Treatment modalities in localised prostate cancer

It is clear that prostate cancer is an important neoplastic disease for the NHS to manage. It has been well studied that prostate cancer will affect almost all males if they live for a sufficient duration, which is an important consideration in line with the demographic changes occurring within the developed world. In the second of a two-part series, this article looks at treatment options.

The second part of this two part series will focus upon reviewing the current evidence base for recommended treatment modalities for patients with a confirmed diagnosis of prostatic carcinoma, a common tumour in males in the UK. Part one published last month looked at the general background of this neoplastic disease including epidemiology, the controversy of screening for prostate cancer, usual clinical presentation and how a diagnosis is confirmed.

Localised prostate cancer

Localised prostate cancer refers to cancer that is only located within the prostate gland. Unlike many other forms of cancer, prostate cancer has an indolent course in many patients. This has been highlighted by a recent paper that reviewed patients with prostate cancer with a Gleason score of 6. The paper found that long-term 15-year prostate cancer mortality outcomes of watchful waiting was less than the mortality rates for other causes of death.¹ Treating localised prostate cancer is difficult as a result of the uncertain course of the disease and multiple treatment options. Patients have a prostate cancer risk calculated based upon either a PSA score, Gleason score or clinical TNM stage score.

The clinical guideline on prostate cancer recommends five treatment/management options be considered by clinicians for patients with localised prostate cancer, which will be outlined individually. It should be noted that NICE^2,3 concluded, after reviewing the evidence, that patients with local disease should not be treated with cryotherapy or high-intensity focused ultrasound unless part of a randomised controlled trial alongside standard interventions.

Research into these treatments is required to assess efficacy and cost-effectiveness. Firstly, watchful waiting is defined as a conscious decision by a medical management team to avoid active treatment of a condition. Treatment is only commenced if severe and unpleasant symptoms of progressive disease develop. In the context of prostate cancer this generally refers to men who have multiple health conditions and/or a low chance that the cancer will progress significantly in the patients’ lifespan.

This method aims to avoid patients being exposed to side effect(s) of treatment and multiple hospital appointments without any major benefit. This option is of great importance when considering patient-centred care. If patients do develop distressing symptoms due to disease progression (generally urinary symptoms), these patients are managed with hormonal therapy (excluding orchidectomy) that are outlined in Box 1.

Secondly, clinicians may offer active surveillance to younger and/or fitter gentlemen where radical treatment options would be considered. The concept is to delay treatment until there are early signs of progression. Martin et al4 showed that active surveillance achieves the best results when protocols include a three to six monthly PSA level and an annual transrectal ultrasound biopsy. The results of these investigations help stratify patients into low, intermediate and high risk groups. Patients deemed to be at high risk should receive radical treatment, while patients at intermediate risk should only be considered for radical treatment within the context of patient symptoms.^3,5 There are a number of treatment options open to patients.⁵

Currently, there is no strong evidence that one treatment is vastly superior to another.^3,5 Doctors should offer either radical prostatectomy or conformal (external beam) radiotherapy to treat some patients with intermediate and all patients with high risk prostate cancer.4 Brachytherapy is only recommended for intermediate risk cancer and such patients should be reviewed for the presence of lower urinary tract symptoms (LUTS) as significant LUTS is a contraindication to brachytherapy. Importantly, patients receiving these treatments (for both local or locally aggressive disease) should have two to three months of hormonal therapy to debulk the tumour prior to aggressive treatment options (neoadjuvant treatment) .

Crucially , neoadjuvant treatment has been associated with improved disease-free and overall survival rates.^3,5,6 External beam radiotherapy is the most commonly used treatment for patients with localised prostate cancer, with out-patient daily dosing treatment taking between four to 12 weeks.⁶ A systematic review by Nilsson et al7 concluded that radiotherapy is an effective treatment method for prostate cancer for intermediate and high risk groups, especially when combined with endocrine treatments.

Radical prostatectomy is a significant surgical procedure with the potential to cause incontinence and erectile dysfunction. Therefore, full assessment of patient comorbidity is an essential part of the decision-making process. Bill- Axelson et al⁸ demonstrated that the surgical procedure provides improved outcomes and reduced symptoms for patients compared to watchful waiting. Importantly, recent research has shown that laparoscopic surgery may reduce hospital in-patient stay and reduce blood loss compared to the traditional retropubic and perineal approaches.^9,10

Brachytherapy is a radioactive therapy delivered by radioactive molecules at a low dose rate (radioactive seed insertion into prostate) or high dose rate (radioactive wires are temporarily inserted into the prostate). There is currently limited evidence for the use of brachytherapy with no randomised controlled trials being found after a PubMed search (keyword: brachytherapy). However, systematic reviews for low and intermediate risk patients conclude that PSA free survival after treatment is similar to that with the other treatment methods.^4,11 Currently, evidence is lacking for the long-term outcomes for patients treated with brachytherapy deemed as high risk prior to treatment. Furthermore, evidence reviewed in the NICE clinical guidelines⁵ found that while the side effect profile of treatments differed, the actual presence of adverse affects post-treatment were comparable.

Locally advanced prostate cancer

There is not an internationally agreed definition for localised advanced prostate cancer. Clinicians often refer to cancer that is located within the prostate gland and has also spread to local organs and tissues including the bladder and rectum. These patients have a high risk of having pelvic lymph node involvement.⁶ Importantly, the most recent NICE guideline has changed previous guidance about bisphosphonates from following a trial by Mason et al.¹²

The NICE guideline now does not recommend prescribing bisphosphonates for bone protection in the context of hormonal manipulation. NICE has also concluded that clinicians should make a decision between either radical prostatectomy or radiotherapy as there is no evidence for improved survival rates for patients receiving post-prostatectomy radiotherapy. Patients who opt for radiotherapy may also be offered pelvic radiotherapy in certain circumstances.

