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Â鶹Éç Radio 4’s Inside Health is hosting a special debate on the current state of the NHS. Dr MarkÌýPorter and guests discuss what needs to give.

The last few months have seen the service creaking under unprecedented demand, and there is likely to be worse to come.Ìý Something needs to give. Is it simply a matter of more resources, or do we also need to change our expectations of what the NHS provides? Is rationalisation and rationing the way forward?

Mark is to discuss the issues with a panel including regular contributor Margaret McCartney GP, Claire Marx, president of the Royal College of Surgeons, and Chris Hopson, chief executive of NHS Providers.

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Submit a question for the panel by following the links below or on the ‘Contact Us’ tab above

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INSIDE HEALTH

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Programme 1.

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TX:Ìý 03.01.17Ìý 2100-2130

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PRESENTER:Ìý MARK PORTER

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PRODUCER:Ìý ERIKA WRIGHT

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Porter<?xml:namespace prefix = "o" ns = "urn:schemas-microsoft-com:office:office" />

Hello and welcome back to a new series of Inside Health.Ìý Little in medicine is quite as black and white as it’s often portrayed. So, along with our normal eclectic mix of medical matters, uncertainty is going to be a recurring theme over the next few months. ÌýAnd if there is one area riddled with uncertainty, it’s the diagnosis and treatment of prostate cancer - the subject of today’s programme.

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Roger

I didn’t choose to have cancer but I chose to do something about it, if you like.Ìý I had it removed.Ìý I’m no expert but – you know get another blood test, go and get a check, it’s no big deal.

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Porter

Have any of your friends done just that as a result of what’s happened to you?

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Roger

I believe some of them are going to and I spoke to my brother and he’s – I think he’s going to go and have his done.Ìý It makes sense.Ìý I can’t see why you wouldn’t.

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Hamdy

I think what we have to do is inform the men that if we treat them there is a high chance that the treatment is unnecessary.Ìý But we can’t distinguish the good apples from the bad apples.Ìý And that’s the dilemma that we have.

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Dave

It’s a matter of weighing up the consequences of having treatment and in most cases there will be after effects and with what I’ve got now, which is a good life.

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Porter

So it was an informed decision to go for active surveillance?

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Dave

Yes.Ìý

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Porter

Some people might find that hard though – the prospect of knowing that there’s a cancer inside them that effectively isn’t being treated.

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Dave

My view was that I’m fit and healthy, I don’t feel I’ve got cancer.

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Porter

Prostate cancer is common. Most men over 75 will have some cancer in their prostate but will never know unless their doctors go looking for it. And while it won’t pose a serious threat to most, for some it will prove fatal. ÌýAnd yet its management remains one of the most controversial areas in modern medicine. But before we find out why - some essential basics.

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The prostate gland - which can vary in size from a walnut to a large Satsuma - sits under the bladder between a man’s legs. Its function is to produce liquid to mix with sperm to form semen.

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It normally gets bigger with age and the resulting compression on the outlet of the bladder results in symptoms like getting up in the night and poor stream. And most of these are just due to age related change - not cancer - indeed cancer often causes no symptoms.

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One way to pick up otherwise silent cancers is to do a PSA blood test. ÌýPSA is a protein produced exclusively by the prostate and disease of the gland - cancerous or otherwise - allows it to leach into the blood, raising levels. So a high PSA suggests something may be awry with the gland, but it’s a blunt tool.

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Ed Rowe is a Consultant Urologist based in Bristol. I joined him in one of his busy clinics at Weston General Hospital.

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Rowe

PSA isn’t a tumour marker, per se, it is a prostate marker and it can be elevated with prostate cancer but it can also be elevated for non-cancerous reasons, such as just benign enlargement or a urinary tract infection – these sort of things can also put the PSA up.

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Porter

How accurate a predictor of problems is it?Ìý I mean if you’ve got a high PSA does it necessarily mean you’ve got something wrong?

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Rowe

No it doesn’t.Ìý If the PSA, for example, is between four and 10 and you’re a 60 year old man you have about a 25-30% chance of having prostate cancer.Ìý And even then many men who do have prostate cancer will have a relatively low grade small volume tumour, which isn’t a life threatening situation and they can be safely monitored.

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Porter

What about if you’ve got a normal PSA – does that rule out having a cancer hidden away somewhere in your prostate?

