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Advances and Controversies in Bladder Cancer Treatment

Treatment of Metastatic and Unresectable Disease

Dean F. Bajorin, MD

MVAC

The four-drug combination of MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) has been the standard of care for initial treatment of patients with advanced transitional cell carcinoma (TCC) for years. This approach was based on the data from 2 randomized trials demonstrating the superiority of MVAC over the three-drug combination CISCA (cyclophosphamide, doxorubicin, and cisplatin) and single-agent cisplatin. Toxicity for MVAC was substantial, however, since the regimen was associated with a 3%-5% toxic death rate, and patients frequently experienced mucositis and infections.

Cisplatin and Gemcitabine
Several new two-drug combinations have been recently studied in advanced TCC. However, only 1 regimen, gemcitabine plus cisplatin, has been compared to MVAC in a phase 3 trial. Von der Maase[1] reported data from a study of 405 patients with stage IV urothelial TCC who were randomly assigned to up to 6 cycles of cisplatin/gemcitabine vs MVAC. The 2-drug combination was associated with a response rate (49% vs 46%), time to treatment failure (5.8 vs 4.6 months), and median survival (13.8 vs 14.8 months) similar to those seen with MVAC, but with markedly less toxicity. Patients treated with gemcitabine/cisplatin had less treatment-related toxic deaths (1% vs 3%), less neutropenic sepsis (1% vs 12%), and less grade 3 or 4 mucositis (1% vs 22%). The combination of gemcitabine and cisplatin is considered an alternative regimen to MVAC, with comparable activity and substantially less toxicity.
Despite this improvement, survival in these patients is still limited. Attempts to improve therapy focus on increasing activity with three-drug regimens, reducing the toxicity associated with cisplatin, and including agents targeted to growth factor receptors. Results with the combination of paclitaxel, gemcitabine, and cisplatin were reported by Bellmunt and colleagues[2] responses were seen in 78% of patients. This three-drug combination is undergoing prospective comparison with the gemcitabine-and-cisplatin combination in both Europe and the United States.

Carboplatin and Gemcitabine
Since many TCC patients are older and are frequently unable to tolerate cisplatin-based therapy due to poor renal function, regimens substituting carboplatin for cisplatin have been studied extensively. At ASCO 2002, Ramirez and colleagues[3] reported on a combination of gemcitabine and carboplatin in patients with moderate-to-severe renal dysfunction. The combination was well tolerated with no renal toxicity and low hematologic toxicity. The major response rate was 59%. Dreicer and colleagues[4] from the Eastern Cooperative Group reported on the activity of a non-platin-containing regimen, docetaxel and gemcitabine. This study included previously treated patients, and a major response rate of 20% was observed.

Carboplatin, Gemcitabine, and Paclitaxel
Hussain and associates[5] from the Wayne State University had previously reported on the combination of carboplatin dosed to a targeted area under the concentration x time curve (AUC), gemcitabine, and paclitaxel, in which the objective response rate was 68%. In that study, 32% of patients experienced a complete response and the median survival was 14.7 months.
At ASCO 2002, this group reported the preliminary results of the same three-drug regimen plus trastuzumab in patients with HER2 protein overexpression.[6] Forty-one patients were evaluated for HER2 overexpression; 19 of them (46%) had 3+ expression by immunohistochemistry. Only 16% of patients had HER2 gene amplification and 26% had serum assays positive for HER2 by ELISA. Nine of the 10 patients evaluable for response to the 4-drug regimen experienced a major response. One complete response was observed. The trial is designed to accrue approximately 40 patients to assess the overall response rate and survival, and accrual to the trial is still in progress. At this time, however, the approach of combining the 3-drug combination appears to be feasible.

Controversy on the Use of Perioperative (Adjuvant and Neoadjuvant) Chemotherapy
The use of perioperative chemotherapy in muscle-invasive disease is very controversial but presentations at ASCO 2002 and 2001 provided support for survival benefit from neoadjuvant chemotherapy. The long-awaited results from the Intergroup-0080 trial evaluating the benefit of neoadjuvant MVAC in urothelial cancer of the bladder did not disappoint the oncology community at ASCO 2001.

MVAC Chemotherapy
Presented at last year's plenary session by Natale and colleagues,[7] a substantial survival benefit, greater than 2 years, was observed for patients receiving neoadjuvant MVAC. In terms of the primary objective, the study sought to detect a survival improvement with MVAC from 27 to 40 months, an improvement of 13 months. The actual improvement in survival was more than twice this value (3.8 years vs 6.2 years). These data were quite compelling, supported by a very positive hazard ratio (0.74 95% CI 0.55-0.99) (P < .05) favoring the chemotherapy arm. Confirming data supporting the benefit of neoadjuvant chemotherapy were needed to confirm that the intergroup trial did not represent spurious data. Such confirmation was provided at ASCO 2002.

