Ian F. Tannock, MD,PhD, Princess Margaret Hospital,Toronto, Canada
With comments by Daniel Petrylak, MD, Columbia University Medical Center, New York, NY
The 2007 ESMO conference Lugano (ECLU) was designed to provide an educational overview of recent advances in the systemic therapy for common types of cancer, with the opportunity for attendees to submit abstracts describing original research. For prostate cancer, there was a 40-minute plenary review followed by 10 minutes of questions from a young oncologist, Dr. Rachel Whelan, Swansea, U.K., and then 10 minutes of questions from attendees (the format was similar for other disease sites). The present paper summarizes the review of recent advances and controversies related to prostate cancer, the discussion around the plenary review, and the two abstracts that described clinical research related to prostate cancer.
Hormonal Therapy for Prostate Cancer
Important questions relating to androgen deprivation therapy (ADT) for prostate cancer include the following:
- Is there a role for maximum androgen blockade (MAB)?
- Is optimal therapy continuous or intermittent?
- What is the role of second and third-line hormonal therapies?
- What are the toxic side-effects of hormonal therapy?
- Is there a role for ADT as adjuvant to surgery or radiotherapy?
- Is there a role for ADT in the patient with rising PSA after local therapy?
Maximum Androgen Blockade
The hypothesis that combined use of a peripheral anti-androgen such as flutamide or bicalutamide with either orchiectomy or a luteinizing hormone releasing hormone (LHRH) agonist would result in a higher rate and/or longer duration of response was reasonable. However, a patient-based meta-analysis that included more than 8,000 patients in 27 trials was published in 2000, and showed no significant survival benefit for this approach,(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn1 "_ednref1") and a large trial published since that overview also showed no survival benefit and poorer quality of life with MAB.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn2 "_ednref2"),(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn3 "_ednref3") According to these results, this treatment approach has been shown not to improve outcome and is expensive; therefore, it does not appear to be the most appropriate therapeutic choice.
Continuous Versus Intermittent Therapy
The hypothesis that intermittent use of ADT might delay emergence of hormone-refractory disease as compared to continuous ADT was supported by experiments in rodent models published by researchers in Vancouver.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn4 "_ednref4") This hypothesis has now been addressed in several clinical trials: a small trial that included 68 patients has been published,(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn5 "_ednref5") and three larger trials have been presented at meetings of the American Society of Clinical Oncology (ASCO)(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn6 "_ednref6"),(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn7 "_ednref7") and the American Urological Association (AUA).(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn8 "_ednref8") The trials used different agents and slightly different criteria (based on serum levels of PSA) for stopping and restarting treatment. However, each of them indicates that progression-free survival and overall survival are at least equivalent when intermittent therapy is used as compared to continuous therapy (Table 1). Given that intermittent therapy is cheaper, and lowers exposure to potentially toxic agents (see below) it should be regarded as appropriate standard management of patients requiring ADT.
Table 1: Summary of randomized controlled trials of intermittent versus continuous androgen blockade
Three of the four trials summarized in Table 1 used MAB, and given that this has no advantages over use of orchiectomy or an LHRH agonist alone for continuous treatment, a reasonable question posed by Dr. Whelan is whether intermittent therapy using an LHRH agonist alone is appropriate treatment. The trial conducted by Tunn, et al. supports this approach, and it seems reasonable to use an LHRH agonist intermittently, with a peripheral anti-androgen given only for a short time to prevent disease flare when initiating the treatment in a patient at risk of symptoms such as spinal cord compression.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn8 "_ednref8")
Second and Third-line Hormonal Therapies
About 90% of men respond to initial therapy with orchiectomy or an LHRH agonist with improvement in symptoms, if present initially, and reduction in serum PSA level. At progression, approximately one-third will respond to the addition of a peripheral anti-androgen (e.g. bicalutamide). Of those who respond and then progress on this treatment, about 20% respond to withdrawal of the peripheral anti-androgen. Some men, particularly those with good responses to first-line ADT and with slowly-progressive disease, may respond to further hormonal treatments such as dexamethasone, estrogen, or ketoconazole (a non-specific inhibitor of steroid synthesis) with hydrocortisone. In one trial, 260 men were randomized to receive anti-androgen withdrawal alone or anti-androgen withdrawal plus ketoconazole and hydrocortisone. There was a higher PSA response with the addition of ketoconazole (27% versus 11%) and delay in time to progression, but no difference in overall survival.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn9 "_ednref9")
In general, primary hormonal therapy is continued, despite disease progression, when patients are treated with chemotherapy, and this is required in most clinical trials of chemotherapy. However, one small study suggested that if ADT is stopped during chemotherapy, there might be a high rate of further response to ADT after chemotherapy.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn10 "_ednref10") This hypothesis deserves to be tested formally in a larger trial.