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Rowe

No it doesn’t.Ìý If the PSA is below that normal range it means that the prostate cancer, in particular a significant prostate cancer that’s a life threatening situation is less likely but it doesn’t rule it out completely.Ìý On the converse side of that the PSA does provide an early warning signal for prostate cancer and the chance to pick it up early, particularly for men who have a more aggressive and significant form of the disease.Ìý But it’s also possible to have prostate cancer and a normal PSA level and that is the problem or one of the problems with PSA testing.Ìý It’s a controversial area with some quite strong opinions on both sides of the argument.

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Hamdy

There is unequivocal evidence that PSA testing saves lives.Ìý But at a cost.Ìý And the cost is that you have to treat and you have to diagnose so many others in order to save one man from dying of prostate cancer or from having disease progression.

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Porter

Freddie Hamdy is Professor of Surgery and Urology at the University of Oxford, and chief investigator of the landmark ProtecT study looking at the management of men with prostate cancer picked up by abnormal PSA levels.

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Hamdy

What happened is in the early ‘80s a blood test appeared called PSA or Positive Specific Antigen, and this new blood test allowed men to be tested and then for that to trigger biopsies of the prostate because above a certain level there was a risk of prostate cancer.Ìý But a high PSA level did not mean that you had cancer, you needed to have the biopsy.Ìý When that happened there was a whole backlog of early prostate cancers in men who didn’t have any symptoms which were diagnosed.Ìý At the same time there was a surgeon in the US and an anatomist in Europe who together refined and developed the operation of radical prostatectomy, to remove the prostate for cancer purposes.Ìý And these two developments in parallel meant that many new men were diagnosed, they probably didn’t need to be diagnosed because their disease was indolent.Ìý Indolent means that they are not likely to cause any harm over a period of lifetime and they were treated.Ìý So two things emerged over time.Ìý First of all, over detection of cancer and the second one is that many of these cancers were over treated.

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Porter

Now that’s the first stumbling block for many people listening to this, is that first of all that you can over diagnose cancer, that seems counterintuitive.Ìý Secondly, you can over treat it, that seems counterintuitive too.

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Hamdy

Yes, yes.Ìý So over detection of a cancer means that you detect cancers which over a period of a lifetime are not likely to cause harm.Ìý And what you do in actual fact is that you give a patient the label of being a cancer patient when he didn’t need to know that he had that cancer.Ìý Once patients know that they have cancer one automatic reaction is to say I want that cancer treated which then will push them perhaps to receive a treatment, the treatment itself will be unnecessary and therefore over detection can lead to over treatment.

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Porter

So in the case of the prostate we’ve got the PSA blood test, which allowed us to pick up some cancers that might never have reared their heads otherwise, so that’s the over diagnose.Ìý And the over treatment was this operation and the consequences of that would be what?

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Hamdy

There’s no treatment without consequences and the consequence of treatment largely related to the surgery are leakage of urine afterwards, so loss of control to an extent; loss of sexual function, so inability to get spontaneous erections which for men in their 50s and 60s is quite an important part of their life.

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Porter

But of course most men who are going through this, once you’ve been told you’ve got cancer, let’s say they have radical surgery, I mean they assume that their life has been saved don’t they?

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Hamdy

Exactly.

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Porter

A scenario all too familiar to GP Dr Margaret McCartney.

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McCartney

Yeah my heart sinks very often when we hear celebrities tell us that their life was saved by having a PSA test done.Ìý And part of this is what’s called often the popularity paradox and that’s where bad tests become more popular.Ìý The worst a test is, the poorer it performs, the more false alarms we create.Ìý And the more false alarms are created the more treatment people have for conditions that were never going to become life threatening and were never going to harm people in any way.

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Porter

Margaret, looking at the latest research it suggests that we have to treat something like 30 or so men with radical treatments like radiotherapy and surgery to save one of their lives and of course the problem is we don’t know which life we’re saving out of those 30.Ìý Now Public Health England has just recently lowered the PSA threshold.Ìý You talk about it being a bad test, the PSA threshold has been dropped to three for men in their 50s and 60s, which is lower than the current guidance, which means more men are going to be likely to enter this path of uncertainty doesn’t it?

