Clinical Case 117: Cancer Fishin’

OK – this case is for all the GPs and Internal Medicine types out there.  This is a relatively common scenario…  how do you play it?

Here’s the case.

Bruce is a 53 y.o. accountant.  He is a little overweight at 89 kg (BMI 31).  He is otherwise relatively well, he cycles to the cafe each morning in lycra and drinks a cappuccino in his helmet… why do they do that?

He has hypertension which is controlled by ramipril 5 mg daily.  No other meds or relevant medical history.  He is interested in his health and even has annual “Mens’ Health checks”.  He was in last month for one – which was unremarkable other than a borderline BP and his prostate screen (post full consent and shared decision-making) revealed a normal DRE and PSA level.

Today he has come to see you with a discharge letter from the local hospital.  He was admitted for work-up of “unilateral leg swelling” which occurred spontaneously last Friday.

The letter reads:

Dear Dr Leeuwenburg,

Thanks for following up Bruce who had an unprovoked DVT diagnosed on Doppler.  US showed a 5 cm proximal DVT at the Femoral-saphenous junction (L) leg.

He also had a series of tests: FBP, UECr, LFTs, Ca, Mg, PO4, CRP, TFTs, a prothrombotic screen was unhelpful and serum rhubarb – these were all normal.  WE did a CXR to be sure and this was also reported as normal.  

Bruce was commenced on enoxaparin until his warfarin was therapeutic.  He’s on 8 mg nocte with an INR of 2.3 today .  Please chase his subsequent INRs

Oh – and – please screen for occult malignancy as we have not found anything yet.

Yours truly….

So Bruce is sitting in front of you looking a bit worried.  He says that he feels fine, and the leg swelling is improving.  He was a bit spooked when the “young-looking” hospital doctor told him that DVTs “like this” are usually due to some underlying problem “like cancer”.  He really wants to know what to do next.  Does he have cancer?

OK – so here are my questions to you:

Q1:  What is the chances that Bruce has an occult malignancy?

Q2:  what screening tests, inquiries, imaging etc would you recommend / order for Bruce?

Specifically will you get a CT of the torso?

Q3:  Does it really matter if he has an asymptomatic cancer? Will it reveal itself in time anyway?

Let me know your thoughts…

But in case you were wondering.  Here is the link to the recently published SOME trial out of Canadia in the NEJM in June 2015

They looked at a limited vs. “limited + CT ado-pelvis” strategy and found not much difference.  Both groups had about a 1% cancer rate at work up and had a similar “diagnosis rate” of cancer in the following year.  So the CT didn’t help reduce the time lag to diagnosis much.

However, there is of course a risk of finding incidentalomas and the harms associated with those and their further IX or Rx…

So for me it si back to simple thorough Hx, Exam, do the things you would normally do for a 50 yo bloke and watch him.  Really a great case for Shared decision-making here now that we have some rough numbers that we can present to the patient as risk ?


Hypercalcemia in a nutshell

Have seen a few patients with hypercalcemia recently and it has gotten me thinking.   It is one of those areas of medicine where the complex endocrine physiology and diseases can seem a bit overwhelming.  When we approach it in a practical sense it is much simpler than the head-spinning Med school lectures left us believing!

So lets break it down.

How high is high?  The normal range for  calcium in plasma is 2.2 – 2.6 mmol/l, however it is common to find “asymptomatic” mild hypercalcemia.  I put asymptomatic in parentheses as the symptoms of early hypercalcemia can be very subtle, vague or easily mistaken for other diseases.

Generally hypercalcemic patients are consistently symptomatic at levels > 3.0 mol/l.  Once one gets up above 3.5 mmol/l the more severe symptoms occur – this is an emergent situation.

Symptoms of hypercalcemia:

Weakness, lethargy. malaise. Polyuria and polydipsia Table showing the common symptoms at presentation and how this has changed over the past 20 years from JAMA 2012.  We seem to be diagnosing raised Ca more in asymptomatic patients or in the work-up for other common problems eg. osteoporosis, hypertension, depression

Bone pain may be general and non-specific, related to underlying aetiology eg. myeloma, metastatic disease or Paget’s, pathological fractures occur in osteoporotic bones

Abdo symptoms – pain may be non-specific Pancreatitis, severe constipation, nausea and vomiting.