Two original presentations at the ESMO meeting are relevant to the question of third-line hormonal therapy.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn11 "_ednref11"),(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn12 "_ednref12") These presentations evaluated the PSA response rates in Phase II trials of the experimental drug abiraterone, which provides selective blockade of androgen steroid synthesis. This agent was reported to lead to a high rate of PSA response in men who had progressed after two or more lines of ADT, and in men who progressed after chemotherapy. A large Phase III trial is planned to define the role of this interesting agent.
Toxic Side-effects of Hormonal Therapy
Side effects of ADT include impotence, gynecomastia (sometimes with tenderness), hot flashes (“male menopause”), loss of muscle and bone, anemia, and increased risk of cardiovascular events. Some studies have suggested that ADT may also lead to decline in cognitive function but these results are inconsistent.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn13 "_ednref13"),(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn14 "_ednref14") Several randomized trials have demonstrated that administration of a bisphosphonate, such as pamidronate or zoledronate, can prevent loss of bone in men receiving ADT, and a recent trial demonstrated that an annual injection of zoledronate is sufficient.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn15 "_ednref15") This treatment is probably not necessary if men can exercise, but it is reasonable to check bone density at intervals after initiating ADT, and to give annual zoledronate if bone loss is detected.
Recent evidence has shown that long-term ADT may increase the risk of diabetes, myocardial infarction (MI), congestive heart disease (CHF) and sudden death (Table 2).(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn16 "_ednref16") These potential serious side effects should be discussed with men who are initiating such treatment, particularly those with pre-existing risk factors for cardiac disease and diabetes.
Table 2: Cardiovascular effects of hormonal therapy in >73,000 men age >65 treated for localized prostate cancer between 1992 and 1999, and observed through 2001 (>1 in 3 received ADT). Data of Keating, et al.16
Events per 1000 person-years
ADT as Adjuvant to Surgery or Radiotherapy
A previous randomized study of the European Organization for Research and Treatment of Cancer (EORTC) indicated that radiotherapy with concomitant and three years of adjuvant ADT improves progression-free and overall survival for men with locally-advanced prostate cancer compared to radiotherapy alone.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn17 "_ednref17")7 Other studies performed by the Radiation Therapy Oncology Group (RTOG) have shown that long-term adjuvant ADT after radiotherapy improves progression-free and overall survival(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn18 "_ednref18")8and that neoadjuvant and concurrent short course ADT improves progression-free survival with a trend to improved survival.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn19 "_ednref19")9 There has been no benefit of neoadjuvant ADT pre-surgery, while a small randomized trial suggests benefit of adjuvant ADT for high-risk patients.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn20 "_ednref20")0 With this background, a recent EORTC trial compared concomitant ADT and radiotherapy with either six months or three years of adjuvant therapy for men with locally advanced prostate cancer.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn21 "_ednref21")1 The hypothesis, particularly important in view of increasing evidence for toxicity of ADT, was that six months of adjuvant ADT would not be inferior to three years of such treatment. However, this hypothesis was not supported by the study, and there was better survival following three years of adjuvant ADT, which should remain standard.
ADT in the Patient with Rising PSA after Local Therapy
Many men who undergo radical local treatment by prostatectomy or radiation therapy will show biochemical recurrence as defined by a rise in serum PSA. This causes great anxiety in otherwise asymptomatic men, and many of them are started on ADT. However, except for the minority of men with a high Gleason score (8-10) and or a short PSA doubling time (<3 months), the median time between the first rise in PSA and symptoms due to disease is many years, and the median survival after PSA recurrence is very long – in one large study it was in excess of 16 years.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn22 "_ednref22")2,(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn23 "_ednref23") Given the toxicity of ADT and the long natural history of the disease in most patients, ADT should be used sparingly in this situation. Measuring serum PSA in men with no symptoms after local treatment can cause unnecessary anxiety and toxic therapy and may therefore be unnecessary; however, this practice will most likely continue.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn24 "_ednref24")4
Chemotherapy for Prostate Cancer
Men with metastatic prostate cancer will eventually develop hormone-refractory prostate cancer (HRPC) unless they die from other reasons prior to this occurrence. There is increasing evidence for benefit from chemotherapy in such men, especially in those with diffuse symptoms. However, before using chemotherapy, the caring physician should optimize pain control (if pain is present) with regular dosing of narcotic medication, such as morphine, and give regular laxatives to control the constipation that will be caused by narcotics. Radiotherapy should be considered for dominant sites of pain, especially if localized to a single site. Chemotherapy or bone-seeking radioisotopes (strontium or samarium) should then be considered, especially for those with either symptomatic disease or with a rapid rate of PSA progression, such that symptoms are likely to soon occur in the absence of treatment. Important questions relating to chemotherapy include the following:
- Is the survival benefit due to docetaxel-based chemotherapy compared to mitoxantrone sustained with longer follow-up?