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McCartney

Yes.Ìý The intention is good, the intention is there is to try and reduce the amount of deaths that are being caused, it’s to try and avoid as many bad case scenarios as possible and that’s a good intention.Ìý The problem is that it has unintended consequences.Ìý It means more people are being referred who don’t have a disease that they were going to die from but having tests and investigations which may only offer them side effects because they were never going to benefit from the test or investigations under offer because they were never destined to die of that particular disease.Ìý And that’s the dilemma – on one hand you may help to get a faster diagnosis or help some people but it’s at the cost of side effects to many more.Ìý This is a sea of uncertainty and I really fear that as doctors and patients we’re slightly adrift upon it.

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Hamdy

There have been many attempts to try and categorise the men into high risk, low risk and intermediate risk, that attempted to put patients in pigeonholes.Ìý The problem is we now know that these pigeonholes are not necessarily accurate.Ìý So we can underestimate or we can overestimate the risk of the disease progressing over a lifetime and causing harm.Ìý So in some men we over treat but in some men we undertreat – we have 11,000 men who die of prostate cancer every year in the United Kingdom and the reason they die of prostate cancer is because we don’t identify them early enough and it’s also because we undertreat them.Ìý And it’s really important to focus on these men now that we know that we over treat and over detect a lot of the others.

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Porter

And the challenge looking forward is to pick up these men and work out which of these men need aggressive treatment?

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Hamdy

The biggest challenge is at an early diagnose to be able to say this is a good cancer, this is a bad cancer.Ìý To pick the bad cancer and to give them everything we have in terms of treatment so that we prevent them from dying of what can be a really quite bad disease.

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Porter

And at the same time that would hopefully enable us not to over treat the people who don’t need it.

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Hamdy

Absolutely, absolutely.

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Roger

My name’s Roger Lamming, I’m 54 years old.Ìý I was seeing a specialist about something else, found a lump, kept an eye on it.Ìý The PSA blood levels were okay, I think they were a little bit high but not astronomical that red card and you think right you’ve got to do something about it instantly.Ìý But I think it was after about a year a consultant suggested that I ought to have a biopsy.

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Porter

What was that like?

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Roger

I was aware that it was being done but it wasn’t painful.

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Porter

How long did it take for the result to come back?

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Roger

It took about 10 days, came back clear, no problem at all.

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Emberton

So a man has an elevated PSA and that is a trigger for what we call a trans-rectal ultrasound biopsy.

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Porter

Mark Emberton is Professor of Urology at University College London and chief investigator of the PROMIS study - a trial looking at whether MRI scanning of the prostate might improve diagnosis, as biopsy often misses cancers.

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Emberton

Ultrasound is great at telling you where the prostate is but it doesn’t tell us what’s in the prostate.Ìý So under local anaesthetic, the man’s awake, we put a probe in the back passage, then allows us to direct six needles to the left and six needles to the right.Ìý Now we have no idea whether that man has a prostate cancer.Ìý If he does have a prostate cancer we have no idea where it is and actually worse still, as you can imagine, there are parts of the prostate that you can’t reach – you can’t go round the corner to hit what’s called the apex and hitting the anterior part of the prostate, which is the bit that’s furthest away from the rectum, is difficult to do and causes quite a lot of pain.

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Porter

Your six needles are going to the left, your six needles are going to the right, it’s in a gland that could be the size of a tangerine, I mean you don’t really know where they’re going do you, other that they’re going into the prostate you hope?

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Emberton

No you’re quite right.Ìý And of course if you don’t know where the cancer is and you’re sending needles randomly into an organ you can make several errors – you can miss it completely and tell the man he’s all clear when he’s not; you can miss classify it and tell the man that actually he’s got disease that doesn’t really matter when in fact he does or – and this is the kind of difficult one – you can pick up what we call indolent or incidental cancers.Ìý So we know now that most men will develop small cancers as they age but most of these small cancers really don’t matter.Ìý And if you’re sending a needle blindly into the prostate you have a chance of picking these up and giving this man a label for life of having prostate cancer.

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Porter

When you explain it that way it’s hardly surprising that our conventional ultrasound guided biopsy misses so many cases.

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Emberton

Yes and it’s really interesting why we’ve tolerated it for so long.

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Porter

Because it’s the best we had to offer I suppose.

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Emberton

It is but I think we weren’t faced with our error.Ìý MRI reveals the error.