CMV Chemotherapy
The largest reported trial in the literature with power to detect a 10% difference in survival was the intergroup trial performed by the Medical Research Council and the EORTC. This study evaluated CMV (cisplatin, methotrexate, vinblastine) for 3 cycles, followed by the participating institutions' recommended management of the primary lesion vs similar primary tumor management without neoadjuvant chemotherapy. Primary tumor management in this trial included cystectomy, or radiation therapy, or both. When first reported with an accrual of 976 patients and a median follow-up of 4 years, a 5.5% advantage in 3-year survival for patients receiving neoadjuvant CMV was observed. However, the survival advantage was not statistically significant. Dr. Hall and others,[8] on behalf of the EORTC, provided an update of this trial at ASCO 2002, showing that, with a median follow-up of 7 years, the patients treated with chemotherapy had a statistically significant superior survival vs those randomized to no chemotherapy (P < .05).
The results of these 2 trials together with those previously reported by the Nordic Cooperative Bladder Cancer Study Group trial of Malmstrom and associates[9] support a survival advantage with neoadjuvant chemotherapy. The Nordic Trial was conducted in 325 patients randomized to neoadjuvant doxorubicin plus cisplatin vs no chemotherapy. The authors assessed a 15% survival benefit in the subset of patients with T3 and T4 disease (P = .03) but no differences in patients with T1 and T2 disease. A multivariate analysis showed that chemotherapy and T stage were independent prognostic factors for survival and that the relative death risk for patients who received chemotherapy was 0.69 compared with the control group.
Presentations at ASCO 2001 and 2002 now demonstrate that neoadjuvant chemotherapy, specifically cisplatin-based combination chemotherapy, enhances survival. Patients with muscle-invasive disease should be presented with this information as well as with the opportunity to receive combined-modality therapy. Unfortunately, similar data do not exist for adjuvant chemotherapy. Therefore, the rationale exists for testing adjuvant chemotherapy in randomized trials, particularly in patients with extravesical or node-positive bladder cancer.
The EORTC has launched a trial to evaluate the benefit of adjuvant chemotherapy vs observation. Patients are randomized to receive surveillance or 1 of 2 cisplatin-based regimens, gemcitabine plus cisplatin or MVAC. This approximately 1300-patient trial will be conducted on 3 continents. A separate trial led by the Memorial Sloan-Kettering Cancer Center is testing the hypothesis that maximizing combinations of chemotherapy doublets may be beneficial. After local control surgery, enrolled patients are randomized to receive standard therapy or experimental sequenced therapy. The standard arm is gemcitabine plus cisplatin and the experimental arm is sequential doublets, gemcitabine and doxorubicin, followed by paclitaxel and cisplatin.

Patients With Superficial TCC
Seventy percent of bladder tumors are superficial at presentation and are managed conservatively by endoscopic resection. Sixty to 70% of superficial tumors recur and 20% to 30% of recurrent tumors will progress to muscle invasion or metastasis. The high progression rate (up to 45% with grade 3 tumors) has led to the widespread use of intravesical therapy. Intravesical instillation of biological and chemotherapeutic agents promotes direct contact with the bladder mucosa and tumor. Bacillus Calmette-Guérin (BCG) is the most effective agent in the treatment of CIS and decreases the rate of progression. However, only two-thirds of patients respond to BCG, and one-third of the responders will have recurrent disease. Recurrence after BCG treatment is associated with a poor prognosis and a significant proportion of patients will progress. Historically, intravesical therapy using older chemotherapeutic agents has not been particularly effective for high-grade, superficial disease. Therefore, cystectomy is commonly performed to control disease in patients deemed to be refractory to BCG.
At ASCO 2002, Dalbagni and coworkers[10] reported a phase 1 trial of gemcitabine given by the intravesical route twice weekly for 3 weeks, followed by a 1-week rest, then another 6 treatments over 3 weeks. Patients included in the study had BCG-refractory disease and had refused cystectomy. Eighteen patients were entered on study and the therapy was well tolerated, with acceptable bladder irritability and minimal systemic side effects.
Seven of 18 patients (39%) achieved complete remission (CR) in response to therapy -- 3 at 1000 mg, 1 at 1500 mg, and 3 at 2000 mg of gemcitabine. Eleven patients failed to achieve a CR, but evidence of chemotherapy effect was observed. One of the 11 patients underwent a radical cystectomy for a muscle-invasive tumor. Four of the 11 patients achieved a mixed response defined as a negative bladder biopsy but with persistent positive cytology. A phase 2 study is ongoing to characterize the efficacy of this approach at a recommended dose of 2000 mg.

