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National Collaborating Centre for Cancer (UK). Prostate Cancer: Diagnosis and Treatment. Cardiff (UK): National Collaborating Centre for Cancer (UK); 2008 Feb. (NICE Clinical Guidelines, No. 58.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Chapter 6 – Locally Advanced Prostate Cancer

6.1. In men with prostate cancer, does the addition of adjuvant therapy to radical therapy improve outcomes?

Short Summary

Evidence about neoadjuvant and adjuvant hormonal therapy comes from a systematic review (Kumar et al. 2006) of 21 randomised controlled trials. Evidence about adjuvant radiotherapy comes from two randomised trials (Bolla et al. 2005; Thompson, Jr. et al. 2006).

Neoadjuvant and adjuvant therapy with radical prostatectomy

Randomised trials report significant toxicity with adjuvant therapy in addition to prostatectomy (Kumar et al. 2006). With the exception of one small trial in node-positive men (Messing, 1999), these trials have not demonstrated significant benefit in overall survival. It is possible that modest survival benefits will emerge with longer follow-up.

Neoadjuvant and adjuvant therapy with radical radiotherapy

Several randomised trials (Kumar et al. 2006) have shown that adjuvant androgen deprivation improves overall survival in men receiving radical radiotherapy. Sub group analysis suggests that the survival benefit of adjuvant hormonal therapy is greatest in men with high grade disease. Most of the evidence relates to goserelin given for three years or more, but a single randomised trial (Tyrrell et al. 2005) suggests the survival benefit of adjuvant bicalutamide monotherapy is comparable.

PICO

POPULATIONINTERVENTIONCOMPARISONOUTCOME
Men who are to have radical therapy for prostate cancer Single modality radical treatment
  • Overall survival
  • Disease specific survival
  • Biochemical disease-free survival
  • time till salvage hormone intervention
  • disease recurrence (local, distant metastasis or biochemical i.e. PSA progression)
  • Pathological staging (which can be expressed in a number of ways either as organ confined rates, pathological over-staging or down-staging compared to clinical staging)
  • side effects
  • quality of life
  • cost

(The search strategy developed from this PICO table and used to search the literature for this question is in Appendix C)

Evidence Summary

Neoadjuvant hormonal therapy with prostatectomy

Evidence comes from ten randomised trials included in the Kumar and co-workers (Kumar et al. 2006) review. See table 6.1.1 for the summary of outcomes. Men treated with neoadjuvant hormonal therapy were significantly more likely to have organ confined disease, and less likely to have positive surgical margins or positive lymph nodes. There was no significant effect of neoadjuvant hormonal therapy on overall or disease free survival.

Table 6.1.1. Evidence profile for neoadjuvant hormonal therapy with radical prostatectomy.

Table 6.1.1

Evidence profile for neoadjuvant hormonal therapy with radical prostatectomy. Question: Should neo-adjuvant hormonal therapy and prostatectomy vs. prostatectomy alone be used for prostate cancer? Systematic review:Kumar, Shelley, Harrison, Coles, Wilt (more...)

Kumar and co-workers (Kumar et al. 2006) could not pool data about treatment toxicity in their review, for any of the treatment combinations. Data from individual studies suggests a significant increase in adverse events in patients receiving neo-adjuvant hormonal therapy, with hot flushes being the most common. Two trials (Prezioso et al. 2004; Soloway et al. 2002) reported a case of myocardial infarction in the hormone treatment group, one of which was fatal. One trial (Klotz et al. 2003) reported two cases of pulmonary embolism, one in the standard care group and a fatal case in the hormonal therapy group.

Adjuvant hormonal therapy with prostatectomy

Evidence comes from three randomised trials included in the Kumar and co-workers (Kumar et al. 2006) review. See table 6.1.2 for summary of outcomes. Men treated with adjuvant hormonal therapy had significantly better disease free survival at 5 and 10 years after surgery. In meta-analysis there was no difference in overall survival at 5 years after surgery, although Messing and co-workers (1999 2006) reported a significant survival benefit with adjuvant hormone therapy. In the Wirth study (Wirth et al. 2004), men treated with adjuvant hormonal therapy had significantly lower overall survival at 10 years after surgery, than the standard care group.

Table 6.1.2. Evidence profile for adjuvant hormonal therapy with radical prostatectomy.

Table 6.1.2

Evidence profile for adjuvant hormonal therapy with radical prostatectomy. Question: Should adjuvant hormonal therapy plus prostatectomy vs. prostatectomy alone be used for prostate cancer? Systematic review:Kumar, Shelley, Harrison, Coles, Wilt and Mason (more...)

The Messing study (Messing et al. 1999) reported a significant increase in grade 1 and 2 side effects in the adjuvant hormone group. The Wirth study (Wirth et al. 2004) noted that discontinuation due to adverse effects was twice as likely in the adjuvant hormone group.

Adjuvant radiotherapy with prostatectomy

Evidence comes from two randomised trials (Bolla et al. 2005; Thompson, Jr. et al. 2006). See table 6.1.3 for summary of outcomes. There was no significant effect of adjuvant radiotherapy on overall or disease specific survival, although follow-up in the Bolla trial is not yet long enough to establish survival outcomes. Biochemical failure and clinical failure were significantly less likely in the group receiving adjuvant radiotherapy. Complications were significantly increased in those receiving adjuvant radiotherapy when compared to standard care.

Table 6.1.3. Evidence profile for adjuvant radiotherapy with radical prostatectomy.

Table 6.1.3

Evidence profile for adjuvant radiotherapy with radical prostatectomy. Question: Should adjuvant radiotherapy vs. no adjuvant radiotherapy be used for men having radical prostatectomy for prostate cancer? Patient or population: men with pathologically (more...)

Neoadjuvant hormonal therapy with radiotherapy

Evidence comes from four randomised trials included in the Kumar and co-workers (Kumar et al. 2006) review. See table 6.1.4 for summary of outcomes. At five years after radiotherapy, biochemical and clinical disease free survival were significantly better in those who had neoadjuvant hormonal therapy. Five year overall survival was not significantly affected by neoadjuvant hormonal therapy.

Table 6.1.4. Evidence profile for neoadjuvant hormonal therapy with radical radiotherapy.

Table 6.1.4

Evidence profile for neoadjuvant hormonal therapy with radical radiotherapy. Question: Should Neo-adjuvant hormonal therapy plus radiotherapy vs. Radiotherapy alone be used for prostate cancer? Systematic review:Kumar, Shelley, Harrison, Coles, Wilt and (more...)

Three studies presented data on adverse events. Between 16 and 27% of patients (Lamb et al. 2003; Pilepich et al. 2001) had to stop the flutamide part of hormonal therapy early, usually due to liver function abnormality or bowel side effects. Patients also experienced transient sexual dysfunction while on maximum androgen blockade. Hot flushes were also a common adverse effect of hormonal therapy (Fellows et al. 1992).

Adjuvant hormonal therapy with radiotherapy

Evidence comes from four randomised trials included in the Kumar and co-workers (Kumar et al. 2006) review. See table 6.1.5 for summary of outcomes. Adjuvant hormone therapy was associated with improved overall survival at five and ten years after radiotherapy. Adjuvant hormonal therapy was associated with improved disease specific survival at five years after radiotherapy, and improved disease free survival at ten years.

Table 6.1.5. Evidence profile for adjuvant hormonal therapy with radical radiotherapy.

Table 6.1.5

Evidence profile for adjuvant hormonal therapy with radical radiotherapy. Question: Should Adjuvant hormonal therapy plus radiotherapy vs. radiotherapy alone be used for prostate cancer? Systematic review:Kumar, Shelley, Harrison, Coles, Wilt and Mason (more...)

The adjuvant bicalutamide study (Tyrrell et al. 2005) suggests that mild to moderate breast pain and gynaecomastia are common side effects of this therapy (seen in 74% and 69% of patients respectively). Withdrawal due to adverse events was 29% in the adjuvant bicalutamide group compared to 10% in the standard care group.

Adjuvant chemotherapy with prostatectomy or radiotherapy

One randomised trial from the pre-PSA era (Schmidt et al. 1996), did not observe a survival advantage of adjuvant estramustine or cyclophosphamide over standard care in men with positive lymph nodes after prostatectomy or radiotherapy. A number of small phase I or II trials report the use of adjuvant and neoadjuvant chemotherapy (Macvicar & Hussain 2005). Large phase III trials are underway of neoadjuvant or adjuvant docetaxel or mitoxantrone with prostatectomy (CALGB-90203, SWOG-9921, and RTOG 0521).