Increased gastrin output can lead to peptic ulcer disease.

Renal tract stones are amongst the commonest presenting complaint / symptoms in hypercalcemia

Depression / anergia is common. Anxiety Psychotic symptoms: hallucination CNS depression, somnolence and eventually coma do occur at high levels

Hypotonia and hyporeflexia Can mimic focal neurological lesions

Hypertension is common at lower levels – may pick this on screening for secondary causes of BP rise. ECG: short QT, wide T wave and J waves Extremely high levels lead to VT /VF arrest

Causes of hypercalcemia

Pick up any medical textbook and you will find a long list of causes of hypercalcemia (same with pancreatitis).

However, in reality the list is pretty simple.  There are 2 big causes, one lesser and then daylight until the small print causes.

This is almost always due to a parathyroid adenoma. Multiple parathyroid hyperplasia – is a rarer cause associated with other endocrine dysfunction.

Very rarely a malignant parathyroid tumour.

Adenomas may occur in the context of MEN-1 syndrome (pituitary, gastric (ZE) and pancreatic neoplasia.

Parathyroid tumours also form part of MEN2a (phaeo, thyroid medullary carcinoma)

Hypercalcemia occurs in metastatic breast, lung and renal cancers.

Tumours with humoral-mediation via a PTH-related peptide include lung and renal cancers

Haematological malignancy: multiple myeloma, leukemias and lymphomas.

Hypercalcemia in the setting of known malignancy is usually easier to diagnose, though on occasion can be the presenting symptom of a malignancy

Too much Vit D or calcium supplementation can occur.May happen in intentional dosing, in intoxication with D3 or during renal failure if doses are not adjusted.

Lithium toxicity results in excessive PTH – hence a picture more like primary hyperPTH.

Thiazide diuretics and excessive thyroxine replacement can increase bone turnover and hence lead to high Ca.

Sarcoidosis also causes hypercalcemia through excessive Vit D activity

Acute renal failure might result in Vit D / Calcium toxicity if doses are not adjusted.

Severe secondary hyperparathyroidism can occur in chronic renal failure – as Hildy has reminded me – it is the tertiary hyperPTH that causes the hypercalcemia in chronic renal failure

Aluminum intoxication can cause raised Ca in dialysis


Management of Hyperclacemia

The management of hypercalcemia does to some extent depend on the underlying cause, however most of the causes are not readily remediable in the acute sense – hence we have treatments which can be applied to get the calcium down until the smart docs arrive and work out what is going on!  Often the cause is readily apparent on the previous history – cancer, known endocrine disease, renal failure etc.  So here is a quick skim through the management of hypercalcemia in the acute setting.

Patients with severe hypercalcemia are usually 4 – 6 litres down on water.  So they need rehydration, especially if they have concomitant renal failure as a result.  The decreased renal filtration results in a vicious cycle – they can then excrete less calcium.  So correcting urine output is the key in the acute, severe patient.

Normal saline has been he traditional fluid used in this setting.  Not much evidence to confirm or repute this practice and I imagine other IV fluids would also work – one needs to replace the lost electrolytes also – and this requires individualised monitoring.  Fluid resuscitation alone will not likely reduce the calcium level much – so this is really a resuscitative measure.

Traditionally a loop diuretic such as frusemide has been used along with saline therapy – however this has come into question in recent years.

Largely this is because frusemide has little or no evidence base to show it helps and the introduction of newer, proven effective agents mean there is little role for this potentially harmful intervention.  So in my practice I think I would prefer to use a drug that works, rather than one that might or might not be effective.

Bisphosphonates work by blocking bone reabsorption by osteoclasts.  They are potent – in that they work well and consistently – but they do take a while to work. 24 – 48 hours is the peak activity.  Traditionally they are used in malignant, bony disease, however they do work for other indications.  They are also widely used in prophylaxis for patients with bony mets.

