58:685
    • View In Article
    • MEDLINE
11. Sawada N, Ishikawa T, Fukase Y, Nishida M, Yoshikubo T, Ishitsuka H. Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res. 1998;4:1013
    • View In Article
    • MEDLINE
12. O’Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III results. J Clin Oncol. 2002;20:2812
    • View In Article
    • MEDLINE
    • CrossRef
13. Li Y, Hussain M, Sarkar SH, Eliason J, Li R, Sarkar FH. Gene expression profiling revealed novel mechanism of action of Taxotere and Furtulon in prostate cancer cells. BMC Cancer. 2005;5:7
    • View In Article
    • MEDLINE
    • CrossRef
14. Kishi H, Igawa M, Kikuno N, Yoshino T, Urakami S, Shiina H. Expression of the survivin gene in prostate cancer: correlation with clinicopathological characteristics, proliferative activity and apoptosis. J Urol. 2004;171:1855
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (799 KB)
    • CrossRef
15. Nadella P, Shapiro C, Otterson G, Hauger M, Erdal S, Kraut E, et al. A pharmacobiologically based scheduling of capecitabine and docetaxel results in antitumor activity in resistant human malignancies. J Clin Oncol. 2002;20:2616
    • View In Article
    • MEDLINE
    • CrossRef
16. Petraki CD, Sfikas CP. Histopathological changes induced by therapies in the benign prostate and prostate adenocarcinoma. Histol Histopathol. 2007;22:107
    • View In Article
17. Biven K, Erdal H, Hagg M, Ueno T, Zhou R, Rowley B, et al. A novel assay for discovery and characterization of pro-apoptotic drugs and for monitoring apoptosis in patient sera. Apoptosis. 2003;8:263
    • View In Article
    • MEDLINE
    • CrossRef
18. Gleave ME, Goldenberg SL, Jones EC, Bruchovsky N, Sullivan LD. Biochemical and pathological effects of 8 months of neoadjuvant androgen withdrawal therapy before radical prostatectomy in patients with clinically confined prostate cancer. J Urol. 1996;155:213
    • View In Article
    • Full-Text PDF (104 KB)
    • CrossRef
19. Bear HD, Anderson S, Smith RE, Geyer CE, Mamounas EP, Fisher B, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2006;24:2019
    • View In Article
    • CrossRef