Navigating the Complexities of Renal Tumors with Dr. Mark Lloyd

Dr Gavin Nimon: 0:28

You may not be aware, but cancer of the kidney, or renal cancer, is in the top 10 cancers that affect men and women, with twice the incidence of men, or one in 50 chance of a lifelong risk of developing it. If diagnosed early, it'd be quite curable. Today we're going to learn more on Aussie Med Ed. Good day and welcome to , the Australian Medical Education podcast, a program born during COVID times to emulate the general chit, chat and banter around the hospital with the idea of educating the medical, student and GP alike. I'm Gavin Nimon, an orthopedic surgeon based in Adelaide, and it's my pleasure to bring to you. And today we're joined by Dr Mark Lloyd, a urological surgeon with 20 years of experience. He's a graduate from the University of Adelaide and a member of the Royal Australasian College of Surgeons and the Urological Society of Australasia. He's a senior lecturer with the University of Adelaide and his interests are kidney and bladder health, men's health and prostate disorders. He's going to talk to us about renal cancers and how they're diagnosed and treated. I'd like to start by acknowledging the traditional owners of the land on which this podcast has been the Kaurna people, and pay my respect to the elders, both past, present and emerging. Well, it's my pleasure now to introduce Dr Mark Lloyd, a friend and colleague from the Queen Elizabeth Hospital in Adelaide. He's a specialist in renal carcinoma and he's going to give us some insight about this particular condition. Welcome, Mark.

Dr Mark Lloyd: 1:43

Thanks, Gavin. Thanks for asking me to talk today about renal tumors and renal carcinoma in particular. It's a particular interest of mine. I'm a surgeon and I perform surgery on renal tumors on a regular basis. I'm very pleased to answer any questions that you have about renal tumors and the presentation and treatment of them. Thanks, Gavin.

Dr Gavin Nimon: 2:05

Yes, great to have you on board. Perhaps you can outline why renal cancer is important and what the subgroups there are of renal cancer.

Dr Mark Lloyd: 2:12

So renal cancers comprise about 5% of adult malignancies, so they are a common malignancy. So we do need to know about them because of the frequency of their occurrence. So really they can be divided into primary malignancies of the kidney and secondary malignancies of the kidney. Now secondary malignancies of the kidney are fortunately quite rare. So we're mostly dealing with primary malignancies of the kidney. Now the vast majority are renal carcinoma, which is a primary kidney cancer, and most of them are to clear cell carcinomas. And you might wonder why they're called clear cell carcinomas. That's because the staining on histology, when they perform a stain on the cells, are washed out and so appear clear or see-through on the histology of the H&E stain. So that is about 80% of renal tumors. Are these clear cell carcinomas, which is a primary tumor of the kidney? There are some variants of this and that includes papillary renal cell carcinoma, which comprises about 10% of renal malignancies, and this is more aggressive than the typical clear cell, and also chromophobic carcinoma, which also has a typical appearance on H&E staining, and this comprises about 5% of tumors and has a low malignant potential. So those are the three different types of renal cell carcinomas. Now there are in the differential diagnosis a number of different diagnoses which can be responsible for a mass in the kidney, and those can include other types of tumors, such as lymphoma, which may occur in an elderly person, or a Wilms tumor, which is seen in children and usually under the age of five years. There are other benign conditions which can occur, which include benign tumor, which is called an angiomyalipoma, which is composed of, as the name suggests, blood vessels, muscle cells and fat and has a typical appearance on a CT scan, and an oncocytoma, which is a type of benign renal tumor which is very slow growing.

Dr Gavin Nimon: 4:30

Well, that's a nice simple classification system, but how do these renal cancers present? What's the most common way they present to you?

Dr Mark Lloyd: 4:37

We were taught back in medical student days that someone would appear with a classic sign of pain in the loin, a mass in the abdomen and blood in urine. But the fact is that most of these tumors these days are referred with an incidental finding on an ultrasound. So it used to be that these tumors were diagnosed when the situation was quite advanced. But now we've been increasingly being referred tumors which are really quite small, with early detection on ultrasound, which is great because it means they're more easy for us to treat.

Dr Gavin Nimon: 5:12

And if you're were suspecting a renal cancer, is an ultrasound the best way of investigating for one, perhaps for someone who has blood in the urine or you're concerned about a renal mass.

