Does cytotoxic chemotherapy give a survival benefit or any other benefits in terms of quality of life improvement, control of pain or other symptoms compared to patients not receiving chemotherapy or receiving different types of chemotherapy?

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Does cytotoxic chemotherapy give a survival benefit or any other benefits in terms of quality of life improvement, control of pain or other symptoms compared to patients not receiving chemotherapy or receiving different types of chemotherapy?

Metastatic prostate cancer refers to patients in whom the cancer has spread beyond the primary site. This chapter deals with adenocarcinoma only. Most commonly, metastatic disease involves bone and lymph nodes and less commonly, viscera such as the lungs and liver. Patients with metastatic prostate cancer may be considered as hormone naïve or castration-resistant.

Hormone-naïve metastatic prostate cancer

Hormone-naïve patients are treated with hormone deprivation therapies including gonadotrophin releasing hormone (GnRH) agonists, orchidectomy and anti-androgens. The response rate is high and the median duration of response is approximately 18–24 months,[1] with 20% of patients living five years or more.

Small, non-informative RCTs performed over the past 20 years using minimally active chemotherapy demonstrated no benefit from the use of cytotoxic agents in the hormone-naïve setting.[2] Continuing large phase III studies are currently examining the role of chemotherapy, which is active in the castrate-resistant setting, in combination with androgen deprivation therapy in the hormone-naïve setting.

Castration-resistant prostate cancer

Castration-resistant prostate cancer (CRPC) includes patients with evidence of disease progression despite castrate levels of testosterone. About 20% of these patients may initially respond to secondline hormone manipulations, but almost all ultimately progress. At least three clinical states exist:

  • patients with a rising PSA who are asymptomatic and have no objective radiologic evidence of metastatic disease
  • patients with a rising PSA who are asymptomatic but who do have objective radiologic evidence

of metastatic disease

  • patients with a rising PSA who have objective radiologic evidence of metastatic disease and

symptoms.

In general, the first group of patients (asymptomatic rising PSA) are not treated with chemotherapy but may be suitable candidates for clinical trials and/or second-line hormone manipulations. The second and third groups are candidates for the use of systemic chemotherapy as discussed below or as part of a trial.

Old studies examined a variety of chemotherapy agents in combination or as monotherapy. These studies were generally of poor quality, had limited patient numbers, used agents with low efficacy and were constrained by difficulties in evaluating efficacy in this patient population.

Modern chemotherapy for CRPC was established by the studies of Tannock et al and Kantoff et al.[3][4] Both studies examined the efficacy of mitoxantrone against a control arm of prednisolone orhydrocortisone respectively. Tannock et al documented that treatment with mitoxantrone resulted in a significant improvement in pain, quality of life and PSA response. There was no survival benefit although this was not a study endpoint. Kantoff et al reported similar outcomes.

Subsequently, two pivotal large multicentre phase III studies[5][6] have demonstrated a survival benefit while maintaining improvements in quality of life for patients receiving docetaxel-based chemotherapy for their CRPC. These two studies form the basis for the current standard of care in Australia, docetaxel chemotherapy for CRPC.

Tannock et al (TAX 327 study) enrolled 1006 patients who were randomly assigned to docetaxel 30mg/m2 weekly for five of every six weeks, docetaxel 75mg/m2 every three weeks or mitoxantrone 12mg/m2 every three weeks.[5] All patients received 5mg bd of prednisolone. GnRH was continued. The majority of patients were Karnofsky performance score >70 and nearly half were asymptomatic. Up to ten cycles were planned for mitoxantrone and the three-weekly docetaxel group where median cycles completed were 5 and 9.5 respectively. Median survival was superior in the three-weekly docetaxel arm compared with mitoxantrone arm (18.9 months and 16.5 months; p=0.009). Three weekly docetaxel also led to better pain control (35% versus 22%; p = 0.01), improvement in quality of life (22% improvement versus 13 % improvement; p=0.005) and PSA decline of >50% (48% vs 32% P <0.001). In contrast, weekly docetaxel when compared with mitoxantrone did not result in statistically significant improvements in survival or pain control.