Pelvic radiotherapy has a number of side effects (burns, damage to pelvic organs) and requires multiple out-patient appointments. Therefore, pelvic irradiation should only be considered if the patient has a >15% risk of pelvic lymph node involvement and is on systemic hormonal therapy. Neoadjuvant treatment has been outlined in the previous section. It is crucial to ensure that patients are treated for three to six months prior to radical therapy to debulk the tumour. Adjuvant therapy is currently being reviewed for patients with advanced localised disease.
The benefits of adjuvant therapy are currently unclear after a Cochrane review concluded that randomised controlled trials in the field showed evidence of significant toxicity.¹³ Toxicity and adverse drug reactions included sexual dysfunction, headaches, weight gain and hot flushes.¹³ In contrast, more recent work by Bastide et al14 showed that adjuvant therapy improved survival in patients with prostate cancer with seminal vesicle invasion. Current guidelines only advocate adjuvant therapy of two-year duration if the patient has a Gleason score of ≥8. NICE (2008) has stated it will review this area when it next updates the guideline to assess if all patients should be recommended hormone treatment.

Metastatic prostate cancer

Metastatic prostate cancer refers to cancer that has spread outside the prostate gland and pelvic lymph nodes.6 Hormonal therapy provides the backbone for managing metastatic disease2,4 and the majority of patients respond well.3 First-line hormonal treatment is androgen withdrawal. The efficacy of surgical and drug castration and subsequent androgen withdrawal is similar.¹⁵ The patient should choose the method of androgen withdrawal, after a discussion about the pros and cons to each option with their doctor (reversibility, side effects). An anti-androgen (bicalutamide) can be added if resistance develops. Importantly, patients should not be offered androgen withdrawal and antiandrogen therapy as first-line because there is only a modest benefit to survival and significant costs.6 Finally, current hormonal therapy is continuous although some researchers have suggested that intermittent androgen withdrawal treatment may lead to reduced side effects for patients and similar survival benefits.⁵

Therefore, NICE (2008) has commissioned research looking into this area. Chemotherapy and steroids may be used in some patients as over time some patients may develop hormonal-refractory disease. In these patients dexamethasone can be trialled that works by suppressing adrenal androgens.6 Steroids may be considered for earlier use if the patient has bone pain related to metastasis to help with the inflammatory component. NICE (2008) advocate the use of docetaxal (chemotherapy) in combination with a steroid (generally prednisolone) for patients with hormone-refractory metastatic disease with 60%+ Karnofsky performance status.

A meta-analysis of over 2000 patients showed improved survival and outcomes for male patients with 50%+ Karnofsky performance status.16 Patients with late stage disease should be managed in both primary and secondary care. Patients should be subject to regular GP review to assess their general well-being and treat symptoms associated with metastatic disease such as cachexia, malaise and pain. In addition, GPs should examine patients for signs of obstructive uropathy, bowel obstruction or haematuria.

Palliative care principles

The vast majority of patients with prostate cancer are over 50 years old and subsequently may have comorbid disease(s). The age of this patient cohort is a major factor in the mortality rates associated with the cancer as treatment options may not be appropriate for an individual within the general medical context of the patient. Therefore, clinicians working with these patients must be aware of key principles in palliative care. Palliative care is the total care of patients with active progressive, advanced disease for whom prognosis is limited. In these patients the aims of care shift from aggressive curative treatment, to attempt to achieve a quality of life chosen by the patient within the limitation of their disease.¹⁷

Palliative care attempts to allow a patient achieve a “good death” in which the patient has control, autonomy and independence in the decision making and medical management.18 The aim of the whole process is to avoid a soulless death and support the patient through the process medically and physiologically.18 Clinicians aiming to practice palliative care should actively treat troublesome patient symptoms (eg. pain or urinary symptoms) and discuss a care plan and patient wishes with the patient and, if appropriate, their family.

Conclusion

It is clear that prostate cancer is an important neoplastic disease for the NHS to manage. It has been well studied that prostate cancer will affect almost all males if they live for a sufficient duration, which is an important consideration in line with the demographic changes occurring within the developed world. Therefore, clinicians and nurses both require a comprehensive understanding of the background to prostate cancer, some of the controversy surrounding screening tools currently used and the major treatment options for the benefit of their patients. This paper has attempted to achieve the above objectives.

In conclusion, although reductions in mortality and morbidity have occurred secondary to major advances in the treatment of prostate cancer, research into this field is still as important as ever. Prostate cancer still was the primary cause of death for over 10,000 men in 2008 in Britain and thus we should strive to improve the availability and efficacy of treatments for the adult male population.

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Lloyd Hughes, Senior Medical Student, University of Dundee Medical School

Email: [email protected]

Conflict of interest: none declared

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References

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12. Mason MD, Sydes M, Glaholm J, et al. Medical Research Council, P. R. (2007) 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: 765–76

13. Kumar S, Shelley M, Harrison C, et al. Neo-adjuvant and adjuvant hormone therapy for localized prostate cancer [protocol for a Cochrane review]. Cochrane Database of Systematic Reviews 2006 Issue 2 Chichester (UK): John Wiley & Sons, Ltd, 2006

14. Bastide C, Rossi D, Lechevallier E, et al. Seminal vesicle invasion: what is the best adjuvant treatment after radical prostatectomy? BJU Int. 2011 Aug 18. [Epub ahead of print] doi: 10.1111/j.1464- 410X.2011.10332.x

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