Dr Mark Lloyd: 5:20

An ultrasound is pretty good but may miss some small renal masses. An MRI or a CT scan will have a very good sensitivity for detecting renal masses. The key thing here is to make sure that someone who has hematuria that is, blood in the urine has a proper investigation not only of the kidneys but also of the bladder to exclude a carcinoma. So we would suggest that everyone who has blood in the urine undergoes at least an ultrasound or preferably, if there is visible blood in the urine, a contrast CT scan of the urinary tract.

Dr Gavin Nimon: 5:57

And Mark, t he fact that these cancers are picked up, incidentally, to my mind might suggest that they're a bit more slow growing than the average type of cancer we're worried about. Is that the case?

Dr Mark Lloyd: 6:06

Yes, that's exactly right. So a typical renal tumor has a growth rate of between 1 and 3 millimetres per year. So this is a slow growing tumor and it's thought that many renal tumors which are detected have been there for many years prior to detection and in fact it takes quite a bit of growth for a renal tumor to become symptomatic in terms of either pain or blood in the urine. So these tumors, especially in elderly patients, there is a role for surveillance, which is conservative management of a renal tumor. If the patient is not fit for surgery, then that is an appropriate treatment choice for those patients.

Dr Gavin Nimon: 6:48

Now, obviously back pain is quite common, but what aspects of back pain will make you a bit more concerned to investigate for renal cancer? Sure?

Dr Mark Lloyd: 6:55

So I think with the history, if someone has central back pain that's more likely to be related to the spine. If anyone has symptoms of loin pain, then that is more suggestive of a renal abnormality. It's difficult, on history too, tell those two things apart to be honest. So I think if someone has back pain, if they have look, if they have risk factors for a renal tumour, so those risk factors for arenal tumour would be age, smoking and male gender. Those significant risk factors should be taken into account and a previous history of cancer. So any other cancer in any other system increases the risk of cancer in the urinary tract. So I think if patients have those risk factors and there is some suspicion that back pain could be malignant, then they should have an ultrasound or a CT scan. And the other thing of course to remember in the elderly patient would be prostate cancer, which has a predisposition to bony metastases that can also present with back pain. So I think if there's doubt and there's concern about the possibility of a renal malignancy, a urine test to exclude e-maturia should be done and in men with possible prostate malignancy a PSA test should be obtained to screen for those conditions and if there is concern, then a CT scan of the abdomen will help with that diagnosis.

Dr Gavin Nimon: 8:28

And putting it into perspective what would be the chance, or how often have you seen someone who presented with a simple back pain to an orthopedic surgeon then be identified as having a renal cancer?

Dr Mark Lloyd: 8:38

It's not common but I have seen actually more likely, I have seen patients with kidney stones who've presented with back pain that in the younger age group that is a more common finding and again, those patients usually also would have blood in the urine. So look, I don't think this is a common finding and I know that the guidelines for back pain in the primary healthcare setting suggests that imaging is not a routine. So I think that if a GP is seeing a patient with back pain, they should be concerned. If the patient has risk factors or family history of malignancy, those patients should be the ones that should be screened. And obviously, if the patient does have imaging for their spine and no specific cause is found, then you would go on to investigate other organ systems.

Dr Gavin Nimon: 9:26

And do all renal cancers have blood in the urine? Or if you have a negative dipstick, does that exclude renal cancer as a cause?

Dr Mark Lloyd: 9:33

You can still get it. A dipstick testing for blood in the urine is commonly done as a screening medical test and it's commonly done by insurance companies prior to taking out occupational health insurance. So we do get patients referred with microscopic hematuria but in those younger patients, the vast majority of those patients investigations prove negative. So in fact up to 10% of the population, sometimes higher than that, can have incidental microscopic hematuria. So microscopic hematuria has poor specificity for an abnormality of the urine retract because of the common false positives associated with blood in the urine. But I think screening is a different situation to investigating someone with symptoms. If someone has symptoms and they have a positive urine dipstick, then the chance of an underlying abnormality is much higher, obviously, than if you're screening an asymptomatic patient.

Dr Gavin Nimon: 10:36

You've touched upon the risk factors. Are there any other risk factors apart from male and smoking and age that you've mentioned as well?

Dr Mark Lloyd: 10:42

There are. So we know that renal carcinomas are increasing in incidents and this is related to hypertension and obesity and chronic kidney disease. So these conditions are increasing in the community and they're known to increase the risk of renal carcinoma. So smoking also increases the risk two to two and a half times, and the male-female ratio is two to one. Patients with diabetes also get chronic kidney disease and this increases the risk of renal carcinoma in terms of the chronic kidney disease, and those patients with end-stage renal failure also have a higher risk of renal carcinoma.

