What's new in the treatment of advanced prostate cancer?

Increased insight into the biology of prostate cancer and the emergence of new therapeutic strategies and chemotherapeutic agents has changed approaches in treating patients with advanced prostate cancer. After secondary hormonal manipulations, new approaches include: second-line hormonal therapy, chemotherapy, immunotherapy with granulocyte macrophage-colony stimulating factor (GM-CSF) therapy, dendritic cell therapy, gene vaccination therapy, inhibition and/or blockade of growth factor receptors or growth factor receptor pathways, inhibition of neo-angiogenesis and inhibition of invasion and metastases.     

Target repositioning optimization in prostate cancer: is intensity-modulated radiotherapy under stereotactic conditions feasible?

PURPOSE: To assess repositioning reproducibility of the prostate when treatment setup conditions before radiotherapy (RT) are optimized and internal organ motion is reduced with an endorectal inflatable balloon. METHODS AND MATERIALS: Thirty-two patients were treated with 64 Gy to the prostate and seminal vesicles using a three-dimensional conformal radiotherapy technique, followed by a boost (two fractions of 5-8 Gy, 3-5 days apart) delivered to a reduced prostate volume (the peripheral tumor bearing zone with 3-mm margins) using intensity-modulated RT. A commercially available infrared-guided stereotactic repositioning system and a rectal balloon were used. Further improvement in repositioning could be obtained with a stereoscopic X-ray registration device matching the pelvic bones during treatment with the corresponding bones in the planning computed tomography (CT). To simulate repositioning reproducibility, CT resimulation was performed before the last boost fraction. Prostate repositioning was reassessed, first after CT-to-CT fusion with the stereotactic metallic body markers of the infrared-guided system, and second after CT-to-CT registration of the pelvic bony structures. RESULTS: Standard deviations of the prostate (CTV) center of mass shifts in the three axes ranged from 2.2 to 3.6 mm with body marker registration and from 0.9 to 2.5 mm with pelvic bone registration. The latter improvement was significant, particularly in the right-to-left axis (3.5-fold improvement). In 10 patients, systematic rectal probe repositioning errors (i.e., >20-mL probe volume variations or >8-mm probe shifts in the perpendicular axes) were detected. Target repositioning was reassessed excluding these 10 patients. An additional improvement was observed in the anteroposterior axis with 1.7 times and 1.5 times reduction of the standard deviation with body markers and pelvic bone registrations, respectively. CONCLUSIONS: Infrared-guided target repositioning for prostate cancer can be optimized with a stereoscopic X-ray positioning device mostly in the right-to-left axis. An optimally positioned inflatable rectal probe further optimizes target repositioning mostly along the anteroposterior axis. Thus a planning target volume with a margin of 2 (right-to-left), 4 (anteroposteriorly), and 6 (craniocaudally) mm around the CTV can be recommended under optimal setup conditions with pelvic bone registration and optimal repositioning of an inflated rectal balloon.     

Phase II study of vinorelbine in patients with androgen-independent prostate?cancer

Purpose:To evaluate the efficacy and toxicity ofvinorelbine in a phase II study in patients with progressive metastaticandrogen-independent prostate cancer. Patients and methods:Forty-seven men with progressivemetastatic prostate cancer refractory to first-line or second-linehormonal therapy were treated with vinorelbine, a semi-syntheticvinca-alkaloid. Vinorelbine was given, on an outpatient schedule, at 25mg/m² weekly for at least eight weeks or until progression orexcessive toxicity. Results: Forty-seven patients were included in the study, 33being evaluable for tumour response, 36 for response to PSA, 21 forclinical benefit and 45 for toxicity. Median actual weekly dose was 19mg/m² (range 12.0–26.2 mg/m²). Six ofthirty-six patients (17%) demonstrated a biologic response with a50% or more decline in serum PSA on two consecutivemeasurements taken at least two weeks apart. The median durationof biologic response was 2.7 months. Two of three patientswith measurable disease obtained an objective response but remainedunconfirmed. No change disease was reported in 23 patients (49%).On entry into the study, 30 patients had symptomatic bone pain andrequired narcotic or non-narcotic analgesics. Clinical benefit fromvinorelbine was achieved in 15 patients out of 21 (32% of theintent to treat analysis population and 71% of the assessablepatients). Due to the low number of questionnaires (QLQ-C30) filled in,it was insufficient to allow any statistical analysis. The mediansurvival was 10.2 months. Toxicity was mainly haematologic with51% of patients experiencing grade 3 or 4 granulocytopenia. Threepatients developed deep vein thrombosis. Non-haematologic toxicity,mainly nausea and neurotoxicity, was mild. Conclusion:The administration of weekly vinorelbine appearsto be a safe treatment for those patients with androgen-independentprostate cancer and poor prognosis features who require chemotherapy.These results provide data for future investigation of vinorelbine incombination regimens.     

What’s new in the field of prostate cancer chemoprevention?

Chemoprevention trials for several malignancies are completed, planned, or underway. Prostate cancer is one of the most common forms of cancer and understandably has received considerable recent attention as a potential target for chemoprevention. This article examines chemoprevention trials for prostate cancer, including the Prostate Cancer Prevention Trial, Selenium and Vitamin E Cancer Prevention Trial, and cyclooxygenase inhibitors in the prevention of prostate cancer.     

Novel cytotoxic and biological agents for prostate cancer: Where will the money be in 2005?

