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Journal of Clinical Oncology, Vol 26, No 24 (August 20), 2008: pp. 4049-4050 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.18.3319
Perspective on "Chemotherapy for Advanced Prostate Cancer: 25 Years Later": Is It a Mirage or an Oasis?Melbourne Oncology Group, Cabrini Health, and Monash University, Melbourne, Australia
Melbourne Oncology Group, Cabrini Health; and Monash Medical Centre, Clayton, Australia To the Editor: Logothetis and Millikan1 provide an insightful and balanced editorial review of 25 years’ progress, the current state of play, and possible future treatment strategies for advanced prostate cancer. They correctly state that randomized trials with docetaxel (D) -based therapy have established it as a useful palliative tool that modestly alters the natural history of castrate-resistant prostate cancer. However, they do not discuss that the key part of this statement may well be the use of the term D-based therapy rather than simply D or chemotherapy. They go on to discuss the key conundrum and paradox that remains the elephant in the room with regard to chemotherapy for advanced hormone-refractory prostate cancer (HRPC). This paradox is that the apparent benefit of this treatment in advanced disease has not translated into a similar benefit in earlier disease settings, which has previously been "the hallmark of successful therapy development in solid tumors."1 What other possible explanations are there for this "notion that early prostate cancer is refractory to the cytotoxic paradigm?" The answer is quite possibly that the high-dose pulses of dexamethasone given with each course of chemotherapy rather than the D were responsible for much of the survival and quality-of-life (QoL) benefit in the two pivotal studies, TAX327 and Southwest Oncology Group Intergroup 99-16.2,3 D, like mitozantrone (M), was combined with prednisone (P) in the pivotal TAX327 study but, more importantly, the patients receiving D in both studies were also treated with large doses of dexamethasone, which the patients receiving M did not receive, for each of the 10 courses. First, corticosteroids are active drugs in metastatic androgen-independent prostate cancer (AIPC) with major prostate-specific antigen (PSA) response rates of 16% to 24%.4-8 This is why P was included as one of the two treatment drugs in both arms of the study. However, the patients who received the D once every 3 weeks (3-weekly) also received a total of 24 mg of dexamethasone as a premedication for each of the 10 treatments, giving a total of 240 mg. Given that dexamethasone is a longer-acting corticosteroid than P and has eight to 10 times the glucocorticoid potency,9 patients who received D received at least twice the bioequivalent dose of corticosteroid (ie, the patients who received D and P received the equivalent of more than 4,000 mg of P for the 30 weeks of treatment, compared with 2,100 mg for the patients receiving M and P). This difference, along with extra and large pulse doses of corticosteroids, may account for the small difference in overall survival of a little more than 2 months for patients receiving 3-weekly D and P compared with patients in the M and P group. Against this contention is that one small study of 12 patients with AIPC treated with 20 mg of dexamethasone every 6 hours for three doses, repeated every 3 weeks, did not show any responses to a median of only one course of this treatment.10 However, the short time allowed for patients to respond to the single-agent dexamethasone in this study may not have been sufficient, as demonstrated by a larger study of 27 patients with AIPC who were treated with a daily dexamethasone dose of 1.5 mg, decreasing to 1 mg daily during the first 3 months of treatment.11 Sixteen of these 27 patients achieved PSA reductions of at least 50%, and 11 of these 16 patients experienced a reduction of at least 80%. Importantly, the median time to PSA nadir was 14 weeks (range, 2 to 76 weeks) and median response duration was 5.4 months. The median survival of the 16 patients with a PSA decline of at least 50% was 15.9 months, compared with 7.7 months for the 11 patients with a PSA decline of less than 50%. The significance of these results when applied to the design of the TAX327 study are magnified by the study of Sartor et al,12 which showed that PSA response rates (greater than 50% decline) are elevated in patients treated with higher doses of glucocorticoids. An analysis of a number of retrospective trials by Morioka et al11 also revealed that PSA response was much higher in patients treated with dexamethasone (57% to 61%) than those treated with low-dose P (16% to 24%). Second, it is well established that corticosteroids can significantly improve QoL in patients with advanced cancer, particularly over the short term of less than 2 weeks. Not