Evidence Table

Kumar, Shelley, Harrison, Coles, Wilt & Mason. Neo-adjuvant and adjuvant hormone therapy for localised prostate cancer [protocol for a Cochrane review]. Cochrane Database of Systematic Reviews 2006 Issue 2. [2]. 2006. Chichester (UK), John Wiley & Sons, Ltd.
Design: Systematic review of RCTs (therapy), evidence level: 1+
Inclusion criteria Study types: Randomised controlled trials or quasi-randomised trials reporting on neo-adjuvant and adjuvant hormonal therapy for localised or locally advanced prostate cancer. Also RCTs that compare schedules of neo-adjuvant or adjuvant hormonal therapy were eligible. Only peer reviewed published articles were included. Participants: Men with stage T1 – T4, N1, M0 prostate cancer, according to the WHO 1997 TNM classification.
Interventions: Primary therapies included radical prostatectomy, radical radiotherapy, brachytherapy or cryotherapy. Neo-adjuvant or adjuvant hormonal therapies consisting of combination hormonal therapy with LHRH agonists plus anti-androgens, or single agent hormone deprivation therapies. Hormonal therapies of any duration were considered. Only studies of either adjuvant or neo-adjuvant hormones were included and not those that are looking at both. Neo-adjuvant and adjuvant hormonal therapies were taken to include those that overlap or were concurrent with radiotherapy treatment.
Interventions Neoadjuvant hormonal therapy with prostatectomy.
Adjuvant hormonal therapy with prostatectomy.
Neoadjuvant hormonal therapy with radiotherapy.
Adjuvant hormonal therapy with radiotherapy.
Outcomes Overall survival, biochemical relapse free survival, clinical relapse free survival, treatment toxicity.
Results See evidence summary (tables 6.1.1 to.
(Messing et al. 2006)
Design: Randomized controlled trial (therapy), evidence level: 1+
Country: United States, setting: Tertiary care
Inclusion criteria Men who had radical prostatectomy and pelvic lymphadenectomy for clinically localised prostate cancer, and who had confirmed pelvic nodal metastases.
Exclusion criteria No radiological evidence of metastases, no previous hormonal therapy
Population number of patients = 98, age range 45 to 78 years, median age = 66 years.
Interventions All men had radical prostatectomy and pelvic lymphadenectomy. Men were randomised to receive either immediate hormone therapy (choice of 3.6 mg goserelin monthly or bilateral orchidectomy) or no hormone treatment until disease progression.
Outcomes Overall and disease specific survival. Disease recurrence (PSA or clinical recurrence).
Follow up Median follow-up was 11.9 years (range 9.7 to 14.5 for survivors). Men were followed up every three months for the first year, with clinical examination and PSA tests, and bone scans at alternate visits. Follow-up frequency changed to 6 months after the first year.
Results Multivariate analysis (Cox proportional hazards) was used to adjust for the effect of Gleason score on the outcomes.
COMPARISON IN MEN AFTER RADICAL RETROPUBIC PROSTATECTOMY, WITH ADVERSE RISK FACTORSIMMEDIATE HORMONE THERAPYDELAYED HORMONE THERAPYOVERALL RESULT
Overall survival17/47 men died (36%)28/51 men died (55%)Favours immediate therapy, adjusted HR for death (deferred vs. immediate) 1.84 (95% CI 1.01 to 3.35)
Disease specific survival7/47 men died from prostate cancer (15%)25/51 men died from prostate cancer (49%)Favours immediate therapy, adjusted HR for death from PCa (deferred vs. immediate) 4.09 (95% CI 1.76 to 9.49)
Disease progression22/27 (47%)44/51 (86%)Favours immediate therapy, adjusted HR for progression (deferred vs. immediate) 3.42 (95% CI 1.96 to 5.98)
General comments Study closed early due to accrual problems (due to changes in clinical practice).
Thompson, Jr., Tangen, Paradelo, Lucia, Miller, Troyer, Messing, Forman, Chin, Swanson, Canby-Hagino & Crawford. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA 296[19]. 2006.
Design: RCT (therapy) evidence level: 1++
Country: United States, setting: Tertiary care
Inclusion criteria Men treated with prostatectomy for stage pT3 N0 M0 prostate cancer. Men had to have adequate bone marrow and liver function and performance status of 0 to 2.
Exclusion criteria positive bones scan result. Urinary incontinence, rectal injury, pelvic infection or urinary extravasation. Previous chemotherapy or radiotherapy were not permitted
Population number of patients = 425.
Interventions Men were randomised to receive either adjuvant radiotherapy or observation after radical prostatectomy. Radiotherapy was given within 17 weeks of radical prostatectomy, at a dose of 60 to 64 Gy in 30 to 32 fractions. 70/211 (33%) of patients in the observation arm received radiotherapy for biochemical or clinical relapse.
Outcomes Metastasis free survival, overall survival, biochemical relapse free survival (only defined for men with post surgical PSA of less than 0.4 ng/ml as PSA greater than 0.4 ng/ml), time to hormonal treatment and complication rate.
Follow up Median follow-up was 10.6 years (IQR 9.2 to 12.7 years). Toxicity was monitored weekly during radiotherapy. Follow up visits were every 3 months for 1 year, every 6 months for the next 2 years and then annually.
Results -
COMPARISON IN MEN AFTER RADICAL RETROPUBIC PROSTATECTOMY, WITH ADVERSE RISK FACTORS
ADJUVANT RADIOTHERAPY
OBSERVATION AND SALVAGE RADIOTHERAPY IF INDICATEDOVERALL RESULT
Distant metastasis free survivalMedian 14.7 years. 76/214 had metastatic disease or diedMedian 13.2 years. 91/211 had metastatic disease or diedNo sig. difference, HR = 0.75 (95% CI 0.55 to 1.02), p=0.06
Biochemical recurrence122/175.60/172Favours adjuvant radiotherapy (p<0.001, HR = 0.43, 95% CI 0.31 to 0.58)
Clinical recurrence84/214111/211Favours adjuvant radiotherapy (p=0.001, HR = 0.62, 95% CI 0.46 to 0.82)
Overall survival71/214 died83/211 diedNo sig. difference (HR=0.80, 95%CI 0.58 to 1.09, p=0.16)
Complications51/21425/211Favours observation (RR=2.01, 95%CI 1.37 to 2.23)
General comments-
Schmidt, Gibbons, Murphy & Bartolucci. Evaluation of adjuvant estramustine phosphate, cyclophosphamide, and observation only for node-positive patients following radical prostatectomy and definitive irradiation. Investigators of the National Prostate Cancer Project. Prostate 28[1]. 1996.
Design: Randomized controlled trial (therapy), evidence level: 1+
Country: United States
Inclusion criteria Patients with localised. potentially curable, prostate cancer
Exclusion criteria Men with clinical disease stages A and B1 were excluded.
Population-
Interventions Following radical therapy patients were randomised to one of three treatment arms. Adjuvant cyclophosphamide 1 gram/m2-IV every 3 weeks for 2 years, estramustine phosphate 600 mg/m2-po daily for up to 2 years, or to observation only.
Outcomes Clinical recurrence (nearly always defined by a positive bone scan) and disease specific survival.
Follow up Average follow up was 10 years.
Results Only patients with lymph node involvement were included in this analysis. In a post-hoc subgroup analysis of those with more than 20% lymph node involvement, men treated with estramustine showed significantly better progression free survival than the observation only group.
COMPARISON IN MEN WITH POSITIVE LYMPH NODES AFTER RADIOTHERAPYADJUVANT CYCLOPHOSPHAMIDEADJUVANT ESTRAMUSTINEOBSERVATION ONLYOVERALL RESULT
Clinical progression free survival45/52 progressed. Median progression free survival was 30.9 months31/42 progressed. Median progression free survival was 37.3 months42/52 progressed. Median progression free survival was 20.9 monthsno significant difference (p=0.1748, log rank test)
Disease specific survival25/52 died. Median disease specific survival was 86.7 months15/42 died. Median disease specific survival was 138.9 months20/52 died. Median disease specific survival was 93.6 monthsno significant difference (p=0.3493, log rank test)
COMPARISON IN MEN WITH POSITIVE LYMPH NODES AFTER PROSTATECTOMYADJUVANT CYCLOPHOSPHAMIDEADJUVANT ESTRAMUSTINEOBSERVATION ONLYOVERALL RESULT
Clinical progression free survival9/16 progressed. Median progression free survival was 51.6 months13/18 progressed. Median progression free survival was 48.9 months11/14 progressed. Median progression free survival was 51.7 monthsno significant difference (p=0.6984, log rank test)
General comments Pre PSA era study. Treatment toxicity not reported in this paper.
Bolla, van, Collette, van, Vekemans, Da, de Reijke, Verbaeys, Bosset, van, Marechal, Scalliet, Haustermans, Pierart & European Organization for Research and Treatment of Cancer. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). [See comment]. Lancet 366[9485]. 2005.
Design: Randomized controlled trial (therapy), evidence level: 1++
Country: International, setting: Tertiary care
Inclusion criteria EORTC trial 22911. Men with previously untreated prostate cancer with a clinical tumour stage T0 to T3, nodal stage N0 and no distant metastases. Pathological stage pT2–T3 pN0 and at least one of the following risk factors: tumour growth beyond the capsule, positive surgical margins or invasion of the seminal vesicles.
Men had to be younger than 76 years, with WHO performance status of 0 or 1.
Exclusion criteria Inappropriate disease stage, previous or concurrent cancer, prior treatment, lack of baseline data or incomplete initial workup.
Population number of patients = 1005, median age = 65 years.
Interventions All men had radical retropubic prostatectomy.
After surgery men were randomly assigned to receive radiotherapy or to a wait and see policy, where treatment was delayed until biochemical or clinical failure.
Radiotherapy within 16 weeks after surgery. A dose of 50 Gy was given in 25 fractions over 5 weeks, to a volume that included the surgical limits. A 10 Gy boost was given in 5 fractions over a week to a smaller volume.
113/503 (22%) of patients in the observation group received radiotherapy for biochemical or clinical relapse.
Outcomes Clinical progression free survival (survival with no clinical, radiological or scintigraphic evidence of recurrence). Biochemical progression free survival, defined as an increase of more than 0.2 ng/ml over the lowest post operative value measured on 3 occasions at least 2 weeks apart.
Adverse effects from radiation, and late complications (using the EORTC scale).
Follow up clinical examinations, with DRE and PSA tests, were done at 2, 4 and 12 months after surgery, then every 6 months until the end of the 5th year, then yearly until death. Median follow-up was 5 years.
Results 220/503 in the wait-and-see group and 131/502 in the radiotherapy group experienced biochemical relapse.
113/503 in the wait-and-see group and 75/502 in the radiotherapy group experienced clinical progression or death.
15/503 in the wait-and-see group and 8/502 in the radiotherapy group experienced death due to prostate cancer.
Acute adverse effects of radiation were mild to moderate in most patients. The following grade 3 acute effects were reported: acute diarrhoea (5.3% of patients), frequency passage of urine (3.3%), dysuria (1.1%) and skin (0.4%).
COMPARISON IN MEN AFTER RADICAL RETROPUBIC PROSTATECTOMY, WITH ADVERSE RISK FACTORSADJUVANT RADIOTHERAPYNO RADIOTHERAPYOVERALL RESULT
5 year biochemical progression free survival74.0% [98% CI 68.7 to 79.3%]52.6% [98% CI 46.6 to 58.5%]Favours radiotherapy, p<0.0001 (log-rank test)
5 year clinical progression free survival92.2% [98% CI 87.8 to 94.6%]81.0% [98% CI 76.4 to 85.5%]Favours radiotherapy, p<0.0001 (log-rank test)
5 year overall survival93.1% [98% CI 90.1 to 96.2%]92.3% [98% CI 89.1 to 95.5%]No sig. difference, p =0.6796 (log rank test)
General comments -

Health Economic Short Summary

The literature search on adjuvant therapy identified 1027 potentially relevant papers. Eight of these papers were obtained for appraisal, of which 5 contained relevant economic evaluations (Konski 2005; Konski 2006; Moeremans 2004; Neymark 2001 and Samant 2003). None of the studies were performed from a UK NHS perspective.