In 2004, docetaxel-based chemotherapy became the first treatment capable of extending life in androgen-independent prostate cancer. The era of therapeutic nihilism in this disease has thus been put to rest and a broad range of agents is being tested with the goal of improving on the successes of 2004. Lessons learned from other tumour types will need to be applied to prostate cancer in order to harness the bounty of available ideas. Target amplification or activating mutations and not merely the presence of a target are likely to be important to the success of targeted agents. Thus, the promise of the current crop of targeted agents is most likely to be realised when pursued in the context of well-credentialed targets and tested in highly translational clinical trials that are capable not only of assessing tumour response, but also of evaluating the status of the targeted pathway. The most promising agents in clinical development are reviewed.     

XMRV: a new virus in prostate cancer?

Several recent articles have reported the presence of a gammaretrovirus, termed "XMRV" (xenotropic murine leukemia virus-related virus) in prostate cancers (PCa). If confirmed, this could have enormous implications for the detection, prevention, and treatment of PCa. However, other articles report failure to detect XMRV in PCa. We tested nearly 800 PCa samples, using a combination of real-time PCR and immunohistochemistry (IHC). The PCR reactions were simultaneously monitored for amplification of a single-copy human gene, to confirm the quality of the sample DNA and its suitability for PCR. Controls showed that the PCR assay could detect the XMRV in a single infected cell, even in the presence of a 10,000-fold excess of uninfected human cells. The IHC used 2 rabbit polyclonal antisera, each prepared against a purified murine leukemia virus (MLV) protein. Both antisera always stained XMRV-infected or -transfected cells, but never stained control cells. No evidence for XMRV in PCa was obtained in these experiments. We discuss possible explanations for the discrepancies in the results from different laboratories. It is possible that XMRV is not actually circulating in the human population; even if it is, the data do not seem to support a causal role for this virus in PCa.     

Changing presentation of prostate cancer in a UK population – 10 year trends in prostate cancer risk profiles in the East of England

Background:

Prostate cancer incidence is rising in the United Kingdom but there is little data on whether the disease profile is changing. To address this, we interrogated a regional cancer registry for temporal changes in presenting disease characteristics.

Methods:

Prostate cancers diagnosed from 2000 to 2010 in the Anglian Cancer Network (n=21 044) were analysed. Risk groups (localised disease) were assigned based on NICE criteria. Age standardised incidence rates (IRs) were compared between 2000–2005 and 2006–2010 and plotted for yearly trends.

Results:

Over the decade, overall IR increased significantly (P<0.00001), whereas metastasis rates fell (P<0.0007). For localised disease, IR across all risk groups also increased but at different rates (P<0.00001). The most striking change was a three-fold increase in intermediate-risk cancers. Increased IR was evident across all PSA and stage ranges but with no upward PSA or stage shift. In contrast, IR of histological diagnosis of low-grade cancers fell over the decade, whereas intermediate and high-grade diagnosis increased significantly (P<0.00001).

Conclusion:

This study suggests evidence of a significant upward migration in intermediate and high-grade histological diagnosis over the decade. This is most likely to be due to a change in histological reporting of diagnostic prostate biopsies. On the basis of this data, increasing proportions of newly diagnosed cancers will be considered eligible for radical treatment, which will have an impact on health resource planning and provision.     

Can chemotherapy alter the course of prostate cancer?

Prostate cancer is perceived to be a disease of older men often diagnosed with widespread metastases that respond to hormonal ablation but for which there are few additional treatment options. Fortunately this perception is rapidly changing as newer combination chemotherapy trials demonstrate improved prostate-specific antigen and measurable response rates and enhanced quality of life. Still, treatment of prostate cancer lags behind treatment of other malignancies. Work remains in understanding the natural history of disease, refining our grouping of patients by stage into clinical trials, and adhering to new response criteria recently developed. Applying the newer active chemotherapy regimens to patients with earlier stage disease should lead to improvements in overall survival.     

Should docetaxel be administered earlier in prostate cancer therapy?

Three randomized studies examining docetaxel early in metastatic prostate cancer were recently reported. The CHAARTED and STAMPEDE studies showed a survival benefit for docetaxel when started with androgen suppression therapy in men with newly diagnosed metastatic prostate cancer. The STAMPEDE study also included men with biochemically relapsed prostate cancer. The benefit was a median of 13.6 months in the CHAARTED study and 10 months in STAMPEDE. The survival benefit in CHAARTED was stronger in those with high volume disease. The benefit in STAMPEDE was greater in metastatic, rather than biochemically relapsed, prostate cancer. The third study, GETUG-AFU 15, was a smaller study without a survival benefit. These data have changed how we treat metastatic prostate cancer at our centers, as we now offer all men with metastatic castration sensitive prostate cancer docetaxel chemotherapy upfront.     

Is there a role for chemotherapy in prostate cancer?

There is evidence from randomised-controlled trials that patients with symptomatic hormone-refractory prostate cancer may experience palliative benefit from chemotherapy with mitoxantrone and prednisone. This treatment is well tolerated, even by elderly patients, although the cumulative dose of mitoxantrone is limited by cardiotoxicity. Treatment with docetaxel or paclitaxel, with or without estramustine, appears to convey higher rates of prostate-specific antigen response in phase II trials, but is more toxic. Large phase III trials comparing docetaxel with mitoxantrone have completed accrual. There is no role for chemotherapy in earlier stages of disease except in the context of a well-designed clinical trial.