only do they reduce the mean intensity of pain, they can reduce fatigue; improve appetite, daily activity, and sense of well-being; and reduce depression and analgesic consumption.4,13-19 Della Cuna et al20 ran a randomized controlled trial that examined QoL with use of methylprednisolone in preterminal cancer patients using three validated scales. They treated patients with 125 mg daily, which is similar in dose equivalence to what the patients receiving D and P received in the 24 hours before their chemotherapy when the QoL assessments were performed. They found that the patient's QoL and sense of well-being were significantly improved compared with placebo from baseline on all three scales. Willcox et al21 compared prednisolone 10 mg per day with placebo and found significantly improved appetite and well-being in a group of patients, most of whom were also receiving chemotherapy. Many of the measures in these studies were being assessed in the QoL data of TAX 327, as assessed by the Functional Assessment of Cancer Therapy–Prostate instrument that the authors used, and which led them to claim improved QoL for 3-weekly D and P. A recent and detailed review by Shih and Jackson22 concluded that corticosteroids are one of the most frequently prescribed medications in the palliative care setting because they can simultaneously treat a constellation of symptoms—a view shared by a recent German study by Nauck et al.23 Given that the patients receiving D and P in the TAX327 study received 240 mg of dexamethasone that the M and P patients did not, then that huge discrepancy quite possibly accounts for the apparent QoL improvement. Third, the timing of the QoL assessments in relation to each of the patient's chemotherapy treatment courses is critically important to their validity for the 30-week period that the patient was receiving chemotherapy. The Functional Assessment of Cancer Therapy–Prostate instrument is a self-report instrument that tests specifically for patient functioning at the point of application only.24 These 3-weekly QoL assessments were performed just before the patients received their chemotherapy, so the 3-weekly patients receiving D and P would have received 16 to 24 mg of dexamethasone in the previous 24 hours, compared with none for the patients receiving M and P. This large premedication dose would have had a substantial effect on the patients’ perceived QoL and performance status because of its ability to reduce nausea, vomiting, fatigue, anorexia and pain; increase the sense of well-being; and would likely account for any apparent QoL improvement in the patients receiving 3-weekly D. This timing of the QoL measure's application just before the administration of chemotherapy would also give a different perceived QoL measure to one performed in the period soon after each chemotherapy treatment, when the acute adverse effects of chemotherapy would be more significant. Fourth, toxicity was much higher in the patients receiving 3-weekly D than in the patients receiving M and P, patients with increased diarrhea (32% v 10%), sensory neuropathy (30% v 7%), stomatitis (20% v 8%), change of taste (18% v 2%), dyspnea (25% v 9%), tearing (10% v 1%), and peripheral edema (19% v 1%). These are substantial differences in significant toxicities for elderly patients and are not consistent with a treatment that improves QoL. In fact, if it were not for the dexamethasone as described above and the timing of the QoL questionaires, the observed toxicities could have been far worse for the patients receiving D and P, and the QoL measures could possibly have shown the opposite results. Fifth, the improved duration and proportion of PSA responses (assessed as either > 30% or > 50% reduction) in the weekly D and P arm of the TAX327 study, which used an identical total dose and dose-intensity to the 3-weekly D and P arm, did not translate into a survival benefit, as the subsequent analysis of PSA decline showed that it should. This study showed that a 30% decline in PSA in 3 months had a high degree of surrogacy for overall survival.25 This suggests that the overall survival results from one of the two D groups is misleading. If so, which one? Three-weekly D is a toxic treatment, and not all clinicians are convinced that it should be used for the many patients with HRPC who have asymptomatic disease.26 Like Clifton Leaf,27 we are all motivated to win the war on cancer. The degree of progress in the chemotherapy treatment of advanced HRPC in the last 25 years has been admirable. However, our desperation to win this war must not lull us into thinking that mirages are oases. There are design flaws in the two pivotal studies of D in HRPC that may have contributed to misleading results that unrealistically raised our expectations for the application of neoadjuvant chemotherapy in early-stage prostate cancer. