ASCO 2015

Improved care has extended lifespan of childhood cancer survivors since the 1970s

Dr Gregory Armstrong - St Jude Children’s Research Hospital, Memphis, USA

You’ve been looking at preventing children who have been cured of cancer from dying, either from reoccurrence of their cancer or from some completely different cause. Can you tell me what it is exactly you were trying to do in this massive study?

That’s right, we can. So this is a study of five year survivors of childhood cancer. This is a study called the Childhood Cancer Survivor Study, so to even be eligible these children had to be five year survivors of their primary disease. From a clinical standpoint, as a clinician, when you walk into the room with a five year survivor you celebrate, you throw the confetti and in your mind you imagine they’ve beaten it, they’re done and they go on about their lives. But the truth is beyond that five year time point 18% of five year survivors will be deceased by thirty years from diagnosis, that’s one in five. So there’s still a battle beyond that five year time point.

What is that goes wrong, then, in childhood cancer in the long term?

So for some survivors they’ll have late recurrence of their primary cancer and that can often be fatal. But as time goes on the real threat for mortality are the late effects of cancer. So children who had radiation and chemotherapy to beat their primary disease but those result in late effects down the road, so a higher risk for breast cancer or brain tumours down the road due to radiation, or heart disease from anthracycline chemotherapy. Things that you may not see until 15-20 years down the road but those risks are increasing with time and they lead to late mortality.

Now, there have been a number of different studies, you hear about more gentle regimens, that have addressed this issue, haven’t there? But you’ve pulled it all together. What specifically did you look at?

One of the brilliant things and one of the miracles of the story of curing childhood cancer is that now 83% of kids will beat their primary cancer. As we’ve learned who it is that will beat their cancer we’ll be able to back off of therapy for primary diseases in many cases. So for Wilms tumour, ALL, Hodgkin’s lymphoma, we can back off of radiation and chemotherapy for low risk patients. So what that’s resulted in is down the road they’re surviving to the five year time point just as well but beyond that they have lower risk for late effects. And what the study shows is lower risk for mortality due to late effects because we didn’t treat them as heavily to begin with.

So what you know about is that techniques have been developing for having more gentle therapies. But what can you now say about what has, in fact, happened as a result of this?

So, as a result of it down the road fewer deaths due to these late effects, fewer deaths due to secondary breast cancer, secondary brain tumours and heart disease. That’s resulted in the extending of the lifespan of survivors. So we can now say we’ve extended the lifespan of survivors, those diagnosed in more modern treatment eras are living longer, living well past their five year time point to 25, 30, 40 years down the road.

Now that’s all very reassuring as a general picture but what are the numbers on this? What do you actually have to do to ensure that your patient has the best possible chance in the long term?

So beyond the five year time point, first of all we have clinical care guidelines for long-term survivors and those guidelines recommend certain screenings and follow-up time periods. What we’d like is for all survivors and their doctors to subscribe to those guidelines. Secondarily, it’s our job as researchers to identify who are the high risk populations for late effects down the road and if we can identify who they are then intervene on them to either prevent or reduce the rate of late effects.

And what’s the sort of trade-off between chemotherapy and radiation and different regimens within chemotherapy?

First and foremost we have to cure their primary disease. So if we still need to use combinations of both to do that we have to do that. But if we can reduce them as much as possible that lowers the risk for late effects. So the radiation and chemotherapy are not the bad guy, they’re the good guy, they beat the primary cancer but moderating them when needed is the best approach.

And how do you do that?

So, for example, that’s come through clinical trials, frontline phase III clinical trials. So if you think there are Hodgkin’s lymphoma or Wilms tumour where brave triallists now decades ago said, ‘We can potentially reduce therapy, maintain excellent five year survival and reduce late effects,’ and so those were brave trials but they succeeded, they showed great five year survival. So, for example, in Hodgkin’s lymphoma in the 1970s survivors received up to 40Gy of chest radiotherapy. Now, currently, some survivors will receive none if they’re early responders to their chemotherapy, so going from lowering dose to potentially eliminating radiation where possible.

What potential impact do you think there might be in the future from the more targeted therapies that are coming down the line?

That’s a great question. We don’t know the answer in regards to long-term late effects because we don’t have enough children with enough of those targeted therapies who are well beyond the five year time point. But with time we hope that we can roll those type of patients into our Childhood Cancer Survivor study cohort and follow them as well. But there’s a mystery there, we don’t know a lot of the late effects of these novel therapies.

So what are the basic clinical messages coming out of this all then?

I think the main clinical message is good news to everyone in the field of extended lifespan of survivors of childhood cancer. So we’re beating cancer and now you’re surviving it longer. But the next step is not just survive it longer, not just extend the lifespan, we need to extend the health span. So it’s one thing to survive longer but we need to make sure the health of those survivors is maximised and that the risk for toxicities are reduced. So extending the lifespan is one thing, let’s now improve the health span.

And the biggest outstanding difficulties might be what? Are they cancer or are there other factors?

They are. The number one threat to life of long-term survivors is second cancer, not the first cancer coming back but a second cancer due to the therapy they received, so as much as we can moderate that. The number two cause of mortality is heart disease, early heart disease. We are talking when survivors are in their thirties and forties, when they’re still young, having their own children, mid-career people. So it’s an important time of life.

So there are some clear messages for clinicians perhaps avoiding some of the cardiotoxic regimens and also getting regimens that are more effective for the cancer.

Sure, we need to be in the search for that or for cardio-protectants, agents that may come along and while you’re administrating the cardiotoxic chemotherapy protect them through cardio-protecting agents. So there are all kinds of strategies and we need to continue them. So far, though, the strategies that have been employed in the last two decades are showing good effects.

So here from ASCO what’s your brief message for clinicians that they should take home from this, then?

First of all for long-term survivors, don’t forget about them. It’s not as if beyond the five year time point they become just like everyone else in the general population, they’re not. They’re different; they’re special. They need long-term follow-up. Secondly, there are a set of guidelines for long-term follow-up, the Children’s Oncology Group has produced long-term guidelines for follow-up and they’re readily available on the Children’s Oncology Group website. So I strongly urge if you have a long-term survivor childhood case in your practice, follow those guidelines.