New Treatments for Prostate Cancer-How Do I Choose?

The many new treatments now available for localised prostate cancer make it more difficult to choose which is the best treatment. Options include radical prostatectomy in all its various forms, including nerve-sparing, non-nerve-sparing and non-nerve-sparing with sural nerve graft and robotic assisted laparoscopic surgery. It also includes conformal external beam radiotherapy, brachytherapy with seeds, high dose rate brachytherapy through wires, high intensity focused ultrasound, active surveillance (watchful waiting) and hormone therapy.With every individual it is important to discuss all these options, including their cure rates, the side-effects of each treatment, the institution and surgeon’s particular expertise and the individual factors that may influence the choice of therapy

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NEW OPTIONS(1) SurgeryThe newer forms of therapy for surgery include careful nerve-sparing prostate cancer surgery, robotic and laparoscopic surgery and sural nerve grafting. Nerve- sparing surgery aims to protect the erection nerves, minimising the side-effects of surgery. What is most critical is that one selects the right cancer to perform this surgery on, otherwise one will tend to leave cancer behind. This tends to occur if the cancer has eaten into the nerve tissue. Certain factors relating to the tumour give one an indication as to whether it is suitable or not suitable for nerve-sparing surgery. These factors are: the clinical stage, the number of biopsies positive on that side and the presence or absence of perineural invasion. The technique of nerve-sparing surgery has increasingly become more and more refined and an experienced nerve-sparing surgeon can, more confidently now, say that one can preserve nerves in patients with the right type of tumour. Potency rates, now as high as 80% or 90%, can be achieved in young patients who are potent and have very early stage tumours having nerve sparing surgery.Robotic-assisted surgery and laparoscopic surgery achieve the same as open surgery, with smaller incisions. By having smaller incisions, this increases the speed of recovery and return to working activities, compared to most series where open surgery is performed. The robotic-assisted surgery in particular, gives excellent magnification and dexterity, although one does loose the ability to feel and touch the tissues. In very experienced robotic units, the more important measures of outcome include cancer cure (negative margins) urinary control (continence) and return of erections (potency) appear to be equal to the best open surgical units in the world, but only after considerable experience. Certain factors make robotic surgery more difficult, e.g. very large prostate, middle lobes of prostate, extreme obesity, advanced cancers which need wide lymph node dissection and extensive cancer at the base of the prostate. Extensive abdominal adhesions from previous surgery may also make this surgery more difficult. Robotic and laparoscopic surgery would appear to be a good option in those patients wishing to speed up their post-operative recovery, minimise blood loss but patients should understand that this is relatively new technology and, as with any new technology, experience is required to gain the excellent outcomes of a very experienced surgeon with a track record low positive margins, high continence results and high potency results. Many of the patients after robotic radical prostatectomy can go home in 48 hours and get back to work in two weeks.Sural nerve grafts have now been used for almost five years, in very selected cases. In some more extensive cancers, to ensure that the cancer is completely removed, it is safer to remove a nerve on one side than it is to preserve it. In these patients a nerve from the leg (the sural nerve) can be used to bridge the gap. Although initial results were very encouraging, more recent results are not as encouraging as we originally thought. Dr Peter Scardino, one of the pioneers of this technique, who has done the most cases, is slightly less enthusiastic than he originally was. A recent development has made this technique a little less attractive as it is now known that not all of the nerves have to be removed to clear the cancer, even when cancer is outside of the shell of the prostate, this leaves one with the opportunity to remove the cancer, yet still preserve the vast majority of the nerve, minimising the need for any grafting. Only certain people would be suitable for a sural nerve graft; these are younger patients who are potent and who require one of their nerves to be removed to ensure a high likelihood of clearing the cancer. As the results are less than encouraging, they must accept a relatively experimental procedure, which has never been properly trialled, and also accept the possibility of some side effects from the site of the grafting of the nerve (the leg).(2) BrachytherapyBrachytherapy using radioactive seeds is a therapy which is an option for patients with localised and early, low-grade prostate cancer. It is only suitable for those with very early stage and Gleason scores less than 7 and a PSA less than 10. The rapid strand system, where the seeds are linked together, can help place seeds on the outside edge of the prostate to ensure the tumour is covered. The technique to do this involves making a volume assessment of the prostate, constructing a template and preparing a plan to place the seeds correctly. Ultimately the procedure places the radioactive seeds in the predetermined position. This therapy, in its modern mode, has now been around for twenty years and in Australia for ten years. This therapy gives an excellent outcome if one chooses the right tumour and particularly if patients with severe urinary obstruction are excluded. Recent information suggests that patients even with PSAs up to 15 can be included and a limited number of patients with Gleason 3+4=7 can be included. Sexual side-effects are the least in this group. Prostates larger than 40cc are unsuitable, in general. It tends to be used more in a slightly older age group (over 60) as results have not been going as long as surgical results.High dose rate brachytherapy