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Treatment

Chapter 15 - Prostate Cancer

Curative treatments for localised, good and intermediate prognostic groups are radical prostatectomy, conformal radiotherapy and, in some cases, brachytherapy. In patients of the good prognostic group, active surveillance is a treatment option with curative intent. Sometimes a “Watchful Waiting policy” is proposed without a curative intent.

Patients with poor prognostic characteristics are likely to receive external radiotherapy with androgen deprivation therapy (ADT) or even palliative treatment with transurethral resection (TUR) and ADT.

Metastatic disease is treated first by ADT, but all tumours progress to castration-resistant prostate cancer (CRPC).

Several trials have shown a benefit of adding docetaxel to ADT upfront in patients with metastatic disease, especially those with high-volume disease. The European Society for Medical Oncology (ESMO) recommends ADT plus docetaxel as first-line treatment of metastatic, hormone-naïve disease in men fit enough for chemotherapy.

There are now several options for mCRPC. Abiraterone acetate, enzalutamide and docetaxel can be offered as first line treatment. The choice of treatment depends on the presence of symptoms or not, the presence of visceral metastases or not, the rapidity of progression, patients’ comorbidities and patients’ preference.

Radium 223 can be used in patients with metastatic CRPC with symptomatic bone metastases without visceral disease: it can decrease pain and analgesic consumption.

Standard approved treatments when progression is observed while on or after docetaxel chemotherapy are cabazitaxel, enzalutamide and abiraterone acetate. Palliative symptomatic treatments are also useful.

There are no prospective studies aimed at establishing standard treatment in senior adult prostate cancer patients. However, multivariate analysis of prognostic factors in clinical trials which established the activity of the different drugs in metastatic CRPC (mCRPC) has demonstrated that age was not an adverse Prognostic factor for response to treatment. Retrospective studies have been performed in the setting of both localised and metastatic disease. The SIOG Prostate Cancer Task Force has published recommendations for the management of senior adult prostate cancer patients (Droz JP et al. 2010, and updated Droz JP et al. 2014) (Figure below). These are used as a basis for the following recommendations for patient management. Updated guidelines are scheduled in 2016.

Principles of the decision tree (International Society of Geriatric Oncology Prostate Cancer Task Force)

Reprinted from Droz JP, Aapro M, Balducci L, et al. Management of prostate cancer in senior adults: updated recommendations of a working group of the International Society of Geriatric Oncology (SIOG). Lancet Oncol 2014:15:e404-e414. doi: 10.1016/S1470-2045(14)70018-X Copyright (2014), with permission from Elsevier

Treatment of Localised Prostate Cancer in Senior Adult Patients

Evidence suggests that only a minority of senior adults with localised prostate cancer receive curative therapy. The 2014 SIOG and EAU guidelines recommend that “Older men with prostate cancer should be managed according to their individual health status, which will be directed mainly by the needs of any associated comorbidities and not according to chronological age.” Panel members did not select a specific chronological cut-off point for treatment recommendations.

Alibhai and colleagues have evaluated treatment efficacy in men aged > 65 years with localised prostate cancer by using a decision model that integrates patient’s age, comorbidity, Gleason score, patient’s preference, and treatment efficacy data (from three complementary data sources including modern radiotherapy results). Their results show that prostatectomy and radiotherapy significantly improve life expectancy and quality-adjusted life expectancy in older men with little comorbidity and moderately or poorly differentiated localised prostate cancer. As healthy men in their 70s or 80s with localised prostate cancer are often managed conservatively, they conclude that “curative therapy should be seriously considered in men up to age 80 years who have high-grade disease.”

Retrospective and cohort studies have demonstrated that the presence of comorbidities in patients receiving a prostatectomy significantly and independently increases the risks of 30-day postoperative complications, long-term incontinence, and overall and non-prostate cancer death. However, the risk of incontinence is known to increase proportionally with age. It is therefore recommended to limit the indication of prostatectomy to patients younger than 75 years.

Several studies have reported that senior adult patients undergoing radiotherapy can achieve outcomes in terms of cancer control and treatment-related late comorbidity similar to those achieved by younger patients. A population-based study of non-metastatic prostate cancer patients aged 65 to 85 years treated with radiotherapy has shown improved long-term survival rates for patients with locally advanced stage receiving adjuvant ADT, but no survival advantage for men with low-risk disease. These findings are consistent with practice guidelines. However, the survival advantage achieved by combining radiotherapy and ADT in high-risk prostate cancer patients may apply only to those with no or minimal comorbidities (i.e. fit patients).