All of the studies evaluated the use of neoadjuvant and/or adjuvant hormonal therapy. Four of the 5 studies compared the use of hormonal therapy as an adjunct to radiotherapy. The choice of adjuvant therapy in the fifth study was described as ‘standard care’, but few further details of it were provided. None of the studies assessed the use of hormonal therapies as an adjunct to radical prostatectomy. All five studies appeared to base their economic evaluation on at least one randomised control trial (RCT). However, all 5 were different because they assessed the cost-effectiveness of different treatment regimens. For example, Konski et al. (2005) compared the use of hormonal therapy, 2 months prior to the initiation of radiotherapy and for the duration of treatment, to radiotherapy alone. Whereas Konski et al. (2006) compared the use of a similar hormonal regimen with hormonal therapy continuing for 2 years after radiotherapy had finished. The overall quality of the evaluations was judged to be good. No study reported a base case incremental cost-effectiveness ratio above £30,000 per life-year/QALY gained. Taking into account both the quality of the clinical evidence and the results of the cost-effectiveness analyses, there was considered to be at least reasonable evidence to support the economic value of hormonal therapies in this setting.

Health Economic Summary

Overview

All five economic evaluations evaluated the neoadjuvant/adjuvant use of hormonal therapies for people in whom radical treatments were planned. Each study considered a different hormonal regimen. In four evaluations, treatments were ‘in addition’ to radiotherapy’, not surgery. None of the studies was performed from a UK perspective.

The overall quality of the evaluations was considered to be good; each was based on a suitable RCT, and appropriate modelling methods appear to have been used by three of the evaluations. Overall, there appears to be at least reasonable evidence to suggest that the use of hormonal therapies as neoadjuvant/adjuvant treatments are cost-effective (compared to no adjunctive therapy). However, it is not clear which hormonal therapy regimen is the most cost-effective, specifically in terms of treatment duration.

Comparison(s)

In three of the evaluations (Konski, 2006, Neymark, 2001 and Samant 2003), the comparator was radiotherapy alone. In Konski (2005), longterm (2 years) androgen deprivation therapy was compared with androgen therapy that only lasted for the duration of radiotherapy. In the analysis that contained bicalutamide monotherapy (Moeremans, 2004) its addition was compared with ‘standard’ care, for which relatively few details were provided but it appeared to included radiotherapy, chemotherapy and surgery.

Population Sample

Men with local and/or locally advanced prostate cancer for which radical therapy is planned.

Costs

All 5 evaluations were performed from a health services perspective, although none were from the UK. They considered resources such as the costs of hormonal therapy, radical therapy, adverse events follow-up and biochemical progression. Costs were estimated using a mixture sources, including results from appropriate RCTs and literature reviews (the latter where modelling techniques were employed). No obvious categories of cost were excluded from the analyses that were likely to bias the results in a systematic manner.

Clinical Effectiveness

In each case, clinical effectiveness was estimated using results from appropriate RCTs. For example, Konski et al. 2006 was based on the Radiation and Oncology Group 92-02, where patients with locally advanced prostate cancer were randomised to receive either 2 years androgen deprivation therapy or no further adrogen deprivation therapy following the end of radiotherapy.

Health outcomes were expressed in terms of life-years gained and quality-adjusted life-years (QALYs).

Results

The results ranged from hormonal therapy as an adjunct to radiotherapy ‘dominating’ radiotherapy alone to costing an additional Euros 27,059 per QALY. No study reported a base case incremental cost-effectiveness ratio above £30,000 per life-year/QALY gained.

Sensitivity Analysis

A number of one- and two-way sensitivity analysis were performed. Broadlly speaking, the results were shown to be sensitive to the time horizon (shorter time horizons were associated with higher incremental cost-effectiveness ratios) and the efficacy of the hormonal therapies. Konski (2006) also reported the results of a probabilistic sensitivity analysis – which suggested there was a 91% probability of long term androgen therapy is cost-effective compared with shorter term adrogen therapy, at the US$50,000 per additional QALY level (although few details of the distributions required to generate this analysis were presented). Similar probablisitic results were also presented in Konski (2005).

Reviewer Comments

All authors concluded that hormonal therapy, within the confines of each individual study, was a cost-effective treatment option.

None of the analysis were performed from a UK NHS prespective, which would have been preferable. However, each analysis was based on a suitable RCT (given each studies objective) – the overall quality of the studies was considered to be good. The analyses did not generally consider the cost-effectiveness of sub-groups, such as those at higher risk of disease progression. Thus there is a possibility that ‘average’ incremental cost-effectiveness ratios that were reported could contain a degree of heterogeneity, and mask appropriate and inappropriate treatment sub-groups. Additionally, as the studies’ evaluated different hormonal regimens, it is not possible to identify which hormonal regimen is the most cost-effective treatment option, particularly in terms of duration of therapy.

Health Economic Evidence Table

Question: What is the cost-effectiveness of different types of neoadjuvant/adjuvant therapies for people in who radical therapy is planned?

Bibliographic referenceKonski, AE. al. Economic analysis of a phase III clinical trial evaluating the addition of total androgen suppression to radiation versus radiation alone for locally advanced prostate cancer (Radiation Therapy Oncology Group protocol 86-10), 2005 International Journal of Radiation Oncology, Biology, Physics 63(3) p. 788–794Konski, A et al. Long-term hormone therapy and radiation is cost-effective for patients with locally advanced prostate carcinoma. Cancer, 2006. 106(1). 51–57Neymark, NI et al. Cost-effectiveness of the addition of early hormonal therapy in locally advanced prostate cancer: Results decisively determined by the cut-off time-point chosen for the analysis. European Journal of Cancer, 2001. 37(14) p. 1768–1774Samant, RS. A cost-outcome analysis of long-term adjuvant goserelin in addition to radiotherapy for locally advanced prostate cancer. Seminars in Urologic Oncology, 2003. 21(3) p. 171–177Moremans K et al. Cost-effectiveness analysis of bicalutamide (Casodex) for the treatment of early prostate cancer. Value in Health, 2004. 7(10) p. 472–481
Source of fundingUnclearUnclearEORTC/AstraZenecaNorthern Cancer Research FoundationAstraZeneca
Economic study typeCost-Utility Analysis (CUA)Cost-Utility Analysis (CUA)Cost-Effectiveness Analysis (CEA), using life-years gainedCEA, using life-years gainedCUA
Population, country & perspectiveLocally advanced, US ($), healthLocally advanced, US ($), healthLocally advanced, France (FF), healthLocally advanced, Canada (CAN$), healthLocal and locally advanced, Belgium (Euros), health
TechnologyHormonal therapy (HT) 2 months before and during radiotherapyLong-Term Androgen-Deprivation (LTAD) and Short-Term Androgen-Deprivation (STAD)
Both given with RT. Drug treatment started 2 months prior to RT and continuing until RT finished. LTAD, treatment continued for a further 2-years
‘Early hormonal therapy’ as an addition to RTAdjuvant, starting at the beginning of radiotherapy, for 3-yearsAdjuvant bicalutamide monotherapy, in addition to ‘standard care’, for a maximum of 5-years (standard care is not well described)
Comparison(s)Radiotherapy (RT) aloneLTAD and STAD compared with each otherRT aloneRT alone‘Standard care’ (SC) alone, which included the possibility of radiotherapy
Source of effectiveness dataSingle RCT with modellingSingle RCT with modellingRetrospective analysis of single RCT data with modellingSingle RCTand modelling. Effectiveness data analysis on an intention to treat analysisSingle RCT with modelling
Cost components included and health care resource utilization (HCRU)Included: costs of drug and radiotherapyIncluded: Initial cost of of androgen treatment, continued androgen treatment, hormone treatment after biochemical failure and cost of treatment in last year of lifeIncluded: length of hospital stay, clinic visits, surgical operations performed, drugs used for treatment and progression and palliative treatmentsIncluded: costs of drug, radiotherapy, laboratory costsIncluded: Costs of adjuvant treatment, follow-up, biochemical progression and metastatic disease
Results – cost per patient per alternativeRT: $29,240; RT+HT: $31,286LTAD: $32,564; STAD: $33,059RT: FF71,000; RT+HT: FF58,300;RT+HT increased costs by an additional $13,200SC: Euros 9,490; SC+HT: Euros 12,565
Results – effectiveness per patient per alternativeRT: 5.48 QALYs; RT+HT: 6.43 QALYsLTAD: 4.13 QALYs; STAD: 3.68 QALYsRT: 5.99 years; RT+HT: 7.05 yearsRT+HT increased survival by an additional 1.2 yearsSC: 8.95 QALYs; SC+HT: Euros 9.4 QALYs
Incremental cost-effectiveness ratio$2,153 per additional QALYLTAD dominatesRT+HT dominates$16,500 per additional life-year gained (LYG)Euros 27,059 per additional QALY
Results-uncertaintyProbabilistic analysis undertaken. 86% probability that RT+HT is cost-effective at the $50,000 per additional QALY levelProbabilistic and deterministic sensitivity analysis performed. 91% probability that LTAD was the most cost-effective option at a $50,000 per additional QALY levelProbabilistic sensitivity analysis. Probability of 76% that RT+HT is a less costly and more effective treatment optionVarious one and two-way analysis performed.Various one and two-way analysis performed, including the tim horizon which was shown to particularly alter the results
Time horizon, discount rate?
Benefits ?%; Costs ?%
10 years
Benefits 3%; Costs3%
Time horizon ?
Benefits ?; Costs3%
10 years
Benefits 3%; Costs?
15 years in the base case
Benefits 3%; Costs3%
CommentsGood quality analysis. Authors stated that RT+HT the most cost-effective optionGood quality analysis., although few details of the distributions used to conduct the probabistic sensitivity analysis were reported. Authors stated that LTAD is more cost-effective than STAD under all reasonable assumptionsHigh quality analysis. The authors concluded that RT+HT should be considered the most cost-effective optionGood quality analysis, although more details of the methods used to extrapolate the survival curves would have been useful. The authors concluded that even under pessimistic assumptions, RT+HT is the most cost-effective optionGood quality analysis. The authors concluded that Bicaultaminde monotherapy is the most cost-effective option, although consideration should be given to different subgroups/risks of disease progression

Health Economic Quality Checklist

(Drummond and Jefferson 1996 BMJ 13, 275–283 (August))