is a more invasive new treatment where very high doses of radiotherapy can be placed accurately into the prostate by wires. This therapy is always combined with external beam radiotherapy and is appropriate for more advanced cancers where the PSA is greater than 10, the Gleason score is greater than 7 and the clinical stage is greater than, or equal to, T2B. These cancers, generally, are more difficult to cure with surgery and high dose rate brachytherapy may be more appropriate. It is particularly useful where there is extensive cancer at the apex or where local conditions, e.g. severe obesity, make surgery impossible. As will all radiotherapy procedures, this tends to be used more in the over 60 year old age group as treatment options are limited if this therapy fails, whereas the reverse is not true with surgery. Furthermore, all radiotherapy procedures have a small risk of increasing second malignancies in adjacent organs after 15 – 20 years.(3) HIFU (High Intensity Focused Ultrasound)HIFU is an emerging new therapy which uses intense heat applied through the rectum to destroy the prostate and the contained prostate cancer. Two devices are currently available: the Ablatherm and the Sonoblate, but most published results have used the more established ablatherm machine. It is generally suitable for patients with tumours which are not too extensive, where the PSA is <20 and they are clinically contained. Follow-up is very limited at this stage, to only five years and therefore it tends to be used on older patients, generally over 65 years of age. It is unknown whether surgery can follow this therapy, but radiotherapy certainly can follow this treatment. The treatment itself is repeatable. Side-effects do occur in the first three months, including prolonged retention and infection. However, long-term side-effects are low, although impotence rates are still relatively high, depending on the extent of the treatment. It is unsuitable for patients who have very large prostates or lots of calcification in their prostate. It is extremely useful in the older patient who is unsuitable for surgery or radiotherapy or who refuses surgery or radiotherapy and particularly suits a patient who has had a previous TURP. Furthermore, it is one of the only therapies that can be used after radiotherapy has failed. It is therefore one of the new, emerging, minimally invasive treatments, albeit with short follow-up, which can treat lower risk tumour in older patients who are unsuitable for or refuse surgery or radiotherapeutic options.(4) Active surveillanceAn increasing number of patients with Gleason 6 tumours, especially in the older age group are having their tumours monitored. It has been shown that may tumours that are Gleason 6, do not require treatment and patients die with their tumour, rather than of their tumour. These tumours can be safely watched, using six-monthly PSAs and yearly or second-yearly biopsies, to ensure that they do not progress. Even younger patients, with low-risk tumours, e.g. these are initially monitoring their tumour due to personal circumstances or with the understanding that not all these tumours need to be treated.(5) Conformal radiotherapyWith increasing experience, radiotherapy can be focused on the prostate more accurately. This requires experienced units in this technique. Even newer technology of conformal radiotherapy are emerging internationally using a technique called a Cyber-knife or tomography. These are not yet available in Australia but have the promise of being able to deliver very accurate radiotherapy and minimising side-effects. Conformal radiotherapy allows one to deliver very high doses of radiotherapy which is necessary to eradicate tumours were PSA’s are higher than 10 with minimal side-effects which can decrease the side-effects to the bowel. As with all radiotherapy procedures, they tend to be used in the 60 year old age group as treatment options are limited if it fails.(6) Other treatment Hormone therapy or cryotherapy are other options. Cryotherapy has generally not taken off in this country. Results are very inconsistent and side-effect profile can be high in inexperienced hands. Hormone therapy is often used in older patients, perhaps over 75, where life-expectancy is limited. Hormone therapy is generally reserved for more advanced and incurable cancer.CURE RATESSpecial tables or nomograms (known as Kattan Tables) have now been developed which help predict the likely cure rates of many of these different therapies. More information on these tables can be found at www.nomograms@mskcc.org. Individual institutions maintaining results should also give results to patients.SIDE EFFECTSRadical prostatectomy side effects have considerably improved over the last ten years. Incontinence is down to very low figures (about 2%) and erectile dysfunction is much less common in selected patients. Nerve sparing techniques in very experienced hands can now give more rapid return of erections and a higher chance of recovery particularly in younger patients. Early post-operative use of medications and/or injection appears to speed up the recovery of erections. Erections can however take up to 12 to 18 months to return. Erection recovery after robotic surgery appears to be similar to open surgery but only after considerable experience in the robotic technique. Brachytherapy side effects are mainly urinary frequency and urgency. Patients who have a very large prostate or a lot of urinary symptoms before brachytherapy are more likely to suffer a complete urinary blockage (retention). Brachytherapy using seeds appears to have the lowest side-effects on sexual function. High Intensity Focused Ultrasound initially causes difficulty in passing urine with frequency and burning and some risk of infection and temporary incontinence but by three months, most of these symptoms have disappeared. Sexual side-effects depend on the extent of the treatment and can vary from 20-80%.Hormone therapy side effects include hot flushes, mood swings, decreased libido, decreased erections, weight gain, lethargy, breast tenderness, and bone loss. All these can be addressed if they become a problem. In particular bone loss can now be prevented by the use of bisphosphonate therapy.