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Logothetis CJ, Millikan R: Chemotherapy for advanced prostate cancer: 25 years later. J Clin Oncol 26:2423-2424, 2008 2. Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitozantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004 3. Petrylak DP, Tangen CM, Hussain MHA, et al: Docetaxel and estramustine compared with mitozantrone and prednisolone for advanced refractory prostate cancer. N Engl J Med 351:1513-1520, 2004 4. Tannock IF, Osaba D, Stockler M, et al: Chemotherapy with mitozantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: A Canadian randomised trial with palliative end points. J Clin Oncol 14:1756-1764, 1996 5. Small EJ, Meyer M, Marshall ME, et al: Suramin therapy for patients with symptomatic hormone-refractory prostate cancer: Results of a randomised phase III trial comparing suramin plus hydrocortisone to placebo plus hydrocortisone. J Clin Oncol 18:1440-1450, 2000 6. Fosså SD, Slee PHTH, Brausi M, et al: Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: A phase III study of the European Organisation for Research and Treatment of Cancer Genitourinary Group. J Clin Oncol 19:62-71, 2001 7. Kantoff PW, Halabi S, Conaway M, et al: Hydrocortisone with or without mitozantrone in men with hormone-refractory prostate cancer: Results of the Cancer and Leukemia Group B 9182 Study. J Clin Oncol 17:2506-2513, 1999 8. Berry W, Dakhil S, Modiano M, et al: Phase III study of mitozantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol 168:2439-2443, 2002[CrossRef][Medline] 9. Langford CA, Gilliland BC: Relapsing polychondritis, in Fauci AS, Braunwald E, Kasper DL, et al (eds): Harrison's Principles of Internal Medicine (ed 16). Philadelphia, PA, McGraw-Hill, 2005, pp 2147 10. Weitzman AL, Shelton G, Zuech N, et al: Dexamethasone does not significantly contribute to the response rate of docetaxel and estramustine in androgen independent prostate cancer. J Urol 163:834-837, 2000[CrossRef][Medline] 11. Moriaka M, Kobayashi T, Furukawa Y, et al: Prostate-specific antigen levels and prognosis in patients with hormone-refractory prostate cancer treated with low-dose dexameyhasone. Urol Int 68:10-15, 2002[CrossRef][Medline] 12. Sartor O, Weinberger M, Moore A, et al: Effect of prednisone on prostate-specific antigen inpatients with hormone-refractory prostate cancer. Urology 52:252-256, 1998[CrossRef][Medline] 13. Bruera E, Roca E, Cedaro L, et al: Action of oral methylprednisolone in terminal cancer patients: A randomized double-blind study. Cancer Treat Rep 69:751-754, 1985[Medline] 14. Popiela T, Lucchi R, Giongo F: Methyl prednisolone as palliative therapy for female terminal cancer patients: The Methylprednisolone Female Preterminal Cancer Study Group. Eur J Cancer Clin Oncol 25:1823-1829, 1989[CrossRef][Medline] 15. Rousseau P: The palliative use of high-dose corticosteroids in three terminally ill patients with pain. Am J Hosp Palliat Care 18:343-346, 2001 16. Loprinzi Cl, Kugler JW, Sloan JA, et al: Randomised comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia. J Clin Oncol 17:3299-3306, 1999 17. Rao A, Cohen HJ: Symptom management in the elderly cancer patient: Fatigue, pain, and depression. J Natl Cancer Inst Monogr 32:150-157, 2004 18. Fleishman SB: Treatment of symptom clusters: pain, depression, and fatigue. J Natl Cancer Inst Monogr 32:119-123, 2004 19. Radbruch L, Strasser F, Elsner F, et al: Fatigue in palliative care patients: An EAPC approach. Palliat Med 22:13-32, 2008 20. Della Cuna GR, Pellegrini A, Piazzi M: Effect of methylprednisolone sodium succinate on quality of life in preterminal cancer patients: A placebo-controlled, multi-centre study—The Methylprednisolone Preterminal Cancer Study Group. Eur J Cancer Clin Oncol 25:1817-1821, 1989[CrossRef][Medline] 21. Willcox JC, Corr J, Shaw K, et al: Prednisolone as an appetite stimulant in patients with cancer. Br Med J (Clin Res Ed) 288:27, 1984 22. Shih A, Jackson KC II: Role of corticosteroids in palliative care. J Pain Palliat Care Pharmacother 21:69-76, 2007[Medline] 23. Nauck F, Ostgathe C, Klaschik E, et al: Drugs in palliative care: Results from a representative survey in Germany. Palliat Med 18:100-107, 2004 24. Esper P, Mo F, Chodak G, et al: Measuring QoL in men with prostate cancer using the Functional Assessment of Cancer Therapy-Prostate instrument. Urology 50:920-928, 1997[CrossRef][Medline] 25. Armstrong AJ, Garrett-Mayer E, Yang YO, et al: Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer. J Clin Oncol 25:3965-3970, 2007 26. Nabhan C: Is chemotherapy the standard for asymptomatic androgen-independent prostate cancer? J Clin Oncol 26:2413-2414, 2008 27. Leaf C: The war on cancer: Why we're losing the war on cancer—And how to win it. Fortune Magazine 149:75-92, 2004
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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