References

1. Von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18:3068-3073.
2. Bellmunt J, Guillem V, Paz-Ares L, et al. Phase I-II study of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma of the urothelium. Spanish Oncology Genitourinary Group. J Clin Oncol. 2000;18:3247.
3. Ramirez A, Maroto P, Gallego H, et al. Carboplatin (CBDCA) -- gemcitabine (GEM) as first-line therapy for advanced transitional cell carcinoma (TCC) of the urinary tract. Feasibility in patients with moderate to severe renal failure. Single center experience. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting; May 18-21, 2002; Orlando, Florida. Abstract 795.
4. Manola JB, Dreicer R, Wiling G. Gemcitabine and docetaxel in advanced carcinoma of the urothelium: report of a phase II Eastern Cooperative Oncology Group trial. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting; May 18-21, 2002; Orlando, Florida. Abstract 796.
5. Hussain M, Vaishampayan U, Du W, et al. Combination paclitaxel, carboplatin, and gemcitabine is an active treatment for advanced urothelial cancer. J Clin Oncol. 2001;19:2527.
6. Hussein M, Smith D, Al-Sukhum S, et al. Preliminary results of Her-2/neu screening and treatment with trastuzumab, paclitaxel, carbplatin and gemcitabine in patients with advanced urothelial cancer. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting; May 18-21, 2002; Orlando, Florida. Abstract 800.
7. Natale, RB, Grossman, HB, Blumenstein, B, et al. SWOG 8710 (INT 0080): Randomized phase III trial of neoadjuvant MVAC + cystectomy versus cystectomy alone in patients with locally advanced bladder cancer. Proc Am Soc Clin Oncol 2001;20:2a.
8. Hall RR on behalf of the Collaboration of Trialists of the MRC Advanced Bladder Cancer Group. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting; May 18-21, 2002; Orlando, Florida. Abstract 710.
9. Malmstrom PU, Rintala E, Wahlqvist R, Hellstrom P, Hellsten S, Hannisdal E. Five-year follow-up of a prospective trial of radical cystectomy and neoadjuvant chemotherapy: Nordic Cystectomy Trial I. The Nordic Cooperative Bladder Cancer Study Group. J Urol. 1996;155:1903-1906.
10. Dalbagni G, Russo P, Sheinfel J, et al. Phase I trial of intravesical gemcitabine in BCG-refractory transitional cell carcinoma of the bladder. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting; May 18-21, 2002; Orlando, Florida. Abstract 799.

Bladder Cancer: Predicting Clinical Behavior

Dean F. Bajorin, MD

Urothelial cancers represent a spectrum of diseases that can be grouped into 3 general categories: superficial, invasive, and metastatic disease. Each differs in clinical behavior, prognosis, and primary management. Research presentations at the recent American Society of Clinical Oncology (ASCO) 2002 meeting focused on new approaches for treatment in all 3 categories of disease.
Additionally, several studies focused on alterations affecting "genetic pathways" and on efforts to decipher these observations for clinical practice recommendations. Alterations in proteins affecting cell-cycle regulation and apoptosis are frequent events in bladder cancer. Preliminary studies reported by several groups demonstrated that identification of such aberrations identifies a group of bladder cancer patients with tumors that harbor aggressive clinical behavior.
Historically, the only factor that reliably has predicted relapse of transitional cell carcinomas (TCCs) has been the pathological stage of disease. Proteins that regulate the G1/S cell-cycle transition and apoptosis have been evaluated extensively to delineate their ability to predict the biologic activity of TCC. The most well studied of the proteins active in regulation of the G1/S transition and their correlations with clinical outcome are p53, pRB, E2F, and p21.
Recent studies presented at ASCO 2002 explored the prognostic value of these proteins in muscle-invasive transitional cell carcinoma.[1-4] These studies, reviewed in the context of parallel studies presented at the ASCO 2001 meeting, allow us to estimate the risk of TCC progression using a prognostic index -- that is, altered expression of more than one protein, such as the cooperative effects of altered expression of p53 and p21 or p53 and Bcl-2.

Role of p53 and pRb in Cell-Cycle and DNA Damage Control
It has been shown that wild-type p53 mediates arrest of the cell cycle in the G1 phase after sublethal DNA damage and is involved in transcriptional control. Like most of the well-characterized transcription factors, p53 proteins have a nuclear localization signal and a sequence-specific DNA-binding domain. The retinoblastoma gene encodes an approximately 105-kd nuclear phosphoprotein. While the amount of pRB does not change during progression of the cell cycle, the phosphorylation state of pRB is cell cycle dependent and is a target for the enzymatic activity of cyclin-Cdk complexes.
pRB is in the underphosphorylated form in G1, and as cells progress into late G1 and early S phase, pRB becomes highly phosphorylated and remains phosphorylated in G2. The underphosphorylated form of pRB is believed to be the functionally active form of pRB in G0/middle G1. pRB can complex stably by the interaction of this region with cellular proteins, including members of the E2F family. E2F is a 60-kd transcription factor implicated in induction of S-phase enzymes such as thymidine kinase, Myc, Myb, dihydrofolate reductase, and DNA polymerase.