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Roger

Went back about four or five months later, had another check, consultant suggested that maybe I ought to have an MRI scan.Ìý You just lie down for half an hour, they play some music to you and they do the scan – very easy.Ìý That came back, I think they were still happy with it but they weren’t sure what the problem was, if there was a problem because I still had this lump.Ìý So the next stage was that they suggested another biopsy but a more invasive one where they would have to give me a general anaesthetic and knock me out completely.

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Porter

And this time they had the MRI to guide them.

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Roger

They took their biopsy from that and was told that they’d found some cancerous cells.

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Emberton

So PROMIS was a trial that aimed to tell us just how accurate MRI was at ruling in and ruling out prostate cancer.Ìý And I think it’s going to change practice probably forever.Ìý What it did is ask around 700 men to have an MRI, which was the new test.Ìý We also asked me to have the old test, which is the random biopsy of the prostate.Ìý And then we asked all the men to have a very special test in which we interrogated the prostate by biopsing at five millimetre intervals.Ìý So a bit like playing battleships with the prostate so that you could determine exactly where the cancer was and see how good MRI was and how good the standard biopsy was.Ìý And they show that our standard of care is really very poor so that our standard biopsy, which we’d been relying on for about 40 years, misses over half of all the clinically important cancers.Ìý So half the men who were told they were all clear were indeed harbouring clinically significant disease.Ìý MRI was about twice as good, it had a sensitivity so its ability to detect clinically significant disease is present in excess of 90%.Ìý And so the majority of patients that had clinically significant disease were successfully detected.

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Porter

Which is a massive benefit.

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Emberton

I mean there’s no perfect test in medicine but MRI is 100% better than the existing test.Ìý And that will mean two things:Ìý MRI will give us locations, so we’ll get a much better diagnosis, fewer men will be told they’re all clear when indeed they’re not.Ìý And the other thing that PROMIS did was to see whether we could safety reassure men they could avoid a biopsy if the MRI was negative.Ìý And if your MRI was negative your risk of having clinically significant disease was so low that we believe we could save about 25% of all men from having a biopsy at all and that would translate to a quarter of a million men a year in Europe alone.

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Porter

And even while the PROMIS study was going on, MRI was already becoming part of the standard investigation in urology clinics like Ed Rowe’s

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Rowe

Men who we find prostate cancer they will need an MRI scan; men who have a negative biopsy but an elevated PSA we want to make sure that we haven’t missed something and so we do an MRI scan on them and also in men who are on surveillance for a small volume low grade prostate cancer we want to make sure that we’re not missing something more aggressive somewhere within the gland and therefore do the MRI scan on them too.Ìý So eventually everyone gets an MRI scan.

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Porter

If that MRI comes back as normal does that rule out cancer?

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Rowe

No, it doesn’t rule out cancer.Ìý The chance of harbouring a more significant cancer are lower.Ìý The MRI scan is good at picking up aggressive significant cancers but not so good at identifying the lower grade smaller volume tumours.Ìý But then again you can argue that they’re the ones we don’t really need to identify in the first place.Ìý The slight problem is that there are some aggressive tumours which are missed on MRI scan and so we’re not quite at the point yet where we can say to somebody your PSA is elevated, your MRI scan is normal therefore there’s no concern here, we’re still currently going ahead and doing the biopsy, even if the MRI scan look normal just to be sure.

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Porter

Let’s assume that you pick up a cancer, can you, as a specialist, with an MRI result, with the biopsy result combined, say to that patient look this is a dangerous cancer or this is a cancer you don’t need to worry about?Ìý Can you tell the tigers from the pussy cats?

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Rowe

No, we don’t have that test yet.Ìý We just have to build a picture for each individual.Ìý Lay out the treatment options for them and then they decide.

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Porter

I suppose the difficult thing for you is in a younger man with what looks like an aggressive tumour the case for aggressive treatment is pretty clear cut and in a man in his 80s with what looks like a so-called indolent tumour you might not do anything other than keep an eye on him.Ìý It’s those men that fall in between those two barriers which I would imagine probably makes up the majority of your workload.

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Rowe

Yeah and that’s the really difficult questions we have to answer every day in our practice.

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Porter

I’m imagining that there are a lot of men out there with borderline PSA readings who are being kept an eye on by their GP.Ìý The prostate gland feels normal, the levels are on the edge, they’re having repeat PSAs – is that a sensible way to manage these men?