Petrylak et al (SWOG) reported superior survival for a combination of docetaxel and estramustine compared with mitoxantrone among 770 men (17.5 months versus 15.6 months; p=0 .02).[6] All patients received 5mg bd of prednisone. Pain relief was similar between arms.

The major side effects of docetaxel were consistent with the known side-effects profile including: alopecia (65%), lethargy (53%), nail changes (30%), neutropenia (32%) diarrhoea (32%) and neuropathy (30%). The incidence of neutropenic sepsis was 3–5% and the incidence of treatmentrelated death was less than 1%.

The combination of docetaxel and estramustine is not relevant to Australia as estramustine is not available. Further, the relatively high risk of thrombo-embolism and other toxicities has resulted in estramustine being dropped from the combination.

A number of issues remain as to the optimal use of docetaxel in patients with CRPC:

  • how to manage men of poor performance status and/or those with organ dysfunction
  • the benefit and timing of docetaxel chemotherapy in asymptomatic men remains unresolved
  • the most efficacious sequencing of docetaxel and radioisotope therapy has not been addressed
  • numerous studies are examining the effect of adding agents to docetaxel in men with CRPC
  • the most effective form of second-line (post-docetaxel) systemic therapy requires exploration.
  • see <http://clinicaltrials.gov> for currently registered trials.

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Evidence summary and recommendations

Evidence summary Level References
Mitoxantrone and steroids offers better pain relief and quality of life than steroids alone. II [3], [4]
Docetaxel and prednisone is associated with better survival, pain relief and quality of life than mitoxantrone and prednisone. II [5]
Compared with mitoxantrone and prednisone, docetaxel and estramustine improves survival without any effect on quality of life or pain. II [6]
In comparison to mitoxantrone, docetaxel causes more grade 3 or 4 neutropenia, fatigue, alopecia, nail changes, diarrhoea, stomatitis, tearing, sensory neuropathy, dyspnoea, changes in taste and peripheral oedema. Mitoxantrone causes more impairment in left

ventricular function than docetaxel. Docetaxel and estramustine in combination cause more cardiovascular events, neutropenic fevers, neurologic and metabolic disturbances and nausea and vomiting than mitoxantrone and prednisone.

II [5], [7]
Evidence-based recommendationQuestion mark transparent.png Grade
Docetaxel in combination with prednisone is appropriate in the first line setting to improve survival, pain and quality of life in good performance patients with castrate-resistant metastatic prostate cancer.
B


Evidence-based recommendationQuestion mark transparent.png Grade
The combination of mitoxantrone and prednisolone also offers palliative benefit but no survival benefit compared to docetaxel.
C


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References

  1. Janknegt RA, Abbou CC, Bartoletti R, Bernstein-Hahn L, Bracken B, Brisset JM, et al. Orchiectomy and nilutamide or placebo as treatment of metastatic prostatic cancer in a multinational double-blind randomized trial. J Urol 1993 Jan;149(1):77-82; discussion 83 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7678043.
  2. Hedlund PO, Jacobsson H, Vaage S, Hahne B, Sandin T, Kontturi M, et al. Treatment of high-grade, high-stage prostate cancer with estramustine phosphate or diethylstilbestrol. A double-blind study. The SPCG-1 Study Group. Scandinavian Prostate Cancer Group. Scand J Urol Nephrol 1997 Apr;31(2):167-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9165581.
  3. 3.0 3.1 Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 1996 Jun;14(6):1756-64 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8656243.
  4. 4.0 4.1 Kantoff PW, Halabi S, Conaway M, Picus J, Kirshner J, Hars V, et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol 1999 Aug;17(8):2506-13 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10561316.
  5. 5.0 5.1 5.2 5.3 Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004 Oct 7;351(15):1502-12 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15470213.
  6. 6.0 6.1 6.2 Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004 Oct 7;351(15):1513-20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15470214.
  7. Taylor CD, Elson P, Trump DL. Importance of continued testicular suppression in hormone-refractory prostate cancer. J Clin Oncol 1993 Nov;11(11):2167-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8229130.

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Appendices