Dr Gavin Nimon: 11:23

So those patients have actually gone on to have had renal failure and had a renal transplant. Do they have a higher risk of developing cancer in that transplant as well, or is that just purely the renal disease itself?

Dr Mark Lloyd: 11:34

It's the renal disease and the immunosuppression that goes along with the treatment of the renal transplant. So the risk of the carcinoma is in the native kidneys, the failing kidneys. The transplanted kidney is always a very healthy kidney, so this has a very low risk of a renal tumor.

Dr Gavin Nimon: 11:55

Gee, that's unfortunate. Then you mean the kidney that's caused the requirement for the transplant is also the one that goes on to get cancer. Do they think about removing that kidney at the time of surgery to prevent this?

Dr Mark Lloyd: 12:06

Yeah, look, that's a great question, gavin. And look in decades ago, when I first trained, patients had their what they call their native kidneys that is, the failing kidneys removed prior to transplantation and the thought was, they're not so much to prevent the tumors, but it was thought that the native kidneys produced chemical messengers that led to kidney disease and hypertension, and they found those conditions the hypertension associated with failing kidneys difficult to treat. Now, with new drugs, they're well able to treat that, but the issue now is that the kidneys are left behind, so they actually undergo regular ultrasound. Of course, if the patient then presents with a mass in the failing kidney, then they have to have a nephrectomy, but the incidence is not so high as to justify patients having a prophylactic nephrectomy.

Dr Gavin Nimon: 13:05

And what's thought to be the cause of renal carcinoma. What's the pathogenesis of it? Does it lead to scarring or generalized inflammation, particularly in these scenarios, or does it occur de novo?

Dr Mark Lloyd: 13:14

It is thought in that situation of those particular patients to be scarring and chronic infection which leads to the development of a renal carcinoma. But that is just a small number of the overall patients who develop renal carcinoma. So 80% of renal carcinomas are spontaneous and sporadic. And they've done a lot of research on the genetics of renal carcinomas and they found a gene called the von Hippel Lindau gene. Now von Hippel Lindau is a syndrome which is associated with increased risk of renal carcinoma and this syndrome was associated with an abnormality in chromosome three called the von Hippel Lindau gene. Now that was investigated and the discovery of that gene allowed the development of an antibody which targeted the cytokine called vascular endothelial growth factor which was produced by this gene. So this was one of the first treatments using targeted treatments towards a cytokine produced by Tumour, and that drug which was developed was called Sunitinib and Sunitinib was the first drug really that we had available to treat patients with metastatic renal carcinoma. Prior to that there was very little treatment for patients with metastatic renal carcinoma Hemotherapy, most chemotherapy drugs being ineffective to treat renal carcinoma.

Dr Gavin Nimon: 14:49

Excellent Look. You mentioned earlier on a Wilms Tumour, which is a tumor that occurs under the age of five. Perhaps you can explain to us what a Wilms Tumour actually is, and is this genus associated with a Wilms Tumour? Is this what causes it?

Dr Mark Lloyd: 15:00

I have to first say I'm not a pediatric urologist so I don't actually see patients with Wilms Tuma. I'm an adult urologist. But Wilms Tuma is a tumor which is developed in the third to fourth year of life. It presents with abdominal pain and hematuria in a young child. It is usually unilateral. It's associated with a defect in chromosome one. It's a different genetic abnormality compared to the adult renal carcinomas. Its management is normally surgical with nephrectomy. It has a good prognosis when it's picked up early and it has an entirely different genetic abnormality compared to the tumors that develop in the adult. The Tumor with Wilms Tumour is often picked up when the tumor is quite big. It's picked up as an abdominal mass and those patients that have a large tumor may need to go on and have chemotherapy treatment. But the prognosis has improved markedly over the last decade in terms of treatment of Wilms Tumour. Yeah, so it's usually rare to have a development of a tumour in the other kidney, which is very fortunate. But, as I said, I'm not an expert in Wilm's tumour because that's a pediatric condition.

Dr Gavin Nimon: 16:25

Yeah, it's a genetic disorder that affects only one kidney. That's really unusual, isn't it? Yeah, that's right.

Dr Mark Lloyd: 16:31

But the surgical treatment would be quite similar to an adult with renal cancer.

Dr Gavin Nimon: 16:35

Now, once you've made the diagnosis of renal cancer, what's the next step? Do you go on to stage the condition and how do you actually stage it?