Role of MDM2 and p21 in the Regulation of p53 and Rb
A relationship between p53 and pRB in cell-cycle regulation is suggested based on the action of 2 novel genes that are regulated by p53: MDM2 and p21 (also known as WAF1, Cip1, or Sdi1) genes. The MDM2 gene maps to the long arm of chromosome 12 and is under transcriptional control by wild-type p53 (wt-p53). The product encoded by MDM2 is a 90-kd zinc-finger protein (mdm2) that also contains a p53-binding site. MDM2 proteins bind to p53 and act as a negative regulator, inhibiting wt-p53 transcriptional regulatory activity and creating an autoregulatory feedback loop.
It is postulated that overexpression of MDM2 inactivates both p53 and pRB. An alternative pathway of p53-pRB interaction is mediated by p21. The p21 gene belongs to a family of negative cell-cycle regulators that function as cyclin-dependent kinase-inhibitory molecules. p21 inactivates cyclin-Cdk complexes that, as described, target pRB phosphorylation. In that context, p21 serves as an effector of cell-cycle arrest in response to activation of the p53 G1 phase checkpoint pathway. These findings imply a link between p53 in cell-cycle regulation, apoptosis, and tumor progression.

Bcl-2 and Apoptosis
Molecules that regulate the mechanisms of programmed cell death have also been evaluated to determine if they predict the clinical behavior of urothelial cancer. Bcl-2, initially discovered in human B-cell lymphoma, is a proto-oncogene intrinsically involved in the apoptosis cascade. Bcl-2 gene overexpression in myeloid malignancies is a consequence of the translocation from its normal location at 18q21 to the immunoglobulin heavy-chain locus at 14q32, resulting in increased production of Bcl-2 mRNAs and their encoded proteins. Bcl-2 belongs to a family of related genes that regulates the apoptotic pathway, with Bcl-2 promoting a negative influence.

Predictive Value of p53 and p21 in the Prognosis of Muscle-Invasive TCC
Two presentations at the ASCO meeting explored the interactions between p53 and p21 in the prognosis of muscle-invasive TCC.[1,2] George and colleagues from the University of Southern California used immunochemistry to study p21, p27, and p53 expression in the primary tumors of 161 patients who underwent cystectomy for muscle-invasive disease.[1] p53 accumulation (generally representing mutations of the TP53 gene) and the loss of p21 expression were highly significant predictors of outcome in both univariate and multivariate analyses. p27 expression did not contribute to the prognostic ability of the model using p53 and p21.
Del Muro and colleagues from Barcelona also explored the prognostic value of these proteins in muscle-invasive TCC treated with an intent to preserve the bladder.[2] Using a similar immunohistochemical approach, they studied the p53, pRB, and MDM2 expression in 82 patients with muscle-invasive TCC treated with neoadjuvant chemotherapy and radiotherapy. pRB and MDM2 did not provide predictive capability. p53 expression achieved statistical significance, and there was a trend toward significance for p21, suggesting that future studies may allow for prognostic factors to identify patients with greater potential for bladder preservation approaches.
Similar studies involving these markers and their integration with proteins that regulate apoptosis had been previously reported by Maluf and colleagues from Memorial Sloan-Kettering Cancer Center, New York, NY. At ASCO 2002 they presented a study evaluating p53, Bcl-2, and MDM2 in patients with muscle-invasive TCC treated with neoadjuvant chemotherapy and cystectomy.[3] This 59-patient study also used immunohistochemistry to evaluate the presence of the various prognostic markers. Altered expression of p53 and Bcl-2 was seen in approximately half of the tumors and altered expression of mdm-2 was seen in approximately one-third. Also assessed were the cooperative effects of cell cycle and apoptotic regulatory gene proteins using phenotypes based on MDM2, p53, and Bcl-2expression.
In patients with all markers intact, the outcome was favorable with a 5-year survival of 54% and a median survival of 9.9 years. When all markers were aberrant the outcome was poor with a 5-year survival of 25% and a median survival of 1.1 years. An intermediate outcome (5-year survival of 49% and a median survival of 4.7 years) was observed for patients with either 1 or 2 aberrant markers. The difference in survival of the 3 groups was statistically significant (P = .01).

Predictive Value of EGFR and HER2
The expression of epidermal growth factor receptor (EGFR) has been studied in human bladder cancer tissue and variability of expression has been observed. The variation in immunohistochemical results may be explained by the use of different anti-EGFR antibodies, by different criteria defining expression, and by the stage of bladder cancer studied. Expression of EGFR has been seen in approximately two-thirds of more than 200 patients reported in the literature and expression seems to be greater with higher stages of tumor. Tumors expressing EGFR are significantly more likely to recur after resection, progress to muscle-invasive disease, and cause death.
At ASCO 2002, Chakravarti and associates[4] explored whether the expression of these receptors is associated with the outcome of patients with muscle-invasive TCC treated on 4 prospective trials evaluating chemotherapy-radiation Radiation Therapy Oncology Group (RTOG) trials designed to attain bladder preservation. Tumors from 73 patients were evaluated using immunohistochemistry for the status expression of both receptors. In contrast to the majority of reports in the literature, this study identified EGFR expression in only a minority (19%) of tumors. However, EGFR staining positivity was significantly associated with improved overall survival (P = .044), disease-free survival, disease-free survival with an intact bladder, and disease-specific survival. There was also a trend toward reduced frequency of metastases in patients whose tumors expressed EGFR. HER2 positivity was significantly associated with reduced complete response rates (P = .026).
These data provide the initial forays into "typing" urothelial carcinomas to potentially identify different treatment paradigms based on expression of various proteins or protein patterns. However, there was general consensus at the meeting that none of these markers should be used in routine clinical practice at the present time.

