Is it to cure?
We want to cure cancer. That was my ambition when I became a cancer doctor. Can cancer be cured? Clearly some cancers can. If you have a skin cancer and you cut off the piece of skin, the chances are it won’t come back. Sure, if it’s a melanoma it may have spread, but most skin cancers aren’t melanomas. In fact insurance policies aren’t loaded if your only history of cancer is non-melanomatous skin cancer. Surgery does cure cancer. The hiccup came with breast cancer. Women who had their breasts off 20 years ago suddenly reappear with bony secondaries. It wasn’t dead; only sleeping. The idea that a cancer could be dormant for many years sowed doubt. Can we ever say you’re cured?
The acute leukemia model
In 1966 everybody with acute leukaemia died – adults in six weeks, children in ten. But 10% went into remission. Remission meant that the patient was well. Not anemic, not apt to bleed, not prone to infections. A complete remission meant that the blood count was back to normal and in the bone marrow no leukemic cells could be seen. Daunorubicin and Cytarabine were new drugs in 1968 or so that turned that 10% into 60% and then 80% by the 1970s. Instead of 9 month remissions, they lasted 2 years or 5 years and one paper said no-one who has survived for seven years has ever relapsed. Was this a cure?
Another false dawn. A few months before I left the National Health Service we admitted a young woman with leukemia 22 years after she was ‘cured’ as a child. She died a few months later with unresponsive disease. Treatment for acute leukemia has got better; patients live for longer and some are apparently ‘cured’ but who can tell?
A patient with acute leukemia typically has between 10 to the power of12 and 10 to the power of 13 leukemic cells in his or her body. When he or she goes into remission there may be fewer than 10 to the power of 9. That’s 1,000,000,000 - a billion cells. With that many, the disease will be back in nine months. Further rounds of chemotherapy or perhaps high dose treatment with an autograft will reduce the number further, but below 100,000 we won’t be able to detect them even with the most sensitive techniques. We just have to hope that there are many fewer than one hundred thousand, or that our defensive troops are up to handling an invading army that big. Acute leukemia cells are usually relatively accessible, being in blood and bone marrow, but there are some sites denying access to chemotherapy. With acute lymphoblastic leukemia these sites are the testicles and the brain. Unless these sites are treated separately the leukemia will relapse. Unless we have some reason to suspect leukemia in these sites and deliberately look for them – by doing a lumbar puncture, for instance – we will not know that we have to treat them, so for the brain at least, we routinely irradiate it.
Does the acute leukemia model fit CLL?
What about CLL? Until recently we didn’t have any drugs capable of producing a complete remission, even if defined in a rather looser way than it is in acute leukemia. Then came fludarabine and its various combinations. For the first time we were getting sizeable numbers of CRs. Even with the supersensitive techniques like the polymerase chain reaction (PCR) or multi-channel flow to detect minimal residual disease (MRD) some patients seem to have no detectable disease. And when we add in Campath these MRD negative patients increase in number. These patients seemed to have fewer than one hundred thousand leukemia cells. Perhaps the defending immune system could mop up the rest?
One thing we know about CLL is that the defending immune system ain’t much cop. If you’re relying on that to save you it’s like relying on the Newcastle back four. (Sorry, a soccer allusion. Substitute the worst defense in the NFL). And most types of treatment make it even worse. You could try using somebody else’s immune system – ie a bone marrow transplant, but only a few are eligible and it’s a pretty dangerous undertaking.
Then there are all those secret sites. Not the brain and testicles this time, but just about everywhere else. Small lymphocytes are wandering cells. Not just in blood and bone marrow, but all those thousands of lymph nodes, and in the gut and the skin and the thyroid and the prostate and the eye sockets – you’d be surprised where I’ve found CLL cells. How are you going to examine all those? CT scans will pick up big lymph nodes but if they are less than half an inch in diameter they won’t be seen. PET scanning will pick them up if there’s a Richter’s transformation, but quiet old CLL cells won’t be seen.
So can we cure CLL?
If you really want to cure someone with CLL you really need to start when there aren’t many CLL cells to kill and blast them with the most effective drugs you’ve got. The problem with that is that the available evidence suggests that there is no benefit in treating asymptomatic, early-stage disease until symptoms develop. Now, that may be because you have got to use more effective treatment than chlorambucil to show a benefit and you have to avoid treating patients who are never going to progress. This is certainly a question worth asking and there are clinical trials in Europe asking it.
So I ask again. Can we cure CLL? Saving an allograft, I don’t think so.