Dr Mark Lloyd: 16:42

Yeah, that's a great question. We perform staging essentially based on the CT scan, which would be our standard investigation. So CT scanning enables us to tell exactly what the stage of the tumour is. If the CT scan at least just of the urinary tract, you will also do a CT scan of the chest to exclude a metastasis in the lungs. So to do the staging we'll use the TNM staging system. So we have a T1 tumour which is between 4 and 7 centimetres in size and that's confined to the kidney. We have a T2 tumour which is 7 to 10 centimetres, a larger tumour. When the tumour becomes larger and pushes into the fat, the perinephoric fat around the kidney, that is classified as a stage T3 tumour. Now the renal cartilomas are interesting in that they can invade blood vessels and in terms of renal tumour, this can spread into the renal vein and also into the vena caver, the main vein in the leading blood to the heart. Now stage T3B involves a tumour into the vena caver below the diaphragm, and it can go above the diaphragm, even into the atria and the heart stage T3C. So you can actually have cardiac involvement of a renal carcinoma. Stage T4 is where the tumour invades surrounding organs and then we have the N stage, which is the nodal stage. There can be stage 1 for one node, stage 2 for more than one node, and then the M or N stage, which is either 0 for no metastases or 1 for detectable metastases. So that's the staging system that we use.

Dr Gavin Nimon: 18:37

A number of nodes assessed. Is that based upon the CT or MRI or based upon the decision of the nodes and histological diagnosis?

Dr Mark Lloyd: 18:45

The staging is a radiological staging system. There is a pathological staging system which is used the following removal of the kidney, and that pathological stage may change depending on what pathologist finds In terms of lymph nodes. There is been no evidence that excision of lymph nodes associated with a renal carcinoma may have an improvement in prognosis. The lymph nodes are usually removed along with the kidney, but we don't normally go searching for lymph nodes when the kidney is removed. Usually the tissue alongside the vena cava or the aorta are removed along with the kidney and then the lymph nodes are analysed at that time Regional lymph nodes if they're involved they're close to the kidney will be removed, but if they're more distant and away from the kidney, those mean that the patient will need some adjuvant treatment. Adjuvant treatment is treatment with another modality after the surgery.

Dr Gavin Nimon: 19:44

Okay, so those patients will then go on to have chemotherapy and other treatment. Going back to when the patients are first and issue referred to you, I presume they're presented an MDT or multidisciplinary team and discussed in that process who makes up the members of that team.

Dr Mark Lloyd: 19:57

Yeah, the patient would be referred, we would see them in the clinic setting, we would arrange the necessary radiological tests and then we would present their findings at a multidisciplinary team meeting which includes a pathologist, a radiologist and an oncologist, and often a radiation oncologist as well. So these are a multidisciplinary team approach, but the treatment of renal carcinoma is primarily a surgical treatment, provided that the disease is surgically receptive.

Dr Gavin Nimon: 20:32

Now we're in sudden cancers. Chemotherapy is undertaken prior to surgery. Is that ever required in renal cancer as well, depending on the stage of the condition?

Dr Mark Lloyd: 20:41

Yeah, that's a great question. So, in terms of the treatment, first the staging I mentioned that the stage T1 was the 4 to 7 centimetre tumours and the stage 2 is the 7 to 10 centimetres. Both two staging systems are used because stage T1 is usually amenable to removal of the tumour without whole kidney, and that's called a partial nephrectomy or a partial removal of the kidney with the tumour in it. The stage T2, which is the 7 to 10 centimetres, as the tumour becomes larger it invades more of the kidney and so the recommended treatment is a total, or we call a radical, nephrectomy. That would also be done if the tumour is invading into the fat where the kidney is removed with the surrounding fat. Obviously, if the tumour is involving the main blood vessels, renal vein or the inferior vena cava, then we usually call on our vascular surgeons to help us with that, and the tumour can still be cured even in that situation, as the tumour can be removed from within the vena cava at the time of surgery.

Dr Gavin Nimon: 21:55

And in that scenario, do they actually remove the vena cava and use a graft to replace it, or do they actually just remove the endothelial wall and leave it to revascularise?

Dr Mark Lloyd: 22:03

Luckily, normally the tumours don't invade the vascular wall. They are more a projection of a tongue of tumour into the renal vein or the vena cava, and so these tumours can be removed without having to remove the wall of the vena cava. It seems that the tumours can exist within the lumen of the vessel without actually invading the vessel itself, so normally the blood vessel or the vein can be closed primarily.

