As everyone knows, there have been dramatic changes in the systemic medical therapy of melanoma over the last four to five years which means that, at last, a lot of patients are able to be treated with drugs rather than surgery and that has changed the entire landscape. However, there are a number of situations where surgery still remains the most effective and probably the safest and cheapest option. The situation with sentinel node positive patients has changed as of the middle of last year when the results of MSLT-II, the second selective multicentre lympadenectomy trial, came out and showed that there was no advantage to doing a complete lymph node dissection for patients found to be sentinel node positive with melanoma. That has generally been accepted worldwide.
Now, there are some circumstances still where it might be desirable and that is when patients are not easily available for careful and regular follow-up, as per the trial protocol, or when there is extensive disease in the sentinel nodes. So that remains to be determined and patients may prefer to have the certainty, if you like, of a complete node dissection under those circumstances. We’re talking more specifically in this debate, however, about the treatment of advanced melanoma, that is people with metastatic disease that’s clinically apparent in lymph nodes or that’s apparent at distant sites – in the lung or the brain or the liver or the bowel or somewhere like that.
Now, the best available modern medical therapy which is probably a combination of ipilimumab and an anti-PD-1 inhibitor produces a complete response rate in the long-term of maybe 20-30%, we don’t have long-term results for these. Median overall survival, however, has improved dramatically from the old days when we really had nothing that was effective. The median overall survival for patients treated with anti-PD-1 and ipilimumab, an anti-CTLA-4 inhibitor, is around 39 months. If surgery is undertaken for isolated systemic metastases similar results or better can be achieved. For patients with macroscopic involvement, that is clinically palpable obvious metastatic nodes in the groin or in the axilla or neck, then the ten year survival rate is around 45% with surgery. We don’t yet have five year survival results for these drug therapies so they have to go away to beat that at this stage. We mustn’t overlook the potentially serious complications of these drugs sometimes, which is not to say that surgery isn’t without complications, it is, but like most things in life it’s a balance.
So we think that in particular circumstances surgery is still very much worthwhile. The rider to that is that there may be benefit in giving neoadjuvant systemic therapy before treating surgically and we’re awaiting with great interest the results of clinical trials of neoadjuvant therapy before surgery. The other uncertainty but it’s becoming clearer month by month, really, is the value of adjuvant systemic therapy after surgery. These days if you have something that’s easily surgically resectable, whether it’s in regional lymph nodes or at systemic sites, then still surgery is probably the best treatment option. If it’s apparently not surgically resectable then it may be possible to give neoadjuvant systemic therapy which may make it surgically resectable. So that’s about where we’re at.
The management of these patients has become very much a multidisciplinary affair. In the old days surgeons looked after metastatic melanoma and that was it, there was no other serious treatment option. That’s all changed and now medical oncologists have much to offer, radiation oncologists have much to offer and it becomes a matter of how you sequence these forms of treatment, what’s the most effective way of sequencing them. That’s best decided, really, in a multidisciplinary team setting where everyone has input where the various options can be discussed, the risks and benefits of each option can be considered and a consensus opinion reached and that seems to be the way that everything is heading.
There is a good consensus really. You can swing a bit more towards systemic therapy if you wish but everyone agreed that if you have a good response to systemic therapy and there is a residual lesion left then that is best treated by surgery. And that’s becoming an increasingly common situation. The responses to these new drugs are amazing and dramatic sometimes but occasionally there’s just one or two foci of disease left. If they are removed surgically then it looks as though the patients are rendered disease free and can go on to long-term disease free survival.
Is there anything you would like to add about the debate?
We all seem to be agreed that the multidisciplinary approach is the way to go, that it’s not surgery or drugs, it’s surgery and drugs and radiotherapy. The unanswered questions are how you sequence those and things like brain metastases. That used to be an absolute death sentence with a median survival of about six or seven months, that’s changed dramatically and that’s very much depending on drug therapy, stereotactic radiotherapy, surgery, they all have a place, they all have a role. It’s already a greatly improved outcome for that particular clinical situation.