Scoring - yes, no, not clear and not appropriateStudy IDKonski et al. 2005Konski et al. 2006Neymark et al 2001.Samant et al. 2003Moremans K et al. 2006
Checklist completed byAlec MinersAlec MinersAlec MinersAlec MinersAlec Miners
Study designWas a research question stated?YesYesYesYesYes
Was the economic importance of the research question stated?YesYesYesYesYes
Was the viewpoint/s of the analysis clearly stated and justified?YesYesYesYesYes
Was the rational for choosing the alternative programs or interventions to be compared stated?YesYesYesYesYes
Were the alternatives being compared clearly described? (that is, can you tell who? did what? to whom? where? and how often?)?YesYesYesYes‘Standard care’ only partially described
Was the form of economic evaluation used, clearly stated?YesYesYesYesYes
Is the choice of the economic evaluation justified in relation to the questions addressed?YesYesYesYesYes
Data collectionWas the source of the effectiveness estimates used clearly stated?YesYesYesYesYes
Were the details of the of the design and results of the effectiveness study given? (if based on a single study)PartiallyYesYesPartiallyPartially
Were the details of the synthesis or meta-analysis of estimates given? (If based on an overview of a number of effectiveness studies)N/AN/AN/AN/AN/A
Was the primary outcome measure/s for the economic evaluation clearly stated?YesYesYesYesYes
Were the methods to value health states and other benefits stated?PartiallyPartiallyN/AN/AYes partially
Were the details of the subjects from whom valuations were obtained given?PartiallyPartiallyN/AN/APartially
Were any productivity changes (if included) reported separately?N/AN/AN/AN/AN/A
Was the relevance of any productivity changes to the study questions discussed?N/ANoN/ANoNo
Were the quantities of resources reported separately from their unit costs?YesNoYesPartiallyYes
Were the methods for estimation of quantities and unit costs described?YesYesYesYesYes
Was the currency and price data recorded?YesPrice year was unclearYesYesYes
Were the details of currency of price adjustments for inflation or currency conversion given?NoUnclearNoNoNo
ModellingWere the details of any model used given?YesPartially, no schematic providedYesNoYes
Was the choice of model and the key parameters on which it was based justified?Yes mostlyPartiallyYes mostlyNoPartially
Analysis and interpretation of resultsWas the time horizon of costs and benefits stated?UnclearYesUnclearYesYes
Was the discount rate stated?UnclearYesYesYes for benefitsYes
Was the choice of discount rate justified?N/ANoYesNoNo
Was an explanations given if costs or benefits were not discounted?N/AN/ANoNoN/A
Were the details of statistical tests and confidence rates given for stochastic data?N/AN/APartiallyN/AN/A
Was the approach to sensitivity analysis given?YesYesPartiallyYesPartially
Was the choice of variables for sensitivity analysis justified?YesYesPartiallyPartiallyPartially
Were the ranges over which the variables are varied stated?Partially, few details of distribution parameters were givenPartially, few details of distribution parameters were givenPartiallyNoYes
Were relevant alternatives compared?YesYesYesNoPartially
Was the incremental analysis reported?YesYesYesYesYes
Were the major outcomes presented in a disaggregated as well as aggregated form?YesYesYesNoYes
Was the answer to the study question given?YesYesYesYesYes
Did the conclusions follow from the data reported?YesYesPartiallyYesYes
Were the conclusions accompanied by the appropriate caveats?YesYesYes mostlyYesYes
This and the following have been retained from Appendix GDid the study allude to, or take account of, other important factors in the choice or decision under consideration (for example, distribution of costs and consequences, or relevant ethical issues)?Yes partiallyYes partiallyPartiallyPartiallyYes, partially
Did the study discuss issues of implementation, such as the feasibility of adopting the ‘preferred’ programme given existing financial or other constraints, and whether any freed resources could be redeployed to other worthwhile programmes?NoNoPartiallyYes partiallyNo
OVERALL ASSESSMENT OF THE STUDYHow well was the study conducted?
Code ++, + or –
++++++
Are the results of this study directly applicable to the patient group targeted by this guideline?YesYesYesYesYes

Reference List

  1. Bolla M, van PH, Collette L, van CP, Vekemans K, Da PL, de Reijke TM, Verbaeys A, Bosset JF, van VR, Marechal JM, Scalliet P, Haustermans K, Pierart M. European Organization for Research Treatment of Cancer. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911).[see comment] Lancet. 2005;366:572–578. [PubMed: 16099293]
  2. Fellows GJ, Clark PB, Beynon LL, Boreham J, Keen C, Parkinson MC, Peto R, Webb JN. Treatment of advanced localised prostatic cancer by orchiectomy, radiotherapy, or combined treatment. A Medical Research Council Study. British Journal of Urology. 1992;70:304–309. [PubMed: 1422689]
  3. Klotz LH, Goldenberg SL, Jewett MAS, Fradet Y, Nam R, Barkin J, Chin J, Chatterjee S. Long-term followup of a randomized trial of 0 versus 3 months of neoadjuvant androgen ablation before radical prostatectomy. Journal of Urology. 2003;170:791–794. [PubMed: 12913699]
  4. Konski AE, et al. Economic analysis of a phase III clinical trial evaluating the addition of total androgen suppression to radiation versus radiation alone for locally advanced prostate cancer (Radiation Therapy Oncology Group protocol 86-10) International Journal of Radiation Oncology, Biology, Physics. 2005;63(3):788–794. [PubMed: 16109464]
  5. Konski A, et al. Long-term hormone therapy and radiation is cost-effective for patients with locally advanced prostate carcinoma. Cancer. 2006;106(1):51–57. [PubMed: 16323171]
  6. Kumar S, Shelley M, Harrison C, Coles B, Wilt T, Mason M. Cochrane Database of Systematic Reviews 2006. 2. Chichester (UK): John Wiley & Sons, Ltd; 2006. Neo-adjuvant and adjuvant hormone therapy for localised prostate cancer [protocol for a Cochrane review] [PubMed: 17054269]
  7. Lamb DS, Denham JW, Mameghan H, Joseph D, Turner S, Matthews J, Franklin I, Atkinson C, North J, Poulsen M, Kovacev O, Robertson R, Francis L, Christie D, Spry NA, Tai KH, Wynne C, Duchesne G. Acceptability of short term neo-adjuvant androgen deprivation in patients with locally advanced prostate cancer. Radiother. Oncol. 2003;68:255–267. [PubMed: 13129633]
  8. Macvicar GR, Hussain M. Chemotherapy for prostate cancer: implementing early systemic therapy to improve outcomes. Cancer Chemotherapy and Pharmacology. 2005;56:S69–S77. [PubMed: 16273364]
  9. Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med. 1999;341:1781–1788. [PubMed: 10588962]
  10. Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, Di’SantAgnese PA, Trump D. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncology. 2006;7:472–479. [PubMed: 16750497]
  11. Moremans K, et al. Cost-effectiveness analysis of bicalutamide (Casodex) for the treatment of early prostate cancer. Value in Health. 2004;7(10):472–481. [PubMed: 15449639]
  12. Neymark NI, et al. Cost-effectiveness of the addition of early hormonal therapy in locally advanced prostate cancer: Results decisively determined by the cut-off time-point chosen for the analysis. European Journal of Cancer. 2001;37(14):1768–1774. [PubMed: 11549430]
  13. Pilepich MV, Winter K, John MJ, Mesic JB, Sause W, Rubin P, Lawton C, Machtay M, Grignon D. Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat.Oncol Biol.Phys. 2001;50:1243–1252. [PubMed: 11483335]
  14. Prezioso D, Lotti T, Polito M, Montironi R. Neoadjuvant hormone treatment with leuprolide acetate depot 3.75 mg and cyproterone acetate, before radical prostatectomy: a randomized study. Urologia Internationalis. 2004;72:189–195. [PubMed: 15084760]
  15. Samant RS. A cost-outcome analysis of long-term adjuvant goserelin in addition to radiotherapy for locally advanced prostate cancer. Seminars in Urologic Oncology. 2003;21(3):171–177. [PubMed: 12810202]
  16. Schmidt JD, Gibbons RP, Murphy GP, Bartolucci A. Evaluation of adjuvant estramustine phosphate, cyclophosphamide, and observation only for node-positive patients following radical prostatectomy and definitive irradiation. Investigators of the National Prostate Cancer Project. Prostate. 1996;28:51–57. [PubMed: 8545281]
  17. Soloway MS, Pareek K, Sharifi R, Wajsman Z, McLeod D, Wood DP Jr, Puras-Baez A, Austenfeld MS, Brawer MK, Bruskewitz R, Chodak G, Coffield SK, Johnson CF, Teague OE, Peretsman S, Thompson I, Cooner W, Fisher HAG, Melman A, Stone N, Klein E, Malkowicz B, Middleton R, Nieh P, Peabody JO, Pow-Sang JM, Rous S, Schmidt J, Smith A. Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-Year results. Journal of Urology. 2002;167:112–116.
  18. Thompson IM Jr, Tangen CM, Paradelo J, Lucia MS, Miller G, Troyer D, Messing E, Forman J, Chin J, Swanson G, Canby-Hagino E, Crawford ED. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA. 2006;296:2329–2335. [PubMed: 17105795]
  19. Tyrrell CJ, Payne H, See WA, McLeod DG, Wirth MP, Iversen P, Armstrong J, Morris C. Bicalutamide (‘Casodex’) 150 mg as adjuvant to radiotherapy in patients with localised or locally advanced prostate cancer: Results from the randomised Early Prostate Cancer Programme. Radiotherapy & Oncology. 2005;76:4–10. [PubMed: 16145740]
  20. Wirth MP, Weissbach L, Marx F-J, Heckl W, Jellinghaus W, Riedmiller H, Noack B, Hinke A, Froehner M. Prospective Randomized Trial Comparing Flutamide as Adjuvant Treatment versus Observation after Radical Prostatectomy for Locally Advanced, Lymph Node-Negative Prostate Cancer. European Urology. 2004;45:267–270. [PubMed: 15036669]

6.2. In men with prostate cancer receiving hormone therapy, are bisphosphonates effective at preventing bone metastases?

Short Summary

A good quality placebo controlled randomised trial (Mason et al. 2007) examined clodronate for the prevention of bone metastasis in men with localised or locally advanced prostate cancer. There was no significant difference in overall survival, symptomatic bone metastases or prostate cancer death between the treatment arms. Dose modifying adverse events were more likely in the clodronate group.