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Rowe

It’s probably okay for a lot of men but I worry about that.Ìý The reason being is that the prostate can feel normal but there can be an aggressive cancer within that gland, even when the PSA’s just above the normal range.Ìý And a PSA that’s low doesn’t mean that there is not an aggressive cancer there.Ìý And so I would urge caution in that situation.Ìý Let us do the MRI scan with the biopsy and then we know what we’re dealing with then.

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Emberton

Cancers are typically hard to predict.Ìý The majority of prostate cancers we know grow slowly but every so often a man does have a cancer that can transform and the PSA rises and if we repeat the imaging we’d see a larger tumour.Ìý But thankfully they are fairly rare.

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Porter

Let’s go back to those men who were found to have an abnormality, you said MRI is much better at picking up those abnormalities so we’ve made a diagnosis of cancer that we might not have made using the conventional method.Ìý Do we know that using MRI to make such a diagnosis improves the long term outcomes for men?

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Emberton

We don’t yet because long term outcomes you need time and MRI hasn’t been around that long.Ìý But it’s hard to see how it wouldn’t.

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Porter

Professor Mark Emberton.

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So MRI can improve diagnosis - but what then? What is the best way to treat the men whose cancers you have now found? Well here the uncertainty continues. When do you need to act fast and decisively using aggressive treatments and when can you just keep a close eye on the men?

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These are the very questions the ProtecT trial - led by Freddie Hamdy and involving tens of thousands of men across the UK - set out to answer.

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Hamdy

So the conventional treatment options at the time we set up the study was either to watch the disease and hope that it will not progress.Ìý The second one was to undertake radical treatments and this could be either surgery – radical prostatectomy to remove the prostate completely with possible side effects – or external beam radiotherapy, which essentially is x-ray treatment.Ìý So these were the three conventional treatment options and it was very difficult to tell individual patients which of these three was the best option for them at the time they were diagnosed.

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Porter

Now the reason why you had to do the trial was is because we didn’t know which the best option was.

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Hamdy

We didn’t know what the best option was and we didn’t know whether the treatments were effective in reducing the effects of the cancer on the patients’ long term longevity.

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Porter

Now once again that seems counterintuitive that, you know, we don’t know that a radical operation – let’s take the case of surgery – is any better in terms of survival for our patients than effectively doing nothing – keeping an eye on these patients but not actively treating them in any way.

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Hamdy

That’s correct.

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Porter

That seems bizarre.

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Hamdy

It is bizarre and that has to do with the biology of the cancer itself.Ìý We know that prostate cancer grows very slowly, we know that some cancers are bad cancers and that they will kill patients and this is what’s caused all the dilemma.

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Porter

So this has run for over 15 years…

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Hamdy

That’s correct.

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Porter

… what did you find?

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Hamdy

What we found is good news overall.Ìý We compared men who were picked up by PSA testing who had disease which appeared to be contained within the prostate, so no evidence of any spread.Ìý And we asked from these men whether they would agree to be randomly allocated to either receiving active monitoring, which is a form of surveillance or surgery, radical prostatectomy or radiotherapy which is x-ray treatment.

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Porter

Just to put that in perspective.Ìý As a GP that’s just the sort of person that I’m referring to my local urologist, they don’t have any signs of trouble, they have a high PSA and we’re worried about it?

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Hamdy

Sure.Ìý So we anticipated about 10% of men to die of prostate cancer over a period of median 10 years and in fact it was 1% only, so 10 times less.

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Porter

It’s pretty reassuring.

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Hamdy

Which was a surprise but good news, so that men don’t have to worry so much once they are diagnosed with this type of cancer.Ìý And it’s very important to distinguish this from more advanced disease that we pick up which is more serious obviously.Ìý The second piece of good news is that for the first time in our study we were able to compare the two radical forms of treatment – so surgery versus x-ray treatment.Ìý And for the first time we showed that they were equivalent.Ìý So there isn’t much to choose between these two treatments.Ìý When patients are faced with difficult choices we cannot say surgery is better for you or radiotherapy is better for you, so they have a wider choice.

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Porter

The interventions may have similar outcomes, but how does the option you choose influence the likelihood of being left with side effects like continence and sexual problems? Jenny Donovan is Professor of Social Medicine at the University of Bristol and co-principal investigator of the ProtecT trial.

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Donovan

We knew what areas might be affected by the different treatments – so urinary function, sexual function, bowel function, quality of life, anxiety, depression and general health.Ìý And so we put them into a questionnaire for the men to fill in.