Brachytherapy is indicated in patients with low-risk prostate cancer. This technique does not appear to be a suitable treatment choice for older prostate cancer patients because its clinical benefit is not established.

Older prostate cancer patients with low-risk disease are more likely to be eligible for a “Watchful Waiting policy” or active surveillance (i.e. delayed curative intervention on progression).

The SIOG Task Force conclusion was as follows:

  • A two-step decision making is performed:
    • 1-  Systematic use of the G8 health status screening tool.
    • 2- If G8 ≤ 14 assessment of comorbidities (Cumulative Illness Score Rating-Geriatrics [CISR-G] scale), dependence status (Instrumental Activities of Daily Living [IADL] and Activities of Daily Living [ADL] scales), nutritional status (weight loss estimation), and screening for neuropsychological problems should be made, as well evaluation of the reversibility of health impairment.
  • Patients can be classified into three health status categories (fit, vulnerable, and frail):
    • Healthy or fit patients are those with a G8 score of more than 14: they are expected to tolerate any form of standard cancer treatment.
    • Vulnerable patients are those with a G8 score of 14 or lower, and should be considered for further geriatric intervention (reversibility of their health impairment) and standard cancer treatment.
    • Frail patients with irreversible health impairment should receive both geriatric intervention and adapted cancer treatment.
  • “Fit” and “vulnerable” senior adults in the “high-risk” group of the D’Amico risk classification, with a chance of surviving >10 years, are likely to benefit from curative treatment.
  • Senior adults in the “low-risk” and “intermediate-risk” groups of the D’Amico risk classification are likely to benefit from active surveillance. There are only a few indications of minimally invasive therapy in these patients.

Treatment of Metastatic Prostate Cancer in Senior Adult patients

Castration-sensitive disease
ADT is the standard treatment for patients with metastatic prostate cancer.

It delays progression, prevents potentially catastrophic complications, and effectively palliates symptoms. Surgical castration and castration by luteinizing hormone–releasing hormone agonists and antagonists are the standard of care.

Adding docetaxel to ADT is recommended in patients, who are fit enough, as first-line treatment of metastatic, hormone-naïve disease. In the CHAARTED trial, the benefit was seen irrespective of age.

ADT is associated with a significant number of side effects, including osteopaenia with increased risk of fractures, and metabolic alterations with increased risk of cardiovascular events.

Bone mass decreases with age, and men > 75 years of age are at particularly high risk of developing fractures. The National Comprehensive Cancer Network (NCCN) recommendations and ESMO guidelines state that men receiving or starting ADT should be evaluated for their risk of osteoporosis.

  • All men receiving ADT should receive calcium and vitamin D supplementation, and baseline bone mineral density should be determined.
  • The routine use of bone targeted therapies in patients undergoing ADT is not recommended unless there is documented evidence of the presence or a risk of osteoporosis or CRPC with skeletal metastases.

Castration-resistant disease
There are no prospective studies aimed at establishing standard treatment in senior adult mCRPC patients. However multivariate analysis of prognostic factors in clinical trials which established the activity of the different drugs in mCRPC has demonstrated that age was not an adverse prognostic factor of response to treatment.

The standard procedure for second-line hormonal treatment is as follows:

  • Cessation of anti-androgen if complete androgen blockade was given as first-line treatment. The addition of an anti- androgen when ADT was used as monotherapy in the first-line setting has no proven survival impact.
  • Abiraterone acetate is registered in this indication (in patients without visceral metastases and non- or mildly symptomatic patients). Enzalutamide is also approved in this indication. It was studied in patients with or without visceral metastases and non- or mildly symptomatic patients.
  • Docetaxel is a chemotherapy treatment that has demonstrated a survival benefit in patients with mCRPC. The tolerability of the 3-weekly docetaxel regimen has not been specifically studied in frail senior adults. The place of weekly and 2-weekly docetaxel in mCRPC should be considered in frail patients.
  • New chemotherapy (cabazitaxel) and hormonal agents (abiraterone acetate and ezalutamide) are now available for second-line therapy of mCRPC, but careful monitoring is needed in older patients. The order in which these therapies should be given is a topic for further research.
  • Palliative symptomatic treatments are useful and include radiotherapy, radiopharmaceuticals, bone-targeted therapies, surgery, and medical treatments for pain and symptoms.

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