PICO

POPULATIONINTERVENTIONCOMPARISONOUTCOMES
Men who have localised or locally advanced disease (T2 – T4)
  • Bisphosphonate
[filled square]

Placebo

[filled square]

Same bisphosphonate (different duration of therapy or route of administration)

[filled square]

Other bisphosphonate treatment

  • Time till development of symptomatic bone metastases
  • Skeletal related events – all associated events including symptomatic fractures and SCC
  • Overall Survival
  • Toxicity
  • Type of progressive disease (bone vs. non malignant bone events)
  • Analgesic consumption
  • Quality of life
  • Need for palliative RT

(The search strategy developed from this PICO table and used to search the literature for this question is in Appendix C)

Evidence Summary

Prevention of bone metastasis

The PR04 trial examined the effect of clodronate on the time to bone metastasis in men with localised or locally advanced prostate cancer (Mason et al. 2007). At a median follow up of 7 years, there was no significant difference between clodronate and placebo arms in terms of symptomatic bone metastases or prostate cancer death (clodronate vs. placebo: HR=1.22 [95% C.I. 0.88 to 1.68]). There was no significant difference between overall survival in the two arms (clodronate vs. placebo: HR = 1.03 [95%CI 0.76 to 1.39]).

The Zometa 704 trial (Smith et al. 2005) examined the use of zoledronic acid for the prevention of bone metastasis in men with rising PSA despite ADT. The trial was closed prematurely due to a lower than expected rate of bone metastasis. While results were published from the 201 patients in the control arm (Smith et al. 2005), literature searches did not find any published data about the 188 patients who received zoledronic acid.

Adverse effects

In the PR04 trial, there were 202 adverse events in the clodronate arm and 181 in the placebo arm. More detail is required to interpret these figures, for example, it is unclear whether some patients experienced multiple adverse events.

Evidence Table

Randomized controlled trials

Mason, Sydes, Glaholm, Langley, Huddart, Sokal, Stott, Robinson, James, Parmar, Dearnaley & Medical Research Council. Oral sodium clodronate for nonmetastatic prostate cancer--results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873). J Natl Cancer Inst 99[10]. 2007.
Design: Randomized controlled trial (therapy), evidence level: 1++
Country: International, setting: Tertiary care
Inclusion criteria Men receiving standard treatment for T2 to T4 prostate cancer, with no evidence of metastases a WHO performance status of 0–2. Patients were recruited between 1994 and 1997.
Exclusion criteria Previous bisphosphonate treatment or long term hormonal therapy.
Population number of patients = 508.
Interventions Men were randomised to receive 4 tablets per day of either oral sodium clodronate (Loron 520mg) or matching placebo. Patients were encouraged to stay on this medication for 5 years or until one of the primary endpoints was reached.
Outcomes Primary outcome was symptomatic bone metastasis free survival. Overall survival, toxicity, rate of events affecting bone and type of progressive disease (bone or soft tissue).
Follow up Minimum follow up was at least 5 years. 38% of patients in the clodronate group completed 5 years of medication, compared to 48% in the placebo group.
Results -
COMPARISON IN MEN WITH PROSTATE CANCER AND NO BONE METASTASESSODIUM CLODRONATEPLACEBOOVERALL RESULT
Symptomatic bone metastases or prostate cancer death80/25468/254Favours placebo but not statistically significant, HR=1.22 (95% C.I. 0.88 to 1.68; p=0.23, log rank test)
Overall survival5 year survival was 78% (95% C.I. 73 to 83%)5 year survival was 79% (95% C.I. 73 to 83%)No sig. diff. in overall survival, HR=1.02, 95% C.I. 0.80 to 1.30, p= 0.90 (log rank test)
Adverse events132/254 experienced one or more adverse events117/254 experienced one or more adverse eventsTended to favour placebo, p=0.18
Dose modifying adverse events105/254 experienced one or more dose modifying adverse events71/254 experienced one or more dose modifying adverse eventsFavoured placebo, p=0.002
General comments Potency of oral clodronate is less than latest generation bisphosphonates (e.g. zoledronic acid).
Smith, Kabbinavar, Saad, Hussain, Gittelman, Bilhartz, Wynne, Murray, Zinner, Schulman, Linnartz, Zheng, Goessl, Hei, Small, Cook & Higano. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 23. 2005.
Design: Randomized controlled trial (therapy), evidence level: 1−
Country: unclear, setting: Tertiary care
Inclusion criteria Men with prostate cancer, no radiographic evidence of bone metastases, and rising PSA despite androgen deprivation therapy.
Exclusion criteria Patients with disease related symptoms, KPS of less than 90, life expectancy less than 6 months
Population number of patients = 389.
Interventions All patients were receiving ADT, either bilateral orchietomy or treatment with a gonadotropin-releasing hormone agonist. Patients were randomly assigned to receive either zoledronic acid or placebo intravenously every 4 weeks for 49 treatments. Patients were also prescribed daily calcium (500 mg) and vitamin D (400 to 500 IU).
Outcomes Time to first bone metastasis (as detected on bone scan or radiograph). Serum PSA.
Follow up Patients were evaluated every month for 48 months, when symptoms were assessed. Serum PSA was measured at baseline and then every 4 months.
Results The Data safety Monitoring Board terminated the study before the target accrual of 991 patients because the rate of bone metastasis was lower than predicted. For the placebo group (n=201): at 2 years, 33% of patients had developed bone metastases. Median bone metastasis-free survival was 30 months. Median time to first bone metastases and overall survival were not reached.
-
General comments No results reported from the bisphosphonate treatment arm, not even adverse effects data.

Health Economic Short Summary

The literature search on the use of bisphosphonates for the prevention of skeletal-related events (SREs) identified 153 potentially relevant papers. Thirteen of these papers were obtained for appraisal, of which 1 full economic evaluation was identified and reviewed (Reed et al. 2004). It examined 4 mg zoledronic acid (versus placebo), every 3 weeks, in men with advanced-stage prostate cancer and a history of metastatic bone disease as a method of preventing SREs. It was a non-UK based cost-utility analysis that was performed from a health services perspective. Results were presented in 2000–2002 US$. The evaluation was considered to be a good quality analysis.

The analysis was based on a single RCT of 15-months duration; treatment costs and benefits were not extrapolated past this period. Approximately 650 patients were entered into the RCT, however only information relating to 360 was included in the economic evaluation (for which baseline details were not provided). Utility scores were calculated using the EQ-5D questionnaire, which were recorded every 3-months as part of the trial design. Resource use was also collected prospectively alongside the RCT.

The results from the analysis showed that patients receiving zoledronic acid experienced fewer hospital days than people receiving placebo, although this difference was not statistically significant at conventional levels (mean of 5.6 vs 8.0 days respectively; p = 0.20). The additional healthcare costs of providing zoledronic acid plus its administration was approximately $5,700. The baseline incremental cost-effectiveness ratio per additional QALY was approximately $160,000, although this varied considerably during the sensitivity analysis. Using $2=£1, translates to an ICER of approximately £80,000 per additional QALY. The authors concluded that the use of zoledronic acid for the prevention of SREs for people with metastatic prostate cancer was unlikely to be cost-effective, which appears to be a reasonable conclusion given the quality of the evidence.

Health Economics Summary

Overview

The objective of this topic is to estimate the cost-effectiveness of bisphosphonates in relief of metastastic bone symptoms and control of metastatic bone disease in men with prostate cancer.

The analysis by Reed et al., identified from the evidence review, estimates the cost-effectiveness of zoledronic acid versus placebo in men with prostate cancer for decreasing skeletal complications.

Overall, this is a well balanced, recent paper where intervention was clearly stated and sensitivity analysis was thoroughly carried out, which supports the robustness of conclusions. The methodology of obtaining preference and applying them to clinical data was clearly stated and justified. However, the multinational nature of the population sample has limited relevancy to the UK health system. The analysis is based on a single randomized control trial. These conclusions provide a valuable guide, but are not conclusive to the UK setting. More economic evidence on this topic is necessary.

Comparison(s)

The analysis by Reed et al. (2004) compared patients with prostate cancer receiving 4 mg of zoledronic acid versus patients receiving placebo.

Population Sample

The analysis was based on a multinational, double-blind, placebo controlled randomized trial of 643 men with advance stage prostate cancer conducted by Saad et al. (Saad et al. 2002).

Costs

The following cost components were included in the analysis: direct medical costs, which included hospitalization, outpatient and institutionalization costs. All costs are reported in US dollars ($). Unit costs in countries other than the USA were converted to year 2000 dollars using purchasing power parities.

Clinical Effectiveness

The authors state that zoledronic acid decreased the incidence of skeletal related events relative to placebo. This result consistent with the conclusions of several other cited studies investigating the efficacy of zoledronic acid in the prevention of skeletal related events.

Results

The cost per patient receiving zoledronic acid was $5,365, while the cost per patient receiving placebo was $5,689. The difference of $324 was insignificant (95% CI: $1,781, $1,146), and the authors concluded that the incremental cost of the intervention could be calculated as the cost of zoledronic acid and its administration at $5,677 +/−3,809.

Incremental cost-effectiveness ratios (ICERs) and cost-utility ratio were calculated. The ICERs were $12,300 per skeletal related event avoided (95% CI: $6,900, $48,700) and $51,400 per additional patient free of skeletal related events during the trial (95% CI: $26,900, $243,700). The incremental cost per QALY was $159,200 (95% CI: $88,500, $786,600)

Sensitivity Analysis

The authors conducted sensitivity analyses by considering following: (a) change in the price of zoledronic acid, (b) community-based utility weights derived from the EQ-5D and (c) the number of days that patient experienced lower quality of life due to skeletal related event.

Reviewer Comments

The analysis was based on a randomised controlled clinical trial, which was appropriate for this topic. The authors conducted a cost study with thorough sensitivity analysis and reported results in an incremental format.

Although the analysis was conducted using patient level data that was collected during the trial, the authors acknowledge some of its limitation with respect to resource use data and EQ-5D measure. The authors further stress the need for future research of this topic.

Health Economics Evidence Table

Question: How cost-effective are bisphosphonates for relief of metastatic bone symptoms and control of metastatic bone disease?