Dr Gavin Nimon: 22:31

Now, Mark, if the treatment of renal cancers predominantly surgery, in effect removing part of the kidney, is there anything you need to do prior to surgery to assess that it's actually safe to proceed?

Dr Mark Lloyd: 22:40

Part of the assessment of the patient, we would assess their kidney function, because if we're removing a kidney, clearly we need to be sure that the other kidney is functioning properly Before the surgery and after the surgery. We'll be monitoring kidney function quite closely to make sure that the other kidney is working well, monitoring urine output, monitoring serum, creatinine and electrolytes postoperatively and an optimising renal function. That can involve checking the patient's medications and may involve involvement of a renal physician if there is renal impairment, and optimising their drugs and avoiding any drugs which are nephrotoxic, that is, drugs that can reduce kidney function, which can include non-steroidal anti-inflammatory drugs, some antibiotics and a range of other drugs which we need to make sure that the patients avoid to optimise their kidney function.

Dr Gavin Nimon: 23:36

Okay, so once you've made the decision to perform a surgery, how has it actually performed? I understand the kidney sits in the retroperitoneum, ie behind the peritoneal cavity. Do you go through the peritoneum or do you actually go through the loin and just behind the muscles?

Dr Mark Lloyd: 23:49

So, Gavin, the nephrectomy is classically performed with an incision in the through the loin, which is a retroperitoneal approach, as you point out. I'll just explain that the peritoneum is an abdominal cavity which contains the intra-abdominal organs, such as the bowel, stomach and other intra-abdominal contents. The peritoneum is a thin layer which lines the abdominal cavity and, you're right, the kidneys, the ureters and the bladder lie behind the peritoneum, so the approach to the kidney can be through the side, which involves not entering the peritoneal cavity but entering the retroperitoneal area and removing the kidney that way. So this was the classic way of performing nephrectomy is through the side, with a retroperitoneal approach. In particular cases, an intra-peritoneal approach is taken, and this is particularly for larger tumours and those with vascular involvement, because the intra-peritoneal approach allows for a better approach to the major vessels which can be involved. Of late, minimally invasive techniques became used. Laparoscopic nephrectomy was developed 20 years ago and is a very effective technique for removing renal tumors which are confined to the kidney. This was followed by robotic approaches allowing on-dome, minimal invasive techniques to be employed, and particularly effective in the situation of a partial nephrectomy, where a partial nephrectomy can be performed with reconstruction of the renal defect via a minimally interventional technique. This partial nephrectomy, performed robotically, would be the mainstay of treatment for small renal tumors in patients who are suitable for surgery. The open surgery is now reserved for those patients who are either not suitable for minimally invasive techniques or who have larger tumors which require an open approach.

Dr Gavin Nimon: 26:00

Okay, and one thing I didn't quite realise until I spoke to Dan Spurnett about prostate cancer was that the actual surgeon is not scrubbed. He actually just operates the machine, while the assistant and the scrub nurse sets up the equipment on the patient, and they remain scrubbed. Yes, that's right.

Dr Mark Lloyd: 26:15

So this shows that robotic surgery is truly a team approach. We need to understand that the robot it's not an intelligent robot, it's what's called a master and slave robot. So the robot will only perform what the surgeon is indicating for it to do with the movements of his hands. Those are mirrored by the robotic instruments within the patient. So it's really important that the two people who are scrubbed with the patient, who is the assistant that is often a second surgeon and the scrub nurse, are well trained and familiar with robotic techniques. And there is a long learning curve to robotic surgery, both for the surgeon and also for the assistant surgeon and the scrub nurse. That takes a long time to learn how to work as a team together.

Dr Gavin Nimon: 27:03

It's truly amazing. I've put my head in to see some of it being done. It's really impressive.

Dr Mark Lloyd: 27:08

It is impressive and it's great. We've got the technology available to be able to treat patients with minimal side effects and minimal morbidity and great results.

Dr Gavin Nimon: 27:17

And just pointing out to the listener, it gives the surgeon an extra pair of hands effectively and also a way to maneuver the hands in a way that the person normally can't move the hands as a normal human being. Is that correct?