FACTORS TO CONSIDER WHEN DECIDING WHAT TREATMENT ONE NEEDS

In general there are five factors to consider when deciding on a treatment. These include:

1. Tumour factors
2. Prostate factors
3. Local factors
4. Patient factors
5. Institutional factors

(1) Tumour factorsThere are seven tumour factors which will dictate the type of treatment which is best for an individual cancer: the clinical stage, the PSA level, the Gleason score, the position of the cancer, the extent of the cancer, the presence of perineural invasion, and the likelihood of disease penetrating through the capsule are all factors which will influence the choice of therapy. For example, nerve-sparing prostatectomy should only be considered in those patients where the cancer is almost certainly confined to the prostate, is not too extensive and of a low clinical stage. On the other hand, brachytherapy seed treatment should only be considered where the PSA is less than 10, the Gleason score is less than 7 and the clinical stage is less than T2B. High dose rate brachytherapy in combination with external beam radiotherapy should be considered where surgery is highly unlikely to cure the cancer such as in patients with very extensive cancer, with a high clinical stage and a PSA between 10 and 30, or where there is a high likelihood of disease penetrating through the capsule – particularly if it is located at the apex, which is difficult to cure surgically. Robotic surgery is more complex when extensive nodal dissection is required with more advanced cancer, or where there is a lot of cancer at the base. Hormone therapy should be considered where there is extensive local cancer unlikely to be cured such as a T4 tumour or where the PSA is greater than 50. HIFU is best with lower stage and grade tumours.Active surveillance should be considered in less aggressive microscopic tumours where for example only one of many biopsies are involved with a microscopic focus of low grade tumour with a low PSA.(2) Prostate FactorsThe size and shape of the prostate as well as urinary symptoms may influence decisions. Urinary symptoms include obstruction, irritation and prostatitis. For example, a very large prostate may not be suitable for seed therapy or high dose rate brachytherapy or HIFU or Robotic surgery. Furthermore a patient with severe urinary obstruction may not be suitable for any radiotherapy treatment. If a patient has severe bladder irritation it may be wise to avoid radical prostatectomy because these patients often become incontinent after surgery. Prostatitis may, for example, suggest that one shouldn’t have seed therapy. Heavy calcification makes HIFU and seed treatment inappropriate. Large middle lobes of the prostate makes seed and robotic surgery difficult.(3) Local factorsFactors that may influence therapy include previous surgery, previous radiotherapy and the pelvis anatomy such as its shape, the presence of a previous injury or general obesity.Where previous surgery has occurred, such as bowel surgery, this may make further surgery more difficult. Where previous radiotherapy has occurred clearly no further radiotherapy is possible. When a patient is extremely obese he may be better and safer to have a non-surgical treatment. If a patient has had a fractured pelvis he may be wise to avoid surgery as this would lead to incontinence.Abdominal adhesions from previous abdominal operation make robotic and laparoscopic surgery very difficult. HIFU and radiotherapy should not be used when colitis of the rectum is present.(4) Patient factorsThe patient factors can broadly be grouped into sexual, urinary, bowel, general health, the type of person and other factors.SexualThe patient’s current sexual status as well as his personal situation in life, ie his relationship and the importance he places on sexual potency are clearly major factors in making a decision. His preparedness to use sexual aids is also an important factor. For example, a man who has recently married a younger partner and wishes to choose the treatment with the lowest chance of sexual side effects would select seed therapy, or careful nerve sparing technique assuming he has the appropriate tumour.UrinaryThe patient’s current status with regard to urinary and irritative symptoms as well as his fear of incontinence may have a bearing on his treatment. For example, if a patient has a particular fear of incontinence then he should not consider surgery.BowelThe patient’s current bowel status with regard to previous treatment, the presence of underlying bowel problems such as ulcerative colitis or Crohn’s disease or irritable bowel symptoms may have a major bearing. If he is particularly fearful of long term bowel side effects such as faecal incontinence, for example, he should not consider radiotherapeutic options.General HealthThe age of the patient and his life expectancy, the presence of longevity in the family, as well as other health problems, the various medications he takes such as Warfarin and the presence of obesity will have an influence on the therapy. For example, if the patient has