By: Eugenia Priedane, Pat Linck, Dyfrig Hughes and Rhiannon Tudor Edwards

Date: 30/03/2006

Bibliographic referenceReed, S. D., J. I. Radeva, et al. (2004). “Cost-effectiveness of zoledronic acid for the prevention of skeletal complications in patients with prostate cancer.” Journal of Urology 171(4): 1537–1542
Source of fundingNovartis Pharmaceuticals Corporation, NJ, USA
Economic study typeCost-effectiveness analysis; Cost utility analysis
Population, country & perspectiveThe study included a population sample from a multinational, double-blind, placebo controlled randomized trial of 643 men with advance stage prostate cancer (Saad et al. 2002). 214 patients were randomized to zoledronic acid and 208 to placebo. Excluding patients without resource use data, 181 and 179 were randomized to the zoledronic acid and placebo arms, respectively. The median age of all patients included in the economic evaluation was 73 years. Ethnicity composition of the sample was split as follows – 85.3% white, 9.7% black, 1.1% Asian and 3.9% ‘other’. Majority of patients came from the USA (59.9%), followed by Canada (21.1%) and Australia (10.6%). The economic analysis adopted a societal perspective.
Comparison(s)Patients receiving 4mg zoledronic acid were compared to those who received placebo.
Source of effectiveness dataEffectiveness data were derived from a single study by Saad et al.(2002)
Cost components included and health care resource utilization (HCRU)The following cost components were included in the study: Direct medical costs, which included hospitalization, outpatient and institutionalization costs. The cost of zoledronic acid in the US was based on the 2002 federal supply schedule from the Department of Veterans Affairs National Formulary. Costs of zoledronic acid outside of the US were based on 2002 ex-factory prices (excluding VAT). In conjunction with the clinical trial resource use data was collected and included information on hospitalization, outpatient visits, treatment, procedures, concomitant medication and institutionalized care.
Time horizon, discount rateTime horizon: 15 months. Discount rate was not applied.
Results – cost per patient per alternativeThe cost per patient receiving zoledronic acid was $5,365 and the cost per patient receiving placebo was $5,689. The difference of $324 was insignificant (95% CI: $1,781, $1,146), and the authors concluded that the incremental cost of the intervention could be calculated as the cost of zoledronic acid and its administration at $5,677 +/− $3,809.
Incremental cost-effectiveness ratios (ICERs) and cost-utility ratio were calculated. The ICERs were $12,300 per skeletal related event avoided (95% CI: $6,900, $48,700) and $51,400 per additional patient free of skeletal related events during the trial (95% CI: $26,900, $243,700). The incremental cost per QALY was $159,200 (95% CI: $88,500, $786,600)
Results – effectiveness per patient per alternativeDuring the trial, 33.2% of patients receiving zoledronic acid and 44.2% of patients receiving placebo experienced skeletal related events. The mean number of skeletal related events per patient was 0.78 in the zoledronic acid group and 1.24 in the placebo group. Confidence intervals and detailed results were not reported.
Results-uncertaintyA sensitivity analysis was performed by varying the following: change in the price of zoledronic acid, community-based utility weights derived from the EQ-5D and the number of days that patient experienced lower quality of life due to skeletal related event. The results of variation the within-trial cost of zoledronic acid from $1,000 to $8,000 ($80 to $635 per dose) were reported. The authors reported relatively small differences in incremental cost per QALY when community-based utility weights derived from the EQ-5D was applied. Cost per QALY was about $50,000 when patients were adversely affected for at least 120 days by each skeletal related event and the cost of each dose of $300 and less than $75,000/QALY when the cost per dose was less than $450.
CommentsThe analysis was based on a randomized controlled clinical trial, which was appropriate for the study question. The authors conducted a cost study with thorough sensitivity analysis and reported results in an incremental format. Although the study was conducted using patient level data that was collected during the trial, the authors acknowledge study some of its limitation with respect to resource use data and EQ-5D measure. It is reported that resource use data was not collected for about 17% of patients and at the individual study visits 9%–16% of EQ-5D measures were missing. The authors further stress the need for future research of this topic.

Health Economic Quality Checklist

(Drummond and Jefferson 1996 BMJ 13, 275–283 (August))

Scoring - yes, no, not clear and not appropriateStudy IDReed et al. (2004)
Checklist completed byEP
Study designWas a research question stated?Yes
Was the economic importance of the research question stated?Yes
Was the viewpoint/s of the analysis clearly stated and justified?Yes
Was the rational for choosing the alternative programs or interventions to be compared stated?Not clear
Were the alternatives being compared clearly described? (that is, can you tell who? did what? to whom? where? and how often?)?Yes
Was the form of economic evaluation used, clearly stated?Yes
Is the choice of the economic evaluation justified in relation to the questions addressed?Yes
Data collectionWas the source of the effectiveness estimates used clearly stated?Yes
Were the details of the of the design and results of the effectiveness study given? (if based on a single study)Yes
Were the details of the synthesis or meta-analysis of estimates given? (If based on an overview of a number of effectiveness studies)Yes
Was the primary outcome measure/s for the economic evaluation clearly stated?Yes
Were the methods to value health states and other benefits stated?Yes
Were the details of the subjects from whom valuations were obtained given?Yes
Were any productivity changes (if included) reported separately?Not applicable
Was the relevance of any productivity changes to the study questions discussed?Not applicable
Were the quantities of resources reported separately from their unit costs?Yes
Were the methods for estimation of quantities and unit costs described?Yes
Was the currency and price data recorded?Yes
Were the details of currency of price adjustments for inflation or currency conversion given?Yes
ModellingWere the details of any model used given?Yes
Was the choice of model and the key parameters on which it was based justified?Yes
Analysis and interpretation of resultsWas the time horizon of costs and benefits stated?Yes
Was the discount rate stated?No
Was the choice of discount rate justified?No
Was an explanations given if costs or benefits were not discounted?Yes
Were the details of statistical tests and confidence rates given for stochastic data?Yes
Was the approach to sensitivity analysis given?Yes
Was the choice of variables for sensitivity analysis justified?Yes
Were the ranges over which the variables are varied stated?Yes
Were relevant alternatives compared?Yes
Was the incremental analysis reported?Yes
Were the major outcomes presented in a disaggregated as well as aggregated form?Yes
Was the answer to the study question given?Yes
Did the conclusions follow from the data reported?Yes
Were the conclusions accompanied by the appropriate caveats?Yes
This and the following have been retained from Appendix GDid the study allude to, or take account of, other important factors in the choice or decision under consideration (for example, distribution of costs and consequences, or relevant ethical issues)?No
Did the study discuss issues of implementation, such as the feasibility of adopting the ‘preferred’ programme given existing financial or other constraints, and whether any freed resources could be redeployed to other worthwhile programmes?No
OVERALL ASSESSMENT OF THE STUDYHow well was the study conducted? Code ++, + or −++
Are the results of this study directly applicable to the patient group targeted by this guideline?Yes

Reference List

  1. Mason MD, Sydes MR, Glaholm J, Langley RE, Huddart RA, Sokal M, Stott M, Robinson AC, James ND, Parmar MK, Dearnaley DP. Medical Research Council PR. Oral sodium clodronate for nonmetastatic prostate cancer--results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873) J Natl Cancer Inst. 2007;99:765–776. [PubMed: 17505072]
  2. Reed SD, Radeva JI, et al. Cost-effectiveness of zoledronic acid for the prevention of skeletal complications in patients with prostate cancer. Journal of Urology. 2004;171(4):1537–1542. [PubMed: 15017215]
  3. Smith MR, Kabbinavar F, Saad F, Hussain A, Gittelman MC, Bilhartz DL, Wynne C, Murray R, Zinner NR, Schulman C, Linnartz R, Zheng M, Goessl C, Hei YL, Small EJ, Cook R, Higano CS. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. Journal of Clinical Oncology. 2005;23:2918–2925. [PubMed: 15860850]

6.3. What is the clinical and cost-effectiveness of pelvic radiotherapy in patients receiving radical radiotherapy for prostate cancer?

Short Summary

The evidence comprises one large randomised trial (Lawton et al. 2005). This trial shows acceptable toxicity and a benefit in biochemical control, which might translate into a more clinically meaningful benefit with longer follow-up.

PICO

POPULATIONINTERVENTIONCOMPARISONOUTCOME
Patients who are to receive radical radiotherapy Radiotherapy to prostate alone
  • overall survival
  • biochemical failure free survival
  • freedom from salvage treatment
  • side effects
  • quality of life

(The search strategy developed from this PICO table and used to search the literature for this question is in Appendix C)

Evidence Summary

The search identified three RCTs comparing whole pelvic radiotherapy plus prostate boost (WPRT) with prostate only radiotherapy (PORT).The trials differed in their eligibility criteria and use of hormonal therapy. Of these trials RTOG-9413 and GETUG-01 are the most relevant to the clinical question. However, only preliminary results from GETUG-01 are available.

  • RTOG 7706 This pre-PSA era trial included patients with relatively good prognosis (no evidence of lymph node involvement, by lymphangiogram or surgical staging). Only 5% of the patients received neoadjuvant hormonal therapy.
  • RTOG 9413 This trial included patients with a predicted risk of lymph node involvement of more than 15%. Patients were randomised to either neoadjuvant (NHT) or adjuvant hormonal therapy (AHT).
  • GETUG 01 This trial included patients without clinical evidence of lymph node involvement. Neoadjuvant or adjuvant hormonal therapy was limited to patients at high risk of lymph node involvement.

Overall survival (OS)

In RTOG 7706 there was no significant difference between the 12 year OS of the WPRT and PORT groups at median follow up of 12 years (Asbell et al. 1998). In RTOG 9413 there was no significant difference between the 5 year OS of the WPRT and PORT groups at median follow up of 5.9 years (Lawton et al. 2005). In a preliminary report of GETUG 01, at median follow up of 3.3 years, no significance in 5 year OS was observed (Pommier et al. 2005).

Progression free survival (PFS)

In RTOG 9413 WPRT was associated with a 4 year PFS of 54% compared to 47% in the PORT group (p=0.02) (Roach, III et al. 2003a). In an update of RTOG 9413 (Lawton et al. 2005) 5 year PFS in the group treated with WPRT+NHT (48%) was significantly better in those treated with PORT+NHT (37%) and WPRT+AHT (38%), but not significantly better than PORT+AHT (40%). Similar results were reported at a median follow-up of 7 years (Lawton et al. 2007). The simple comparison between WPRT and PORT was not reported in this update (Lawton et al. 2005). No significant difference in progression free survival was reported in the preliminary report of GETUG 01 (Pommier et al. 2005). 5 year PFS was 68% for the WPRT group compared to 64% in the PORT group.