- Should chemotherapy be used in minimally symptomatic patients?
- Docetaxel and prednisone is established as preferred first-line chemotherapy: can additional agents improve outcome?
- Which agents should be used for men well enough to receive second-line chemotherapy?
- Should bisphosphonates be used with chemotherapy in men with bone metastases?
Updated Survival in the TAX-327 Study
The TAX-327 study was a large randomized trial that compared treatment with three-weekly docetaxel (75mg/m2), weekly docetaxel (30mg/m2 five weeks out of six) with three-weekly mitoxantrone (12mg/m2), each with prednisone or prednisolone. When 557 of 1,006 patients had died, the primary report indicated that there was a significant difference in survival in favor of three-weekly (but not weekly) docetaxel in comparison with mitoxantrone.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn25 "_ednref25")5 The companion Southwest Oncology Group (SWOG) 99-16 study also showed better survival with three-weekly docetaxel and estramustine as compared to mitoxantrone and prednisone, although an indirect comparison of the studies suggests that estramustine appeared to add only toxicity.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn26 "_ednref26")6 Treatment with docetaxel also led to a higher rate of PSA and pain response, and in TAX-327 to a higher rate of improvement in quality of life (QoL).
The survival of patients in the TAX-327 study has recently been updated, with 867 of the patients now deceased: the median survival is 19.2 months for the three-weekly docetaxel arm, 17.8 months for the weekly docetaxel arm and 16.3 months for the mitoxantrone arm.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn27 "_ednref27")7 Exploratory subgroup analysis also demonstrated consistent differences in survival for older and younger men, for those with and without pain, and for those with higher and lower values of serum PSA. There are more three year survivors among those who were randomized to receive docetaxel.
Chemotherapy in Minimally Symptomatic Patients
Berthold, et al. have analyzed the outcome in the TAX-327 study of patients who were minimally symptomatic at the time they were randomized in the study (because of rising levels of serum PSA). The investigators reported that even patients with minimal pain often had impaired QoL as determined by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) scale, and that there was a higher probability of improvement in QoL in patients who received docetaxel than those who received mitoxantrone.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn28 "_ednref28")8 For patients with minimal symptoms, there was a higher chance of deterioration of QoL in patients who received weekly docetaxel compared to the other arms, and this arm cannot be recommended, except perhaps for men with impaired bone marrow function. This deterioration of QoL is presumably due to toxicity of treatment and/or progression of disease despite treatment. While these results might be taken to support use of docetaxel in minimally symptomatic patients with rising PSA, there is no evidence for a greater effect to improve survival from early treatment in minimally symptomatic men, as compared to waiting until symptoms occur.
Additional Agents Used with Docetaxel
Several large randomized trials are evaluating whether the addition of a targeted agent to docetaxel and prednisone can improve survival for men with HRPC. Agents under study include inhibitors of angiogenesis (bevacizumab and VEGF-Trap), bone-targeted agents such as atrasentan, high dose calcitriol, and immunotherapy. High priority should be given to recruitment into these trials of hormone-refractory prostate cancer patients whose results are expected in the next 2-3 years. In the meantime, treatment with docetaxel and prednisone remains the preferred option for most men outside of a study.
With the increasing use of earlier chemotherapy, many men with HRPC have subsequent disease progression and are well enough to receive second-line therapy. For patients who respond to docetaxel and then have progression after a reasonable interval without chemotherapy, and do not have cumulative side-effects such as neurotoxicity, it is appropriate to reintroduce docetaxel. Because mitoxantrone was the first chemotherapy drug approved for men with HRPC, it is often used after progression on docetaxel. Several small series have evaluated PSA response rate for men with HRPC treated with mitoxantrone after docetaxel and vice versa, and researchers have obtained information about PSA response in those patients in the TAX 327 study who crossed over from one drug to the other.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn29 "_ednref29")9,(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn30 "_ednref30"),(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn31 "_ednref31"),(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn32 "_ednref32"),(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn33 "_ednref33"),(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn34 "_ednref34") These data are summarized in Table 3, and indicate PSA response rates in the range of 6-20% for mitoxantrone used after docetaxel. In contrast, docetaxel retains a high rate of response after initial mitoxantrone, suggesting that using this less toxic agent first in men with slowly progressive HRPC remains a reasonable option.