References

1. George B, Goebell PJ, Datar RH, et al. p27Kip1, p21 WAF/Cip 1, and p53: expression and impact on clinical outcome in invasive bladder cancer. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting; May 18-21, 2002; Orlando, Florida. Abstract 711.
2. Del Muro XG, Munoz J, Condom E, et al. p21 and p53 as prognostic factors for bladder preservation and survival in patients with bladder cancer treated with neoadjuvant chemotherapy. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting; May 18-21, 2002; Orlando, Florida. Abstract 712.
3. Maluf FC, Cordon-Cardo C, Satagopan JM, et al. Evaluating mdm-2 and p53 in muscle-invasive node-negative transitional cell carcinoma (TCC) of the bladder treated with cisplatin-based neo-adjuvant chemotherapy. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting; May 18-21, 2002; Orlando, Florida. Abstract 684.
4. Chakravarti A, Winter K, Wu C-L, et al. Expression of the epidermal growth factor receptor (EGFR) is associated with an improved outcome in muscle-invading bladder cancer. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting; May 18-21, 2002; Orlando, Florida. Abstract 713.

Prostate Cancer: Improving Screening, Treatment, and Prognosis

Tomasz M. Beer, MD

The 38th Annual Meeting of the American Society of Clinical Oncology revealed important new data regarding early detection, natural history, and treatment of prostate cancer. This review focuses on those presentations that discussed data most likely to change clinical practice today, that provided important new understanding of existing therapies and of the natural history of prostate cancer, or that gave a glimpse of promising future strategies.

Early Detection
The plenary session presentation by Dr. E. David Crawford[1] of the University of Colorado will not only change our strategies in prostate cancer screening; it also provides a glimpse of the important information that is likely to emerge from the ongoing PLCO trial. The PLCO is a prospective trial of screening for prostate, lung, colorectal, and ovarian cancer that enrolled 154,000 men and women between 1993 and 2001. The initial analysis presented by Dr. Crawford focused on refining the use of the prostate-specific antigen (PSA) in prostate cancer screening. Currently, the most common approach to PSA screening is to obtain a PSA test annually after the age of 50, and perhaps to begin PSA testing earlier in men at particularly high risk for developing prostate cancer. A PSA > 4 ng/mL typically triggers an evaluation for prostate cancer and 20% to 30% of men with a PSA above 4 ng/mL who get a prostate biopsy are diagnosed with prostate cancer.
Dr. Crawford and colleagues sought to identify patients whose risk of having a PSA above 4 ng/mL is sufficiently low such that testing less often than once every year could be recommended.
In an analysis of 27,863 men aged 55-74, they found that men whose initial PSA is below 2 ng/mL are not likely to have a PSA above 4 ng/mL in the following year. Indeed, men with a PSA < 1 ng/mL had only a 1.6% chance of reaching a PSA above 4 in 5 years and men with a PSA between 1 and 2 ng/mL had a 1.2% chance of reaching a PSA above 4 ng/mL in the following year. Based on these findings, Dr. Crawford recommended that men with a normal prostate examination and a PSA below 1 ng/mL have a PSA test drawn every 5 years, and, similarly, men with a PSA between 1 and 2 ng/mL wait 2 years between PSA tests.
Dr. Crawford estimated that the adoption of such a strategy would save between $500 million and $1 billion annually in the United States. He noted that this report focused on refining the way we use the PSA for the early detection of prostate cancer and did not examine the overall effectiveness of prostate cancer screening. While PSA testing is widely used in the United States, prospectively collected randomized evidence of a survival benefit is not available and this is one of the central goals of the PLCO trial. Considerably longer follow-up will be needed before those important results are available.