Treatment related toxicity

Meta-analysis (see figures 1a and 1b) of the toxicity reported in RTOG 7706 (Pilepich et al. 1987) and RTOG 9413 (Roach, III et al. 2003b) suggests that, compared to PORT, WPRT is associated with an increased risk of gastrointestinal toxicity [relative risk = 2.79; 95% CI 1.31 – 5.94], but no increased risk of genitourinary toxicity [relative risk = 0.96; 95% CI 0.61 – 1.48]. The absolute difference in risk, however, is small: 54 patients would need to be treated with WPRT (instead of PORT) to cause on additional patient to experience grade 3 or 4 gastrointestinal toxicity. The investigators in GETUG 01 did not find a statistical difference between the rates of grade 2 to 4 toxicity in the two treatment arms, but their data were not reported in sufficient detail to be included in the meta-analysis.

Figure 6.3.1. meta-analysis of gastrointestinal toxicity.

Figure 6.3.1meta-analysis of gastrointestinal toxicity

Figure 6.3.2. meta-analysis of genitourinary toxicity.

Figure 6.3.2meta-analysis of genitourinary toxicity

Evidence table

(Asbell et al. 1998)
Design Randomized controlled trial (therapy), evidence level: 1+
Country: United States, setting: Tertiary care
Inclusion criteria Patients with stage A2 (T1bN0M0 ) or B (T2N0M0) prostate cancer, according to Jewett-Whitmore staging (i.e. no evidence of nodal involvement by lymphangiogram or surgical staging). Patients were entered into the trial (RTOG 77-06) between 1978 and 1983. Randomization was stratified by histological grade, hormonal therapy and method of node evaluation (lymphangiogram or staging laporotomy).
Exclusion criteria Previous radiation therapy or potentially curative surgery. Other cancer (apart from skin cancer).
Population number of patients = 449, age range 46 to 47 years, mean age = 68 years.
Interventions After lymphangiogram (LAG) or staging lymphadenectomy (SL) patients were randomized between prophylactic radiation to the pelvic lymph nodes and prostatic bed vs. prostatic bed alone.
For those randomized to receive prophylactic pelvic lymph nodal irradiation, 45 Gy of megavoltage RT was delivered via multiple portals in 4.5 to 5 weeks, while all patients received 65 Gy in 6.5 to 8 weeks to the prostatic bed.
Outcomes Overall survival, recurrence free survival, distant-metastasis free survival and no-evidence-of-disease (NED) survival. Local or regional failure was defined as either progression of measurable disease at any time, or histological verification of tumour 2 years after radiotherapy. Progression of tumour was defined as at least a 25% increase in the palpable tumour mass dimensions.
Morbidity outcomes for this trial are reported in Pilepich et al (1983, 1984, and 1987).
Follow up Follow-up was a median of 12 years and a maximum of 16 years.
Results 117 patients had had staging lymphadenectomy (SL), the remaining 332 had staging lymphangiogram (LAG).
There was no significant difference in survival, NED survival, local control or time to distant metastases, whether treatment was administered to the prostate or prostate and pelvic lymph nodes. Median survival was 10.7 years for the prostate-only group and 10.5 years for the pelvis+prostate group. 12 year survival was 43% and 38% for the two groups respectively [p not significant using the log rank test].
The SL group had greater 12-year overall survival than the LAG group (48% vs. 38%, p = 0.02, log rank test), the LAG group, however, had a greater proportion of older patients
Numeric results
-
General comments Pre PSA era study. Multivariate analysis was not done, but would have been useful for the SL vs. LAG comparison. The authors comment that the accuracy of LAG for staging is questionable, the observed survival difference may be due to this inaccuracy.
(Lawton et al. 2005)
Design Randomized controlled trial (therapy), evidence level: 1+
Country: United States, setting: Tertiary care
Inclusion criteria patients enrolled in RTOG trial 94-13 between 1995 and 1999. All men had histologically confirmed, clinically localised prostate cancer. PSA 100 ng/ml or less. Randomisation was stratified by T stage, PSA and Gleason score. Patients were required to have a predicted risk of lymph node involvement of more than 15% (using Roach’s equation derived from the Partin tables). Karnofsky performance status of 70% or more. Liver function tests less than 1.2 times the upper limits of normal.
Exclusion criteria Patients who were surgically staged. Patients with metastatic disease. Prior hormonal therapy, radiotherapy or chemotherapy.
Population number of patients = 1292.
Interventions treatment interventions included: neoadjuvant and concurrent hormonal therapy (NCHT), adjuvant hormonal therapy (AHT), whole-pelvic radiotherapy followed by a boost to the prostate (WPRT), and prostate only radiotherapy (PORT).
Patients were randomised to 1 of 4 treatment arms: WPRT + NCHT, PORT + NCHT, WPRT + AHT or PORT + AHT.
All patients received combined androgen suppression, goserelin acetate 3.6 mg subcutaneously or leuprolide acetate 7.5 mg intramuscularly (both monthly), and flutamide 250 mg orally (daily) for 4 months. Patients receiving NCHT started hormonal therapy 2 months before radiotherapy (RT), and continued it during RT. Patients receiving AHT started hormonal therapy 2 months after completing RT.
RT was given at 1.8 Gy per fraction to a total dose of 70.2 Gy. WPRT used a conventional four field technique (minimum size 16cm X 16 cm) to a maximum central dose of 50.4 Gy followed by an additional 19.8 Gy to the prostate using a cone-down boost technique. PORT was limited to the prostate and seminal vesicles (minimum size 11cm X 11 cm) to a total of 70.2 Gy.
Outcomes Primary endpoint was progression free survival. Progression (treatment failure) was defined as the first occurrence of local, regional or distant disease; PSA failure or death from any cause.
Secondary endpoints were overall survival, local failure, distant metastases and PSA failure. PSA failure was defined using the ASTRO consensus definition of consecutive and significant PSA rises separated by a month. Toxicity was recorded using the RTOG toxicity scoring scale.
Follow up Median follow up of 5.9 years since study entry.
Results Five year PFS for patients treated with WPRT+ NHT, PORT+ NHT, WPRT+ AHT and PORT+ AHT was 48.3%, 36.8%, 38.1%, and 40.4% respectively. Patients treated with WPRT+ NHT, in pair wise comparison analysis, showed better PFS than those treated with PORT+ NHT (p=0.0041) and a statistically significant improvement over WPRT+ AHT (p=0.0045). WPRT+ NHT showed a trend in progression free survival over PORT+ AHT (p= 0.0656).
Five year overall survival for patients treated with WPRT+ NHT, PORT+ NHT, WPRT+ AHT and PORT+ AHT was 81.6%, 77.8%, 75.5%, and 81.2% respectively. There was no significant difference in overall survival between the treatment arms.
(Lawton et al. 2007)
Design: Randomized controlled trial (therapy), evidence level: 1++
Country: United States, setting: Tertiary care
Inclusion criteria patients enrolled in RTOG trial 94-13 between 1995 and 1999. All men had histologically confirmed clinically localised prostate cancer. PSA 100 ng/ml or less. Randomisation was stratified by T stage, PSA and Gleason score. Patients were required to have a predicted risk of lymph node involvement of more than 15% (using Roach’s equation derived from the Partin tables). Karnofsky performance status of 70% or more. Liver function tests less than 1.2 times the upper limits of normal.
Exclusion criteria Patients staged surgically. Patients with metastatic disease. Prior hormonal therapy, radiotherapy or chemotherapy.
Population number of patients = 1292, age range 44 to 87 years, median age = 70 years.
Interventions treatment interventions included: neoadjuvant and concurrent hormone therapy (NCHT), adjuvant hormone therapy (AHT), whole-pelvic radiotherapy followed by a boost to the prostate (WPRT), and prostate only radiotherapy (PORT).
Patients were randomised to 1 of 4 treatment arms: WPRT + NCHT, PORT + NCHT, WPRT + AHT or PORT + AHT.
All patients received combined androgen suppression, goserelin acetate 3.6 mg subcutaneously or leuprolide acetate 7.5 mg intramuscularly (both monthly), and flutamide 250 mg orally (daily) for 4 months. Patients receiving NCHT started hormone therapy 2 months before radiotherapy (RT), and continued it during RT. Patients receiving AHT started hormone therapy 2 months after completing RT.
RT was given at 1.8 Gy per fraction to a total dose of 70.2 Gy. WPRT used a conventional four field technique (minimum size 16cm X 16 cm) to a maximum central dose of 50.4 Gy followed by an additional 19.8 Gy to the prostate using a cone-down boost technique. PORT was limited to the prostate and seminal vesicles (minimum size 11cm X 11 cm) to a total of 70.2 Gy.
Outcomes Primary endpoint was progression free survival. Progression (treatment failure) was defined as the first occurrence of local, regional or distant disease; PSA failure or death from any cause.
Secondary endpoints were overall survival, local failure, distant metastases and PSA failure. PSA failure was defined using the ASTRO consensus definition of consecutive and significant PSA rises separated by a month. Toxicity was recorded using the RTOG toxicity scoring scale.
Follow up Median follow-up for patients alive at analysis was 7.0 years (range 2 to 10.4 years).
Results Only toxicity of grade 3 or worse was included in the analysis.
Pairwise comparison of the 4 treatment arms suggested a trend towards improved progression free survival in the WPRT+NHT arm when compared to the WPRT+AHT (p=0.022) and PORT+NHT (p=0.066) arms, but not the PORT+AHT arm (p=0.75).
COMPARISON IN MEN AFTER EBRT FOR PCAWPRT+NHTPORT+NHTWPRT+AHTPORT+AHTOVERALL RESULT
Disease progression198/320210/316220/319199/320overall there was no significant difference (log rank test, p=0.065)
Death due to any cause104/32099/316130/319101/320survival was significantly worse in the WPRT+AHT group (log rank test, p=0.027)
Late GI toxicity5%1%2%2%more late GI toxicity with WPRT+NHT (p=0.002)
Late GU toxicitynot reportednot reportednot reportednot reportedno significant group differences (p=0.16)
Acute radiation toxicitynot reportednot reportednot reportednot reportedno significant group differences (p not reported)
Acute hormone toxicity8%5%3%3%more acute hormone toxicity with NHT (p=0.003)
General comments The study was not designed to test the interaction between field size and timing of hormone therapy, and was underpowered to detect such an interaction.
(Pilepich et al. 1987)
Design: Randomized controlled trial (therapy), evidence level: 1+
Country: United States, setting: Tertiary care
Inclusion criteria Patients with stage A2 (T1bN0M0 ) or B (T2N0M0) prostate cancer, according to Jewett-Whitmore staging (i.e. no evidence of nodal involvement by lymphangiogram or surgical staging). Patients were entered into the trial (RTOG 77-06) between 1978 and 1983. Randomization was stratified by histological grade, hormonal therapy and method of node evaluation (lymphangiogram or staging laporotomy).
Exclusion criteria Previous radiation therapy or potentially curative surgery. Other cancer (apart from skin cancer).
Population number of patients = 453.
Interventions After lymphangiogram (LAG) or staging lymphadenectomy (SL) patients were randomized between prophylactic radiation to the pelvic lymph nodes and prostatic bed vs. prostatic bed alone.
For those randomized to receive prophylactic pelvic lymph nodal irradiation, 45 Gy of megavoltage RT was delivered via multiple portals in 4.5 to 5 weeks, while all patients received a minimum 65 Gy (maximum 72 Gy) in 6.5 to 8 weeks to the prostatic bed.
Outcomes Treatment related morbidity. Morbidity was classified using a grading system (RTOG scale?), ranging from grade 1 (minor symptoms requiring no treatment) to grade 5 (fatal complications). Treatment related reactions occurring during the radiotherapy course were not labelled as complications unless they persisted beyond the first month after treatment completion or were classified as grade 3 or higher.
Follow up The minimum follow up was 2 years, median was 5 years.
Results Pelvic irradiation (WPRT), compared to prostate irradiation only, (PORT) was not associated with a significantly increased incidence of treatment related morbidity. Bowel morbidity rates (any grade, WPRT vs. PORT) : diarrhoea (14% vs. 9%), proctitis (10% vs. 11%), rectal/anal stricture (5% vs. 1%), rectal bleeding (10% vs. 13%) and rectal ulcer (2% vs. 0%).
Genitourinary morbidity rates (any grade, WPRT vs. PORT) : cystitis (11% vs. 12%), haematuria (6% vs. 11%), and urethral stricture (7% vs. 7%).
In general a significant effect of prostate radiation dose on morbidity was not observed. Total doses to the prostate of more than 70 Gy, however, were associated with an increased risk of rectal bleeding (p<0.01, Mantel-Haenszel test stratified by grade).
Numeric results
Comparison: Whole pelvic radiotherapy plus prostate boost versus prostate-only radiotherapy
WPRTPORT
GI toxicity (grade 3 or higher)13/2244/228
WPRTPORT
GU toxicity (grade 3 or higher)20/22423/228
(Roach, III et al. 2003c)
Design: Randomized controlled trial (therapy), evidence level: 1+
Country: United Kingdom, setting: Tertiary care
Inclusion criteria Patients enrolled in RTOG trial 94-13 between 1995 and 1999. All men had histologically confirmed, clinically localised prostate cancer. PSA 100 ng/ml or less. Randomisation was stratified by T stage, PSA and Gleason score. Patients were required to have a predicted risk of lymph node involvement of more than 15% (using Roach’s equation derived from the Partin tables). Karnofsky performance status of 70% or more. Liver function tests less than 1.2 times the upper limits of normal.
Exclusion criteria Patients who were surgically staged. Patients with metastatic disease. Prior hormonal therapy, radiotherapy or chemotherapy. Liver function tests 1.2 times the upper limits of normal.
Population number of patients = 1292, median age = 70 years.
Interventions Treatment interventions included: neoadjuvant and concurrent hormonal therapy (NCHT), adjuvant hormonal therapy (AHT), whole-pelvic radiotherapy followed by a boost to the prostate (WPRT), and prostate only radiotherapy (PORT).
Patients were randomised to 1 of 4 treatment arms: WPRT + NCHT, PORT + NCHT, WPRT + AHT or PORT + AHT.
All patients received combined androgen suppression, goserelin acetate 3.6 mg subcutaneously or leuprolide acetate 7.5 mg intramuscularly (both monthly), and flutamide 250 mg orally (daily) for 4 months. Patients receiving NCHT started hormonal therapy 2 months before radiotherapy (RT), and continued it during RT. Patients receiving AHT started hormonal therapy 2 months after completing RT.
RT was given at 1.8 Gy per fraction to a total dose of 70.2 Gy. WPRT used a conventional four field technique (minimum size 16cm X 16 cm) to a maximum central dose of 50.4 Gy followed by an additional 19.8 Gy to the prostate using a cone-down boost technique. PORT was limited to the prostate and seminal vesicles (minimum size 11cm X 11 cm) to a total of 70.2 Gy.
Outcomes Primary endpoint was progression free survival. Progression (treatment failure) was defined as the first occurrence of local, regional or distant disease; PSA failure or death from any cause.
Secondary endpoints were overall survival, local failure, distant metastases and PSA failure. PSA failure was defined using the ASTRO consensus definition of consecutive and significant PSA rises separated by a month. Toxicity was recorded using the RTOG toxicity scoring scale.
Follow up Median follow up was 5 years
Results WPRT was associated with a 4-year PFS of 54% compared with 47% in patients treated with PORT (p =0.02). Patients treated with NCHT experienced a 4-year PFS of 52% versus 49% for AHT (p =0.56). When comparing all four arms, there was a progression-free difference among WPRT + NCHT, PORT + NCHT, WPRT + AHT, and PORT + AHT (60% vs. 44% vs. 49% vs. 50%, respectively; p =.008).
There was no grade 5 (fatal) toxicity. The 2 year rates of late grade 3 or 4 gastrointestinal toxicity were 1.7% and 0.6% the WPRT and PORT arms respectively (p=0.09). The corresponding rate of genitourinary toxicity was 2% in both groups (p=0.85).
For acute grade 3 or 4 toxicity: there was a tendency towards more GI toxicity with WPRT than PORT (2% vs. 1%, p=0.06), but not much difference in GU toxicity (3% vs. 4%. p=0.39).
(Pommier et al. 2005)
Design: Randomized controlled trial (therapy), evidence level: 1−
Country: France, setting: Tertiary care
Inclusion criteria Histologically proven PCa, clinical stage T1b, N0, and M0 to T3, N0, and M0. No metastases by bone scan or chest x-ray. At least one month since prior transurethral resection. At least 2 to 6 months since prior hormonal therapy. Age 75 or younger. Life expectancy of 10 years or more. Karnofsky performance status of 70 or more. Randomisation was stratified into high and low risk groups, using Gleason score, clinical stage and PSA level.
Exclusion criteria Concurrent LHRH agonists, anti-androgen or hormonal therapy (short term (6 months) concurrent or neoadjuvant hormonal therapy was allowed for high risk patients). Prior pelvic radiotherapy. Prior lymphadenectomy, prostatectomy or surgical castration. Other malignancy (except basal cell carcinoma). Adenopathy.
Population number of patients = 444, age range 50 to 75 years, median age = 70 years.
Interventions One arm (group A) of the trial received pelvis and prostate radiotherapy (RT), the other arm (group B) received prostate-only radiotherapy.
The median pelvis RT dose was 46 Gy in group A. The total dose recommended to the prostate changed from 66 Gy (first 3 years) to 70 Gy. The median dose to the prostate was 68.4 Gy in both groups.
Outcomes Study was planned with 5 year progression free survival (PFS) as the primary endpoint. Progression was defined as PSA recurrence (RTOG criteria) or clinical evidence of local or distant recurrence. Acute and late toxicities were recorded according to the RTOG and LENT-SOMA scales. Quality of life was recorded using the EORTC QLQ-C30, IPSS and SFI scales.
Follow up Median follow up for this preliminary report is 3.3 years.
Results Progression rates were 18% in group A and 17% in group B. Using the Kaplan-Meier method, 5-year PFS was 67.8% [95%CI, 59.5–76.2] and 63.6% [95%CI, 54.2–72.9] in groups A and B respectively.
Acute toxicity (grade 3 or 4) rates were 1.8% and 2.4% for the digestive tract in groups A and B respectively (p=0.70). For the urinary tract the corresponding rates were 3.2% and 8.1% (p=0.02).
Late toxicity (grade 2,3 or 4) rates were 27.8% and 24.6% for the digestive tract in groups A and B respectively (p=0.50). For the urinary tract the corresponding rates were 36.6% and 41.2% (p=0.30).
The authors report that there was no significant change in quality of life 1 year after treatment in either group.
General comments This preliminary analysis reports progression free survival at a median follow up of 3.3 years, too early to comment on the primary endpoint of progression free survival. The number of patients in each treatment arm is not reported, cannot use this study for meta-analysis.