Table 3: PSA response on crossover from mitoxantrone to docetaxel and vice versa, reviewed by Berthold and Tannock
Recently, the first results of a large randomized trial of second-line satraplatin (an oral platinum analog) with prednisone versus prednisone alone were reported.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn35 "_ednref35")5 Primary endpoints of the study were progression-free (PFS) and overall survival and the study found a highly significant improvement in PFS, with also higher rates of pain response, time to progression of pain, and PSA response. Satraplatin was reasonably well tolerated when given with an antiemetic agent. All patients had received prior chemotherapy, but only about 50% had received docetaxel. The trial might be criticized for its comparator arm, since the standard second-line treatment used in oncology practice is not prednisone alone, but either mitoxantrone, third-line hormonal therapy or other chemotherapy, although none of these are formally approved as second-line treatments. Satraplatin will likely be approved as second-line therapy for men with HRPC based on this trial.
On the Horizon: Immunotherapy and HRPC
Early results have also been encouraging utilizing the combination of GVAX and ipilimumab.[](http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn36 "_ednref36") GVAX is an immunotherapeutic agent comprising whole tumor cells that include the two genetically modified, non patient-specific prostate cancer cell lines LNCap and PC-3. These cell lines contain many common antigens found in metastatic prostate cancer. The cells have been modified to secrete granulocyte macrophage colony stimulating factor (GM-CSF) to stimulate a systemic immune response to the antigens used in the cell lines. Ipilimumab is a fully human antibody that is targeted against the CTLA-4. CTLA-4 is a molecule present on T-cells that is thought to play a role in suppressing the body’s immune response.
This trial included 12 patients with HRPC and six of these patients were treated at the doses that proved to provide optimal results (3 and 5 mg) and are being used in the Phase III trials evaluating each agent separately. Of the six patients receiving optimal doses of therapy, five patients achieved at least a 50% reduction in prostate specific antigen (PSA) levels that lasted at least two months; two of these patients had a 95% reduction in PSA levels. Two responses are still ongoing with a median 18 month follow-up. Importantly, three of the five PSA responders demonstrated antitumor activity through improvement of multiple bone lesions as determined by bone scan, improvement of pain cause by bone metastases, and resolution of abdominal lymph node disease as determined by computed tomography (CT) scan. One patient had complete resolution of disease by CT scan. Sixty-six percent of the remaining patients who received GVAX plus lower doses of ipilimumab achieved disease stabilization as determined through PSA levels for at least two months. The main new finding in this study was that 5 of the 6 patients at the higher dose developed adrenal insufficiency and/or hypothyroidism requiring treatment. Other side effects occurring in more than 50% included fever, fatigue and anorexia.
The researchers concluded that the treatment combination including GVAX and ipilimumab appears promising in the treatment of HRPC. Future larger trials evaluating this combination and comparing it to other treatment options will help determine its true clinical utility for men with HRPC.
Use of Bisphosphonates with Chemotherapy in Men with Bone Metastases
A large trial compared three-weekly zoledronate with placebo for men receiving chemotherapy for HRPC.(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn37 "_ednref37"),(http://news.cancerconnect.com/highlights-in-prostate-cancer-the-esmo-lugano-conference-2007/#_edn38 "_ednref38") Initially, zoledronate was administered in intravenous doses of 8mg and 4mg; the 8mg dose caused renal toxicity and was subsequently modified to 4mg. Although the 8/4mg arm did not appear to result in significantly reduced bone events, the 4mg arm did show a significant reduction in bone events compared to placebo and this drug is now widely used with chemotherapy. This does not seem to be cost-effective therapy as many of the bone events prevented were not symptomatic, there was no significant improvement in pain control, and there were trends to more toxicity in the zoledronate arms. In addition, given that a yearly injection of zoledronate is sufficient to prevent bone loss in men without bone metastases receiving ADT, it seems unlikely that the drug needs to be given at three-weekly intervals.15 Time-dependent suppression of bone turnover should be studied in patients with bone metastases due to prostate cancer and dosing intervals for this expensive drug should be based on such data. In the meantime, use of zoledronate at three-monthly intervals in selected patients seems reasonable.
Ongoing trials will continue to answer the questions regarding optimal hormonal therapy for early stage prostate cancer. In addition, optimal strategies for the management of HRPC may become clearer as mature data is available from trials evaluating chemotherapy, targeted agents and immunotherapy in the advanced setting.
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