Dr Mark Lloyd: 27:27

That's exactly right. So the robotic arms can move in a 360 degree direction, so that they can actually move in ways that are beyond what the human hand can achieve. This means the only limitations actually are the skill of the operator and the extent that he can move his hands and wrists so that, together with better lighting and better magnification, allows us to perform major surgery but also micro surgery. The DaVinci surgical platform that we use was actually designed originally for vascular surgery and cardiac surgery, so the potentials for it are almost limitless.

Dr Gavin Nimon: 28:07

And, as an extra benefit, I believe the actual person observing a procedure, such as a medical student, can actually see what's going on, rather than struggling to look over someone's shoulder or actually not be able to see into the surgical field.

Dr Mark Lloyd: 28:17

That's exactly right, so they can see all of the surgery that's being performed and exactly how it's being performed. And, if we have, when the surgeon is performing the surgery, he looks through a console which allows 3D vision. If there is a second console, which often there is in several hospitals, then the learning students are able to see the surgery in 3D, which vastly improves the ability to recognize structures and understand what surgery is being performed.

Dr Gavin Nimon: 28:47

Truly amazing. Are there any other options apart from surgery for treating renal carcinoma?

Dr Mark Lloyd: 28:52

So that's a great question. For small renal tumours, we know that they are slow growing and in this situation, particularly for older patients who are wishing to avoid surgery, we can choose a modality of treatment called focal therapy, where the tumour is essentially treated with energy to destroy the tumour in situ without requiring surgery. These treatments can involve application of heat or cold and are called thermal ablation techniques. We can use radiofrequency ablation, cryoablation with freezing the tumour, or microwave energy to destroy the tumour in situ, and these are great techniques, particularly for elderly patients, patients who are wishing to avoid surgery and patients who are of older age.

Dr Gavin Nimon: 29:41

So what you're saying is, in treating the renal carcinoma rather than excising it, you apply thermal treatment, either cold or heat, either through ultrasound or through a probe, to actually destroy the renal carcinoma in situ. Is that correct?

Dr Mark Lloyd: 29:56

Yeah, that's absolutely correct and the follow-up data for these treatments show very effective control of the tumour, with the follow-up data five to ten years remaining very good. So this is a very promising treatment and has minimal side effects and is an exciting new area for treatment of renal carcinoma.

Dr Gavin Nimon: 30:17

Now, does that involve actually stinging a probe into the kidney itself, or is it actually done purely through the skin and radiation through the skin?

Dr Mark Lloyd: 30:25

So these techniques always involve an application of a probe into the kidney. Initially this was done with keyhole surgery, but now these techniques can be done percutaneously in the X-ray department, allowing treatment of a renal tumor essentially on an outpatient basis, without any incision. They are still a percutaneous treatment. The risks are small related to this treatment. This allows the patient to have even outpatient treatment of a small renal tumor. We recommend that tumors less than 2 centimetres are most appropriate for these treatments and usually we will have done a biopsy prior to confirm the diagnosis.

Dr Gavin Nimon: 31:08

So a stage T1 was 4 to 7 centimetres. Is this like a stage zero or something? Is it?

Dr Mark Lloyd: 31:14

This is still a stage T1, but a small T1 tumor. The reason for applying this technique for these small tumors is that we know the small tumors are well treated with this thermal technology and the larger tumors we may will not be able to treat them all at one setting, and there's also a higher recurrence rate for the larger tumors with this focal therapy. So we're only treating those patients in this way who have the best prognosis and wish to avoid surgery.

Dr Gavin Nimon: 31:49

Excellent. So you've done the surgery, you've got the part of the kidney out, or you've done a larger, extensive procedure and taken the whole kidney out with the peri-renal fat. How do you proceed?

Dr Mark Lloyd: 31:59

So once the surgery is finished the patient will be recovered as normal. We will monitor renal function afterwards and the patient usually recovers quite quickly from at least minimally invasive surgery and then they will be seen for a routine review several weeks after the surgery. Then a routine imaging is normally performed between three and six months after the surgery to ensure that there is no evidence of recurrence of the tumor and no evidence of metastasis of the tumor and check the remaining kidney to ensure that is healthy, excellent.

Dr Gavin Nimon: 32:38

With the ones that are at higher stage conditions, the ones that need the large nephrectomies and you're worried they've got metastases. So you could tell me which stage is this involves, but in those ones what? And you involve the other treatment and the adjuvant treatment afterwards what treatment is required and how long does that go for usually?