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Porter

Looking at the active treatment, the surgical arm, what were the main problems that they had afterwards?

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Donovan

And so before they had their diagnosis almost none of them had urinary incontinence, so leakage of urine, almost none of them wore pads.Ìý But after the surgery round about 50% of them needed to wear pads, so at six months.Ìý Now that got better but over the period of the study through to the six years still around about 20% of the men needed to wear pads for urinary leakage.Ìý The other major area of problems was in sexual function and particularly erectile function.Ìý So here at the start of the study around about a third of the men had problems with sexual function and of course sexual function declines over time.Ìý But the surgery also had a severe impact on…

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Porter

And that was most men?

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Donovan

Yes.

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Porter

Looking at the group who’d had the radiotherapy was there any significant difference in terms of those two main side effects?

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Donovan

Yes, so after radiotherapy they had no problems with urinary leakage but they did have almost the same effect on their sexual function at six months.Ìý But that was because they were taking hormone treatment along with the radiotherapy.Ìý So when they stopped that, after around six months, their sexual function recovered.Ìý And then of course with radiotherapy also had increased bowel problems than in the other treatments.

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Porter

But they generally fared better in the sexual function department than the surgery, was there a significant difference?

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Donovan

Yes.

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Porter

Which leaves many men facing a dilemma. They know they have prostate cancer but no one can tell them - for sure - how big a threat it poses or which treatment is best. ÌýMight they end up electing for a therapy that, thanks to side effects, leaves them worse off?

A dilemma faced by 72-year-old Dave, who chose active surveillance rather than aggressive treatment after his cancer was picked up during an operation for something else.

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Dave

As I went through the process with the consultants a lot of the fears were actually released.

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Porter

Because most diagnosis of cancer are pretty worrying aren’t they but prostate cancer’s a little bit different in that regard.

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Dave

To be honest I haven’t worried too much because the consultants are keeping a close eye on me.Ìý

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Porter

And presumably if the active surveillance shows any worrying change you can always resort to treatment, it’s not ruled it out.

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Dave

In fact my PSA has gone up recently.Ìý We still are at a point where we don’t have to do anything particularly.Ìý However, he is going to arrange for a scan and so on, just to check things out.

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Hamdy

The difficulty that we have is that it is still difficult to recognise which patient is likely to need treatment in the long term to avoid them dying of the disease.

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Porter

The men in the study were allocated one of the three arms randomly.Ìý How did the group feel who were given active surveillance when they saw other people in the trial having quite aggressive treatments?

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Hamdy

Sure.Ìý What we found is that within three years of the men starting active monitoring about 25% had moved on to receiving a radical treatment and within 10 years just over half of them had received radical treatments.Ìý And there would be a mixed number of reasons why that happened.Ìý But we know that part of the reason was the anxiety that’s been generated by the diagnosis of cancer, so they were treated not necessarily because the cancer progressed but because they had uncertainty about whether the disease was going to harm them or not.

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Porter

How would you want your prostate investigated?Ìý Assume you had a PSA, for whatever reason, and it’s come back as worryingly high.Ìý What’s the next stage for you – you’d want an MRI presumably?

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Hamdy

Yeah I think what’s inescapable now is that imaging has come a long way and I would want to have an MRI before anybody is trying to do a biopsy on me.Ìý And the reason I would want an MRI is that if there is an abnormality that can be picked up at least the needle for the biopsy can be placed exactly in the right region so that an important cancer is not missed.

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Porter

What happens if the MRI shows nothing wrong, would you be happy with that?

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Hamdy

No because I don’t think MRI rules out completely the presence of cancer and don’t forget that all cancers are different.Ìý So seeing it on an MRI or not seeing it is perhaps not just enough.

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Emberton

I realised that I wouldn’t have a biopsy without an MRI about six or seven years ago and we’ve been doing MRI on everybody since.Ìý And indeed most good centres in the world are doing that.Ìý The detection rates for clinically significant disease are much better.Ìý If you’ve got a target it’s not beyond the wit of man to stick a needle into it, we’re very good at doing that.

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Porter

Do you think we’re going to see more or fewer men undergoing aggressive treatment like radiotherapy and surgery as a result of the more widespread use of MRI?

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Emberton

I often lie in bed and contemplate that and I think the answer is probably the same in number but they’re going to be the right patients.

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ENDS