Hormone-Resistant Prostate Cancer: New Therapies Needed

We read with interest the article, "Hormone-Refractory Prostate Cancer: Choosing the Appropriate Treatment Option," by Drs. Ross and Kantoff in this issue of ONCOLOGY. Prostate cancer is gaining more public attention, and an increasing number of physicians are involved in its treatment. Thus, an extensive review of the management of hormone-refractory prostate caner is welcome.

Pathophysiology and Prognosis

The article is well structured, starting with the biologic basis for the development of metastatic hormone-resistant prostate cancer as well as its natural history. This natural history varies from individual to individual, which must be taken into account while caring for these patients. As the authors point out, patients with a rising prostate-specific antigen (PSA) level without evidence of bone metastases may develop clinical evidence of metastasis only after many years. It is therefore important to take into account the potential side effects of long-term hormonal manipulations, such as an increased risk of diabetes and cardiac disease, which have been documented in a recent publication.[1]

The so-called Halabi nomogram is a valuable prognostic tool in allowing one to prescribe treatment as early as necessary and as late as possible.[2] Prognostic factors such as performance status, Gleason's sum, lactate dehydrogenase (LDH), PSA, hemoglobin, and alkaline phosphatase, as well as the presence or absence of visceral metastases, are important.

Multiple Treatment Options

As pointed out by Drs. Ross and Kantoff, patients with hormone-refractory prostate cancer have several treatment options, including supportive care, secondary hormonal manipulations, chemotherapy, and clinical trials. The importance of best supportive care cannot be overemphasized: The management of these often frail and elderly patients is time-consuming and requires fine clinical skills. All patients requiring narcotic drugs need aggressive management of side effects, particularly nausea and constipation.[3] Careful introduction of these drugs is mandatory.

We appreciated the discussion about secondary hormonal treatments in the article. The addition of an antiandrogen, rotation between antiandrogens, antiandrogen withdrawal, prednisone or prednisone plus ketoconazole, as well as estrogens, all have potential roles in the treatment of the advanced stages of prostate cancer. As pointed out, none of these treatments has been shown to prolong survival, but there are long-term responders, and some of these men might show a survival benefit despite the lack of overall evidence for improvement in median survival in clinical trials.

The paper mentions a study of high-dose bicalutamide (Casodex) at 150 mg/d in combination with hormonal ablation.[4] However, this trial was rather small, and our group does not recommend the use of high-dose bicalutamide for treatment of advanced prostate cancer outside of a clinical trial, because of its potential side effects and high cost.

The authors indicate that an antiandrogen withdrawal phenomena may manifest after 4 to 6 weeks, depending on the half-life of the antiandrogen. While it is important to inform patients of this potential delay (because anxious patients recheck their PSA frequently), antiandrogen withdrawal is quite uncommon and does not appear to occur in the absence of response to adding the antiandrogen.

For patients requiring chemotherapy, we agree with the authors that docetaxel (Taxotere), 75 mg/m

²

every 3 weeks, in combination with low-dose prednisone is the current standard of care. However, we do not agree that there is evidence to support the use of estramustine (Emcyt) in providing palliative benefit. Estramustine has an estrogen moiety and an alkylating moiety. Older studies do not suggest that estramustine is superior to estrogen (although it is more toxic), and comparison of the results of the SWOG 9916 and TAX 327 trials suggests that the addition of estramustine to docetaxel increases toxic effects and does not improve clinical outcome.[5,6] This drug can no longer be recommended to prostate cancer patients.

Further Research Needed

There is a need for further prostate cancer research, particularly in the second-line setting after docetaxel. Roughly 25% of patients are able to undergo second-line chemotherapy, for which there is currently no standard of care. Mitoxantrone probably produces a PSA response rate ranging from 10% to 20% as a second-line therapy, and some patients may have palliative benefit from improved symptoms.[7] Recent data have suggested the efficacy of satraplatin to delay progression (as compared to prednisone alone) in the second-line setting. These data are encouraging but do not shed light on whether satraplatin is more effective than mitoxantrone.

In conclusion, patients diagnosed with hormone-resistant prostate cancer are heterogeneous, and several treatment options are available for this population. Further research is needed, as most of these men will have significant symptoms and most will die from their disease. Patients should be encouraged to participate in clinical trials and thereby accelerate the development of new avenues of therapy. The article by Drs. Ross and Kantoff gives an excellent overview of the current state of the field.

—Dominik R. Berthold, MD
—Ian F. Tannock, MD, PHD

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Keating NL, O'Malley AJ, Smith MR: Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 24:4448-4456, 2006.

2. Halabi S, Small EJ, Kantoff PW, et al: Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol 21:1232-1237, 2003.

3. Grossman SA, Dunbar EM, Nesbit SA: Cancer pain management in the 21st century. Oncology (Williston Park) 20:1333-1351 (incl discussion), 2006.

4. Joyce R, Fenton MA, Rode P, et al: High dose bicalutamide for androgen independent prostate cancer: Effect of prior hormonal therapy. J Urol 159:149-153, 1998.

5. Petrylak DP, Tangen CM, Hussain MH, et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513-1520, 2004.

6. Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004.

7. Oh WK, Manola J, Babcic V, et al: Response to second-line chemotherapy in patients with hormone refractory prostate cancer receiving two sequences of mitoxantrone and taxanes. Urology 67:1235-1240, 2006.