Health Economic Summary

The Guideline Development Group did not rate this topic as a health economic priority, therefore no attempt has been made to review or summarise the relevant cost-effectiveness literature.

Reference List

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  2. Lawton CA, DeSilvio M, Roach IM, Uhl V, Krisch EB, Seider MJ, Rotman M, Jones C, Asbell SO, Valicenti RK, Han BH, Thomas CR Jr. An Update of the Phase III Trial Comparing Whole-Pelvic (WP) to Prostate Only (PO) Radiotherapy and Neoadjuvant to Adjuvant Total Androgen Suppression (TAS): Updated Analysis of RTOG 94-13. 47th Annual ASTRO Meeting. International Journal of Radiation Oncology, Biology, Physics. 2005;63(Supplement 1):S19.
  3. Lawton CA, DeSilvio M, Roach M, Uhl V, Kirsch R, Seider M, Rotman M, Jones C, Asbell S, Valicenti R, Hahn S, Thomas CR. An Update of the Phase III Trial Comparing Whole Pelvic to Prostate Only Radiotherapy and Neoadjuvant to Adjuvant Total Androgen Suppression: Updated Analysis of RTOG 94-13, with Emphasis on Unexpected Hormone/Radiation Interactions. Int J RadiatOncol BiolPhys. 2007 [PMC free article: PMC2917177] [PubMed: 17531401]
  4. Pilepich MV, Asbell SO, Krall JM, Baerwald WH, Sause WT, Rubin P, Emami BN, Pidcock GM. Correlation of radiotherapeutic parameters and treatment related morbidity--analysis of RTOG Study 77-06. International Journal of Radiation Oncology, Biology, Physics. 1987;13:1007–1012. [PubMed: 3597142]
  5. Pommier P, Perol D, Lagrange J, Richaud P, Brune D, Le Prise E, Azria D, Beckendorf V, Martin E, Chabaud S, Carrie1 C. Does Pelvis and Prostate Radiation Therapy Compared to Prostate Radiation Therapy Alone Improve Survival in Patients with Non Metastatic Prostate Carcinoma? Preliminary Results of the Prospective Randomized GETUG 01 Trial. International Journal of Radiation Oncology, Biology, Physics. 2005;63(Supplement 1):S19. Ref Type: Abstract.
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