The main agents used are pamidronate and zoledronic acid – they are pretty safe and well tolerated – the one big risk is the development of osteonecrosis of the jaw in ongoing use.  They are usually given as an infusion – ZA quickly, pamidronate slower.

Calcitonin (salmon) works as it does in nature by increasing renal excretion and also blocking osteoclast activity.  Its onset of action is 4 – 6 hours – so faster than the bisphosphonates – and can be given at 5–10 units/kg daily by slow IV infusion.  Another relatively safe choice, but not available in my small hospital.

So I think this one fits in as a front line agent in severe hypercalcemia where you want to get it down fast.

Steroids work by reducing intestinal reabsorption of calcium. They work on correcting overactive Vit D3 levels – so they work best in diseases such as sarcoidosis, TB or Vit D / D3 intoxication.  This is a cheap and readily available option – but it is slow i.e, takes a few days to work.  The dose is usually 25 – 50 mg per day.

Hydrocortisone can be given IV in the acute setting

Cinacalcet works by increasing the sensitivity of the parathyroid glands to the circulating Ca+ levels – hence increasing the negative feedback loop and decreasing PTH release.

There are really only 2 indications for this drug:

(1) secondary PTH in renal failure and

(2) in primary PTH adenomas where surgery is not an option or malignant adenocarcinoma is responsible for the excess PTH.

Mammography and pink cricket bats

A new review of the breast cancer screening ( mammography ) literature came out in the Lancet this week.  This is essentially an expert panel reviewing old data – nothing new.  The UK-based panel looked a the data from a number of long-running screening cohort studies and produced a set of round number estimates for the benefits, harms and rates of overdiagnosis.  Here are their absolute screening vs no-screening comparison numbers:

  • Screening women aged 50 – 70 would prevent 1 cancer death for every 180 women who actually underwent testing. This is an estimate derived from a heterogenous group of data packets.
  • The relative risk of breast cancer specific (not all cause) mortality was ~ 0.8 (CI 0.73 – 0.89).  So it appears to have a significant impact upon breast cancer specific mortality.
  • Overdiagnosis is the concept that has generated a significant controversy with this new review.  the Panel looked a the various trials and concluded that about 1 woman in 77 screened from 50 until 70 years would have an “overdiagnosed cancer” (just over 1 %) ie. a tumour that would have presumably not caused any illness for that woman if undetected.
  • Of course massive population trials don’t tell you who has the true cancer and who has the “silent” cancer – so all of these women will undergo surgical procedures and some adjuvant therapy for what was not going to be a true disease.  And there will be morbidity associated with this.
  • In summary screening will prevent roughly one breast cancer death for every 3 women who get “overdiagnosed”.
  • There was no mention of “all-cause mortality” – hence no way of saying the true mortality difference between sceened and unscreened women.
  • The 2006 Cochrane review found no difference in overall mortality between screened and unscreened populations – so that is a bit of a fly in the ointment.

So where do the pink cricket bats come in?

For the international readers – one of the best fast bowlers of the modern era was Glen McGrath – he played for Australia and was like ametronome – accurate and bouncy.  His wife passed away from breast cancer a few years back and he started a charity the McGrath foundation.  Each summer our national cricket team put hot pink handles on their cricket bats to raise money for breast cancer research and specialist nurse training in the care of women with breast cancer.

Every time I get into a discussion about breast cancer screening there is always somebody who says it doesn’t have enough evidence and that it should not have such a high public profile.  Seems like a fair point – should we be promoting something that doesn’t have a strong proven benefit.  Well I think this is wrong.

What we need for this devastaing and common disease is more research into screening, prevention and treatment.  The high profile of organisations such as the McGrath Foundation help with this research.  Improved screening technology and more effective / less destructive treatment will hopefully result in a smaller NNT and greater benefit to women who are diagnosed with breast cancer.

The first cricket test starts later this week – Australia vs. South africa – so bring on the pink bats I say!