Dr Mark Lloyd: 32:56

So in terms of the management afterwards, in terms of surveillance following surgery, we tailored the surveillance according to the nature of the tumor, as you said, the patients with the higher stage or higher grade renal carcinoma. These will be followed up more regularly than the patients with the lower grade tumors. So the surveillance does go on for quite a while, usually for at least five years, and some recommend surveillance for a longer period. That will most often be with an annual review, but in patients with the lower stage tumors that may be done every second.

Dr Gavin Nimon: 33:38

So, but if they've got metastases initially on initial presentation, will they still have an nephrectomy and then followed up with chemotherapy, or would they just go straight for a type of chemotherapy?

Dr Mark Lloyd: 33:48

It's a controversial topic and that is decided on an individual case by case basis, normally at the multi-disciplinary team meeting. The decision as to whether to perform the nephrectomy in a patient who has metastatic disease is really based on their performance status. So oncologists often, when they're discussing the role of treatment in a patient, will often use a score called their performance status, which is determined by a number of factors such as their age, their comorbidities, the presence of anemia, the presence of chronic renal impairment these sorts of factors For patients with a high performance status, who are the younger patients with the lower comorbidities. Those patients often do have an nephrectomy and the reason for that would be that patients with a better performance status tend to do better with removal of the kidney. Those patients with a poorer performance status and have high risk for surgery, those patients are better treated with what we call neoadjuvant treatment. So neoadjuvant treatment involves treatment of the patient prior to surgery by an oncologist in the aim to optimise them for surgery. So those patients may well be treated by an oncologist with a number of different drugs which can reduce the size of the tumour and reduce the size of metastasis. But again, as I said, it's done on a case by case basis.

Dr Gavin Nimon: 35:19

And you said earlier that renal carcinoma is not susceptible to the standard chemotherapy agents, but there are new types of drugs that are used. What are the ones that we need to know about and the ones that are new innovations that have come through for treatment of renal carcinoma?

Dr Mark Lloyd: 35:32

Those drugs. There are a number of different drugs and, as I mentioned initially, that developed out of research into the cytokines with which their renal carcinomas produce. So renal carcinomas produce cytokines which increase vascularity of the renal tumours. So vascular endothelial growth factor is a cytokine that is targeted with a group of drugs called the tyrosine kinase inhibitors. Now the tyrosine kinase domain is an intracellular domain which is responsible for angiogenesis or development of blood vessels and cell proliferation. The tyrosine kinase inhibitor passes it's an oral treatment and it passes intracellulally and inhibits this domain. Now that can cause a significant 30% response rate in terms of reduction in the size of renal carcinoma and its metastases. There is another group of drugs called the immune checkpoint inhibitors, which are a newer group and these block the T cell program death receptors. So the T cells actually have a receptor with the program death receptor. Now, inhibiting the T cell inactivation by the tumour cells is the action of the programmed death in PD1 receptors. This restores T cell function and T cell immunity, allowing the patients normal T cells to attack the chemo. So that is a group of a new group of drugs which allow for improved response rates. And there's been a study performed recently into a drug released called Pembrolyzumab, which is one of these drugs and that shows a significant improvement in survival following nephrectomy for those patients with a higher stage or higher grade tumor or with metastatic disease. So this has shown an improvement in the three-year survival following nephrectomy for those patients with a higher grade disease.

Dr Gavin Nimon: 37:46

Now, are these drugs reserved for patients in a particular stage or the renal carcinoma, or is it used for any other patients?

Dr Mark Lloyd: 37:52

Yes, so there is. So the Pembrolyzumab. The drug Pembrolyzumab is given for stage T2, high-grade tumors all those with presence of sarcoma in the tumor, and it's also available for anyone with a T4 tumor, which is invasion into the surrounding structures. Anyone with metastatic disease or a stage T3, which is high-grade. So that is, all of those patients with adverse histological or stage or metastatic disease are felt to be suitable for this drug. Pembrolyzumab is a very expensive drug but it has found to be suitable for these patients. So I think we're going to see more patients treated with that post-operative one. We're not just treating those patients with metastatic disease, we're treating those patients with a higher T stage or with a T2 that's high-grade.

Dr Gavin Nimon: 38:47

So as in all staging systems, the TNM classification gives us an idea of prognosis as well as treatment options.