Natural History of Prostate Cancer
Important advances in our understanding of the natural history of prostate cancer were reported at the 2002 ASCO meeting. Cathy Tangen[2] of the Southwest Oncology Group (SWOG) reported an analysis of men who survive for long periods of time despite having metastatic prostate cancer. While the average survival of men with untreated prostate cancer that has metastasized is about 3 years, SWOG investigators found that 7% of such men live beyond 10 years. Having metastases limited to the axial skeleton, good performance status, and no bone pain were all independent predictors of prolonged survival. Further study of why some patients survive many years with advanced prostate cancer may provide clues about how we might extend the survival of all patients with this disease.
Another important group of patients whose outcome may be better than previously thought was the subject of extensive discussion at ASCO educational sessions and of a presentation by Dr. Mohammed Elshaikh[3] of the Cleveland Clinic. These are patients who have had treatment with curative intent, prostatectomy or radiotherapy, and now have a rising PSA indicating cancer recurrence. Pound and others previously showed that half of such patients develop metastases after 8 years, and about 50% are alive after 13 years, suggesting that a rising PSA is not necessarily a death sentence in prostate cancer.[4]
Additional data supporting the notion that we ought not view a rising PSA by itself as a catastrophe came from Dr. Elshaikh's presentation. Dr. Elshaikh studied 10-year survival of 1055 patients treated with prostatectomy or external beam radiation. Forty-two percent of these patients had a rising PSA. Ninety-four percent of patients without a rising PSA and 78% of those with a rising PSA were alive 10 years later (P < .001) indicating that a PSA recurrence is associated with an increased risk of death. A multivariate analysis, however, showed that the Gleason score, clinical stage, and radiation dose (< 72 Gy vs > 72 Gy) were statistically significant predictors of death at 10 years while a rising PSA was only weakly associated with risk of death (P = .084).
An analysis of those patients with high-risk prostate cancer (cT2b-3, PSA>10 ng/mL, or GS > 6 at diagnosis) revealed that a rising PSA in this group is associated with earlier death (10-year survival of 92% without a rising PSA and 75% with a rising PSA, P < .001). Ninety-four to 95% of patients with low-risk prostate cancer were alive at the end of 10 years and there was no difference in survival between patients who did and did not have a rising PSA. While longer follow-up may reveal excess deaths from prostate cancer in low-risk patients with a rising PSA, it is clear that many men have a good prognosis despite a PSA recurrence. It is unclear at this time whether the early application of additional treatment in men with a rising PSA can improve long-term survival. The toxicity of any proposed intervention should be carefully balanced against the relatively good prognosis that men have without any treatment.

Treatment of Localized Prostate Cancer
Dr. Alan Pollack[5] of the University of Texas MD Anderson Cancer Center reported important new information about the influence of dose on the efficacy of external beam radiotherapy. While many preliminary studies have suggested that higher doses of radiation yield better disease control, this was the first randomized study to examine the question rigorously. Dr. Pollack compared conventional 4-field box radiotherapy with a dose of 70 Gy to 6-field conformal radiation delivered to a dose of 78 Gy in 301 patients with median follow-up of 60 months. The patients were stratified by known risk factors for recurrence including clinical stage, Gleason score, and pretreatment PSA.
To date, no difference in local recurrence was seen, but an advantage with respect to overall recurrence (predominantly by PSA) was observed. When all patients were analyzed, 64% of the 70 Gy and 70% of the 78 Gy were recurrence-free after 6 years (P = .03). This difference was more pronounced in patients with a pretreatment PSA > 10 ng/mL (43% vs 62%, P = .01). There was no difference in patients with a PSA < 10 ng/mL, with both groups having a 75% chance of being free of recurrence at 6 years.
Despite the conformal field, >/= grade 2 rectal toxicity was more common in the higher- dose group (26% vs 12 %, P = .001) and there was a trend towards a higher incidence of bladder toxicity. Rectal toxicity is far more common when > 25% of rectum is exposed to >/= 70 Gy of radiation. Thirty-five percent of patients in this study were exposed to radiation doses above 70 Gy to the rectum. Newer conformal radiation strategies typically can reduce the frequency with which the rectum receives such high doses of radiation. While it is too early to know if low-risk patients will ultimately benefit from higher doses of radiation, and whether overall survival can be improved, this preliminary report provides the first randomized evidence that higher doses of radiation lead to improved cancer control.
New approaches to the treatment of high-risk clinically localized prostate cancer were highlighted. While the definitions of high-risk prostate cancer vary, typically this group consists of patients who have a < 50% chance of cure with currently available treatments. This is an area in which breast cancer investigators have made substantial strides by combining surgery and/or radiation with effective systemic therapy. A number of investigators presented preliminary results of such efforts in prostate cancer including efforts to combine docetaxel,[6,7] docetaxel plus estramustine,[8] and paclitaxel[9] plus radiation or radiation and hormonal therapy. Combinations with surgery included docetaxel plus mitoxantrone[10] and docetaxel plus estramustine.[8,11] All of these were preliminary feasibility studies. Large national randomized trials have begun to examine the role of antineoplastic therapy in the management of high-risk but potentially curable prostate cancer. These trials clearly merit the support of the patient and medical communities.

Hormonal Therapy for Prostate Cancer
Studies of front-line hormonal therapy focused on adverse effects of treatment. Dr. Celestia Higano[12] examined intermittent hormonal therapy, a strategy that involves androgen deprivation for 9 months followed by a break from treatment until the PSA reaches a predetermined target. Dr. Higano showed that 2% to 4% of bone mass was lost at both hip and spine during the first and the second cycle of androgen deprivation. A loss of 0.5% to 1% per year is expected in this age group. Accelerated loss of bone mass is a concern because it can lead to osteoporosis which in turn is associated with bone fractures. Bone loss stabilized or recovered modestly during breaks in androgen deprivation. How overall bone loss over long periods of time compares on intermittent and on continuous androgen deprivation remains to be determined.
Dr. Paul Sieber[13] reported bone mineral density results in 103 patients randomized to conventional androgen deprivation or high-dose bicalutamide (150 mg per day) After 96 weeks of treatment, patients treated with bicalutamide gained 2.4% of bone mass at the spine and 1.1% at the hip, while patients treated with conventional androgen deprivation lost 5.4% at the spine and 4.4% at the hip (P < .00001). High-dose bicalutamide is often used as front-line therapy for advanced prostate cancer in Europe but rarely used this way in the United States, where it is considered an experimental strategy.

