Hodgkin’s lymphoma has been a disease that we knew how to cure in the majority of patients for the past 30-40 years, even when the disease is in advanced stage and spread throughout a patient’s body. But we have continued to try to find better ways of accomplishing that so a larger proportion of the patients are cured with the primary therapy. It has proven difficult to effectively improve on the standard recipe of ABVD, a four drug chemotherapy regimen, without having to dramatically increase the toxicity of the primary therapy. The advent of a new effective targeted agent, brentuximab vedotin, opened the possibility that we could integrate that into primary therapy and accomplish the goal of curing more people but not having to unacceptably accelerate or increase the toxicity. The design of the trial was to establish just that.
We took the standard treatment, gave that to half of the 1,300 patients who participated in the trial from around the world, and we gave an experimental treatment in which one drug was taken out, bleomycin, and one drug, the new drug, the targeted agent, brentuximab vedotin, was added in and conducted a straightforward comparison of outcome for the two groups of patients that had been randomised. Ultimately it’s what I would call a single variable experiment – the only thing different between the two groups of patients was whether they received the experimental treatment or not.
What we found was that using a measure of the success of the primary chemotherapy at the ability to eradicate all signs of the disease that about a quarter of the patients in which treatment failure was encountered with the standard recipe that this was eliminated in about a quarter of the patients by the experimental treatment. So there are still patients that are not cured even by the experimental treatment but the proportion of them is smaller, it’s fewer than the patients who would have experienced treatment failure with the standard regimen.
The challenge with treating Hodgkin’s lymphoma and other often curable diseases is that you want to recognise whether the primary therapy has worked or not as early as possible. That’s straightforward if the disease gets worse despite the treatment, that would be progression; it’s straightforward, unfortunately, if the patient dies and that has to be considered a failure of the regimen. But there’s a third group of patients that are important to define. This is the people who take the primary regimen but despite that have persistence of the disease in question. It may not get any worse, it’s just simply still present and that’s evidence that the primary therapy has failed. We carefully define the circumstances under which we would consider that to have happened. We looked at the post-treatment evaluation and if that indicated signs that the disease may have persisted, and then, in addition, if the managing clinician taking care of the patient chose to institute additional treatment we took that as evidence that the primary treatment had failed, there was a necessity to move to secondary treatment. We did that in such a way to carefully eliminate the potential for bias of having clinicians electively throw in treatment which may or may not have been necessary. We were able to satisfactorily undertake to do that. This is the same challenge that other triallists in other clinical trials have had to address. They have typically used measures entitled event free survival or freedom from treatment failure; we chose to call this a modified progression free survival but it’s the same measure, it’s the measure of how often do we have sufficiently compelling evidence that the primary therapy didn’t work that we can judge it to have been a failure.
All of the patients experienced the adverse events associated with the chemotherapy drugs that are titled AVD because they were common to the two regimens. The experimental regimen added brentuximab vedotin which brings some unique additional toxicity. The first that we discovered during the course of the trial was that more patients experienced what’s called febrile neutropenia; this is infection associated with a low white blood cell count. This occurred more frequently in the experimental arm and we instituted a measure, or at least recommended a measure, to try to prevent that from happening – the use of prophylactic growth factors to encourage neutrophil growth. When that was used it appears to have reduced the likelihood of febrile neutropenia to very close to the level seen with the standard arm.
The next kind of toxicity we had to address is what’s called peripheral neuropathy. Both brentuximab vedotin, the experimental drug, and vinblastine, the standard drug that’s common to ABVD and the experimental regimen, they’re both neuropathic, they both injure peripheral nerves. So what we examined was how frequently peripheral neuropathy occurred and, not unexpectedly, it did occur more often in the experimental arm. However, we also examined what clinicians were able to do about that - with appropriate adjustments of the schedule and dosing that impact was minimised. Then finally we looked to see with the passage of time how often patients recovered from that side effect and the large majority either completely recovered, didn’t have it in the first place or recovered enough to make it less troublesome. So it fell, then, within the bounds of what I would consider acceptable toxicity when a treatment is intended to be able to cure the disease.
The third important toxicity is that associated with the use of the drug bleomycin. We were able to eliminate that completely in the experimental regimen and we saw a commensurate drop in the incidence of lung damage or toxicity and, importantly, in the incidence of severe lung damage or toxicity. So we were able to gain an improvement in the side effect profile by eliminating that troublesome additional toxicity. So there’s no doubt but that there is a change in type and an increase in toxicity with the new regimen but it’s within what I would call the bounds of what clinicians and patients find acceptable if appropriately managed in the situation where we’re trying to cure an otherwise malignant disease.
What will be the impact of this research?
I hope the impact is that we have been able to redefine what should be considered the benchmark against which other treatments should be measured. We constantly strive to improve the outcome for patients with Hodgkin’s lymphoma and, undoubtedly, there will now be additional experiments crafted to compare this new frontline regimen to another, hoping that that will bring about further benefit. The ultimate goal, of course, is to cure all the patients. We’re edging our way towards that by reducing the number of patients that have a failure of their primary therapy with each of these major clinical trials.
But this has been a challenging business. ABVD was originally described in the 1970s and is still in common use largely around the world. Displacing it with a different choice has proven to be a substantial task and we think that we’ve been able to redefine, at least, the attractive options for frontline treatment with the new experimental regimen.
Will this treatment be a lot more expensive?
There’s no question that when you make things turn out better with new drugs today across all of cancer you automatically make things much more expensive. Society has decided that for a collection of diseases that expense is acceptable. So we have diseases like multiple myeloma, chronic lymphocytic leukaemia, where there has been an enormous increase in the cost of primary management of patients. I don’t think that the escalation in cost here is quite as enormous but it is still definite and is a substantial run-up. But one needs to then conduct a careful analysis to see if the undesirable effects that are associated with failing to cure something potentially offset the increased costs. This requires an elaborate and careful pharmacoeconomic analysis still to be achieved. We had to define the fact that it worked better, the science part of that is done, we did establish that. Now the proper analysis to look at the improvement in cost because of avoided secondary treatments comes anywhere near offsetting the increase in cost associated with having to give the new agent to all the patients, an analysis I look forward to seeing.