Dr Mark Lloyd: 38:53

Yes. So I think if we were just treating those patients with metastatic disease, our results from this sorts of treatment would not be as good. The ground is moving towards treating those patients who have stage T2 and T3 disease to improve their survival even when there is no metastatic disease detected. So this needs to be weighed against the side effects of treatment, obviously, Fortunately, the side effects of these more modern drugs are much less than previously, mostly relate to some tiredness and some fatigue and loss of appetite, which generally quite mild side and, in general, what's the prognosis for enocarsinoma? So the prognosis is really on the, again on the staging. So it depends on the T staging. So a patient with a T1 tumour would have a disease-free survival of over 90%. A patient with a T2 tumour would have a disease-free survival of 80% and then that reduces to 70%. For T3 disease which is into the fat and then for those patients with a more extensive disease, the prognosis is clearly reduced and those patients particularly have metastatic disease. This also reduces the survival rate. So patients with higher stage and higher grade disease have a worse prognosis.

Dr Gavin Nimon: 40:20

You said previously that CT scans the mainstay of staging a renal carcinoma. Do you use MRI scan at all? Is that used in any aspect of treatment or diagnosis?

Dr Mark Lloyd: 40:29

We do use MRI. It's used particularly for those patients who cannot have a CT scan with contrast. Ct scan with contrast can cause toxicity to the kidney. Those patients with poor renal function may be better investigated with an MRI. The other patients who are best investigated with MRI, those with invasion of the vascular structures. The MRI gives very good pictures of invasion of the renal vein and invasion of the vena cava Excellent.

Dr Gavin Nimon: 41:00

It sounds like this disease itself has had a lot of advances in treatment and staging over the years, Obviously with invention of MRI and now with the idea of using these chemotherapy agents and also robotic surgery. Are there any other advances that are actually either coming through or on the forefront for the future that you're aware of?

Dr Mark Lloyd: 41:16

I think the advances in terms of surgery have already occurred with the advent of robotic surgery allowing minimally invasive treatment for patients. The advances in the future, I'm sure, will be along the genetic lines and as we understand more about the genetics of renal carcinoma. That will allow further improvements in the treatment of patients following surgery. And who knows, one day we may not have to treat these tumours surgically, but I think that is a long way off. Just yet. I think we can see positive improvements with the checkpoint inhibitors and as the genetic conditions become understood more fully, we will have more drugs available to treat these tumours, which is a great thing.

Dr Gavin Nimon: 42:06

So it sounds like renal carcinoma is increasing in the incidence, but the prognosis is actually improving with time as well. Finally, is there any closing points you'd like to make towards the students or anyone listening? Given that the incidence of renal carcinoma is actually increasing, it's obviously something that they might see during their lifetime.

Dr Mark Lloyd: 42:23

I think people should be aware of this. This can present to any doctor I would say, and I recall being referred quite a large renal carcinoma from an ear, nose and throat surgeon colleague of mine who took a thorough history and investigated the patient and I'm sure, saved the patient's life when he presented with some incident or other issue to an ear, nose and throat surgeon. So one thing I haven't mentioned about renal tumours which is really quite fascinating to both medical students and physicians is that renal carcinomas can present with a what's called a perineoplastic syndrome. So perineoplastic syndrome is where the renal tumour, as I mentioned before, releases cytokines and this can produce a clinical situation where the patient may present with a number of different abnormalities which are incidental. So this can include anemia. It can include a high ESR, erythrocyte sedimentation ratio, abnormal liver function tests, hypercalcemia and Cushing syndrome, which is related to excessive adrenocortico hormone. Also it can cause raised prolactin, which can cause lactation, and hyperglycemia related to elevated levels of insulin. I think renal carcinomas should be considered when the patient has a number of abnormalities which can't be explained for other reasons.

Dr Gavin Nimon: 43:54

I'm also aware, too, that the secondaries can be very vascular, as we've talked about, and can be difficult to control, so blood loss needs to be taken into account when you're dealing with treatment of a secondary into a bone, which is not as common but which does occur on occasions.

Dr Mark Lloyd: 44:08

Yes. So yes, I was talking to one of your colleagues, gavin, who resets bony tumours, and his comment was that renal tumours to bone are very vascular. Interestingly, he said that once the tumour is removed from the bone the bleeding almost stops straight away. So I think that relates to the secretion of these tumours, of these vascular associated factors, which cause increased blood vessels and so increased bleeding during surgery.

Dr Gavin Nimon: 44:38

That's brilliant, a really interesting topic and a lot to cover there. So I really appreciate your time, mark. It's been fantastic having you on Aussie MedEd. Thanks once again for coming on Aussie MedEd, mark.

Dr Mark Lloyd: 44:47

Thanks, gavin, it's been my absolute pleasure to talk to you.

Dr Gavin Nimon: 44:50

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