Androgen-Independent Prostate Cancer (AIPC)

Antiandrogen Withdrawal
A considerable portion of the meeting was devoted to the treatment of this most advanced form of prostate cancer. On behalf of SWOG, Dr. Oliver Sartor reported on antiandrogen withdrawal in patients with AIPC.[14] A number of previous reports noted that patients treated with combined androgen blockade (CAB, therapy that adds an oral androgen receptor blocker such as flutamide, bicalutamide, or nilutamide to either orchiectomy or a depot gonadotropin-releasing hormone [GnRH] agonist) who begin to progress can occasionally respond to the discontinuation of the antiandrogen component of their hormonal therapy.
Dr. Sartor's report was the largest prospective study of this issue. Fifteen percent of 218 patients had a confirmed PSA reduction of 50% (PSA response) after discontinuation of the antiandrogen. While this is a modest number, a more impressive 23% of patients were free from progression at 12 months after antiandrogen discontinuation. Clearly, withdrawal of antiandrogens remains the standard initial step in the management of AIPC patients treated with CAB.

Chemotherapy
Currently, mitoxantrone plus prednisone is the FDA-approved standard chemotherapy for AIPC and large randomized trials are examining docetaxel with and without estramustine vs mitoxantrone plus prednisone. Both of these trials are close to completing accrual and until they are completed, the standard of care in chemotherapy for prostate cancer is unlikely to change.

Novel Combinations and Novel Agents
The presentations in this area at ASCO 2002 focused primarily on the early development of novel agents and novel combinations that it is hoped will challenge the winning regimens from the current national trials. Several general areas can be identified:

Chemotherapy Plus Bisphosphonates
Bisphosphonates target bone osteoclasts, reduce bone mass loss, and may retard the ability of cancer cells to thrive in the bone environment. Zolendronate was recently approved by the FDA for use in prostate cancer after studies demonstrated a significant reduction in skeletal complications of prostate cancer in patients treated with zolendronate vs placebo. The data behind this approval have not been published yet and many questions remain about the precise role of this class of agents in the management of prostate cancer. On behalf of the National Cancer Institute of Canada Clinical Trials Group,[15] Dr. Ernst reported that in a randomized trial, the addition of intravenous clodronate to mitoxantrone and prednisone did not improve survival, palliative response, or time to worsening of pain.

Chemotherapy Plus Novel Agents
Many of the novel biologic agents target a variety of biologic "Achilles heels" of prostate cancer. Often, the agents are not designed to exert substantial antineoplastic activity on their own, but rather to enhance tumor response to conventional anticancer agents. Early results with this approach were reported for a number of agents, and selected results are summarized in the Table.

Table. Novel Agents Being Evaluated in Patients With Prostate Cancer

*DPPE, dipalmitoyl-phosphatidylethanolamine
These results should be viewed as preliminary and in many cases studies are ongoing. Nevertheless, these combinations may offer higher activity and/or lower toxicity than currently available therapies. Randomized studies will be necessary to appropriately evaluate the value of these novel strategies.

Biologic Agents Alone
Dr. Michael Carducci[20] of Johns Hopkins University reported preliminary results of a randomized phase 2 study of atresantan,* a selective antagonist of the endothelin-A receptor The analyses are preliminary and provide intriguing and at the same time somewhat ambiguous results. In analyses limited to evaluable patients, atresantan therapy was associated with longer survival than placebo therapy, 583 vs 478 days (P = .03), although the more conventional intent to treat analysis that includes all eligible patients did not show a significant benefit. Ongoing larger phase 3 randomized studies will determine if atresantan can affect the natural history of prostate cancer.

Immunotherapy
Efforts to recruit the immune system to combat prostate cancer remain in the early stages of development. A number of investigators reported early data on a variety of strategies including a dendritic cell vaccine,[21] a granulocyte-macrophage colony-stimulating factor (GM-CSF) transfected killed prostate cancer cell vaccine,[22] and vaccines that rely on novel immunological adjuvants.[23] One study reported the results of a small randomized study that compared treatment with a pox virus expressing PSA and the B7.1 costimulatory molecule with second-line hormonal therapy with nilutamide.[24] Eight of 13 patients in each arm have had stabilization of the PSA, suggesting comparable activity of the vaccine vs second-line hormonal therapy. Although this finding is exciting from a scientific standpoint, it is worth remembering that second-line hormonal therapy with antiandrogens has no effect on survival and only modest activity. The immunotherapy results presented at ASCO this year suggest that this area of investigation remains exciting and holds promise for the future, but they also remind us that prostate cancer immunotherapy is still in its infancy.