a life expectancy of less than10 years and has a slow growing tumour he may be better to consider active surveillance.Type of PersonThe type of person the patient is will largely dictate his ultimate choice. Whether he is the worrying type or the accepting type; whether he is a person who needs to make a joint decision with the doctor or he leaves the decision to the doctor; whether he ‘wants it out’ or has a fear of surgery; whether he is a pragmatic type or has unrealistic expectations of his life expectancy; or whether he is a more conservative or punter type. Finally, there is the natural therapy type. He may also be the technology lover type.Each different type of patient will bias the decision to one therapy or another. For example, the conservative type will always go for a surgical solution whilst the natural therapy type will go more for active surveillance therapy. The worrier will never accept active surveillance whilst the fear of surgery type will always go for a less invasive therapy. The lover of new technology will tend to try Robotic surgery or HIFU.Other factorsOther factors which may influence patients’ treatment choices include geographical location, the particular person’s personal experience with cancer with a friend or family, the family history and the pattern of the cancer, cultural factors, finances or work commitments. For example, a son with a strong family history where the father has died of prostate cancer at a young age will tend to choose early and aggressive treatment. A person who runs his own business may choose quicker treatments (e.g. Seeds, HIFU or Robotic Surgery) to get back to work quicker. (5) Institutional FactorsThe availability of technologies and the local expertise will influence the choice of radical prostatectomy. For example, if Robotic surgery or HIFU are not available locally and travel is difficult this may influence choice.IDEAL CASESEvery treatment method has an ‘ideal patient’. Here are some examples:Nerve-sparing radical prostatectomy is ‘ideal’ for a younger, conservative type patient with normal erections, possibly experiencing urinary obstruction, who has a low volume but high grade tumour.Radical prostatectomy with a sural nerve graft is ‘ideal’ for a younger patient who has good erections, is anxious to preserve his potency and is prepared to ‘take a punt’ on a successful result. He could have a cancer of high volume and high grade and still be suitable for this methodology.Radical prostatectomy without nerve-sparing is ‘ideal’ for a conservative patient of any age who has greater than 10 years life expectancy, poorer erections, is less concerned about his future potency and ‘wants it out’. He may have urinary obstruction and a higher grade, higher volume tumour.Conformal external beam radiotherapy is ‘ideal’ for patients, or who are aged 70 and over, with health preconditions that make surgery inadvisable, or who are obese or averse to surgery, and who have a life expectancy of greater than 10 years. Brachytherapy with seeds is ‘ideal’ for middle aged to older patients who have a fear of surgery and who are sexually potent and anxious to retain their sexual potency. They should have a low volume, low stage cancer in a small prostate, with no urinary obstruction. Obesity is not a problem for this therapy.High Dose Rate Brachytherapy is ‘ideal’ for patients of any age without urinary obstruction, who prefer not to have surgery, or who have medical conditions that make surgery inadvisable. They may have an extensive tumour that is high volume and high stage, and they may be obese.Hormone Therapy is ‘ideal’ for patients who have an incurable tumour (i.e. that has a high PSA and has spread beyond the prostate), or are over 70, or have other health problems that limit treatment options, or who have a life expectancy of less than 10 years. Note that hormone therapy is often administered as a pre-treatment to radiotherapy or brachytherapy with seeds.Active surveillance (or ‘watchful waiting’) is ‘ideal’ for a patient with a low grade, low stage tumour. It particularly suits older patients for whom retention of sexual potency is very important, who prefer ‘natural therapies’, or have a fear of surgery, or are prepared to take the risk, or gamble, that the tumour will not progress.Robotic Surgery is ideal for patients with localised prostate cancer (low to intermediate grade) where the prostate is not too large and has no large middle lobe. Patients wanting to get back to work quicker and are attracted to new technologies are ideal particularly when potency is not the dominant factor. Naturally they need access to an institution that provides this technology.HIFU is ideal in older patients with less extensive cancers who are prepared to accept less trusted new technology. They should have a small prostate even with a previous TURP operation. PSA ideally less than 20. It is also suitable for some younger patients after previously failed radical treatment but only where the radiation did not damage the rectum.

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