*This section mentions investigational drugs.

References

1. Crawford E, Chia D, Andriole G, et al. PSA testing interval reduction in screening intervals: data from the prostate, lung, colorectal and ovarian cancer (PLCO) screening trial. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 4.
2. Tangen C, Crawford E, Faulkner J, et al. Ten-year survival in patients with metastatic (M+) prostate cancer (CaP): analysis of Southwest Oncology Group (SWOG) 8894. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 749.
3. Elshaikh M, Kupelian P, Reddy C, Zippe C, Klein E. Impact of biochemical failure on overall survival after radical prostatectomy or radiation therapy for localized prostate cancer in the PSA era. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 746.
4. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281:1591-1597.
5. Pollack A, Zagars G, Starkschall G, et al. Prostate cancer radiation dose response: final planned analysis of a phase III randomized trial. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 703.
6. Kumar P, Perotti M, Weiss R, et al. A novel therapeutic strategy testing the safety and feasibility of concurrent docetaxel and 3-D conformal radiation therapy (RT) in patients with high risk localized adenocarcinoma of the prostate: progress report of an on-going phase I trial. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 772.
7. DiBiase S, Dawson N, Hussain A, Jacobs S, Naslund, M. A phase II study evaluating external radiation and transperineal implantation with adjuvant docetaxel and total androgen suppression in patients with poor prognosis non-metastatic prostate cancer. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 2487.
8. El-Rayes B, Hussain M, Smith D, et al. Neo-adjuvant docetaxel and estramustine in patients with high risk/locally advanced prostate cancer. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 773.
9. Hussain A, Amin P, Dawson N, et al. Weekly paclitaxel, concurrent radiation (RT) and androgen ablation (AA) in men with recurrent or locally advanced prostate cancer (LAPC). Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 776.
10. Garzotto M, Higano C, Lowe B, et al. Neoadjuvant weekly docetaxel and mitoxantrone in patients with high risk localized prostate cancer: a phase I trial. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 2434.
11. Ko Y, Dewolf W, Olumi A, et al. Neoadjuvant chemo-hormonal therapy followed by radical prostatectomy for high risk prostate cancer (PCa). Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 2465.
12. Jiang P, Miller M, Stern J, Pitzel M, Higano C. The dynamics of bone mineral density during intermittent androgen suppression (IAS) in prostate cancer (PC) patients without bone metastases. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 789.
13. Sieber P, Keiller D, Kahnoski R, et al. Bone mineral density is maintained during bicalutamide ('Casodex') treatment. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 783.
14. Sartor A, Tangen C, Hussain M, Eisenberger M, Crawford E. Anti-androgen withdrawal in prostate cancer: results from SWOG 9426. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 785.
15. Ernst D, Tannock I, Venner P, et al. Randomized placebo controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone alone in patients with hormone refractory prostate cancer (HRPC) and pain: National Cancer Insititute of Canada Clinical Trials Group study. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 705.
16. Beer T, Eilers K, Garzotto M, Lowe B, Henner W. Androgen-independent prostate cancer (AIPC) treatment with weekly high-dose calcitriol and docetaxel. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 707.
17. Raghavan D, Brandes L, Klapp K, et al. Mitoxantrone plus DPPE in hormone-refractory prostate cancer (HR-CAP) with symptomatic metastases -- response in 70% of cases. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 786.
18. Dahut W, Arlen P, Gulley J, et al. A randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 730.
19. Pruitt-Scott D, Ryan C, Stadler W, Vogelzang N. Exisulind (EXI) plus docetaxel (DOC) for hormone-refractory prostate cancer (HRPC). Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 2460.
20. Carducci M, Nelson J, Humerickhouse R, et al. Effects of atrasentan on progression and survival in men with hormone refractory prostate cancer: follow-up to study M96-594. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 708.
21. Schellhammer P, Small E, Higano C, et al. Autologous dendritic cells pulsed with prostatic acid phosphatase (APC8015) for hormone refractory prostate cancer: a phase III randomized, double blind, placebo controlled trial. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 731.
22. Simons J, Nelson W, Nemunaitis J, et al. Phase II trials of a GM-CSF gene-transduced prostate cancer cell line vaccine (GVAX) in hormone refractory prostate cancer. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 729.
23. Slovin S, Ragupathi G, Fernandez C, et al. A bivalent vaccine containing glycosylated MUC-2-KLH and globo H-KLH conjugates using a new semi-synthetic saponin immunological adjuvant, GPI-0100, in biochemically relapsed prostate cancer (PC). Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 781.
24. Arlen P, Gulley J, Novik L, et al. A randomized phase II trial of either vaccine therapy (recombinant pox viruses expressing PSA and the B7.1 costimulatory molecule) versus hormone therapy (nilutamide) in patients (pts) with hormone refractory prostate cancer and no radiographic evidence of disease. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting, May 18-21, 2002; Orlando, Florida. Abstract 728.