Transcript:Keith T. Flaherty, MD: Let’s move into the advanced disease setting. And by that I mean borderline resectable and truly unresectable. So, this could be regional disease or metastatic disease. And, Jonathan, since the more regional version of advanced disease is something that we look to you, as a surgeon, to primarily tackle, how do you look at patients in this setting? Not so much lower stage, but higher stage, in terms of thinking about prognostic factors, how well do you think you’re going to manage the problem with surgery? Who are the borderline cases where maybe medical oncology or systemic therapy collaboration might be useful?

Jonathan S. Zager, MD: Usually, when I have my conversation with the patient, first I think about if I can resect the disease and what functional and cosmetic deformities or problems I’m going to cause. So, that’s how I judge whether it’s resectable or not. Resectability is almost like a state of mind. I can almost resect anything, but would it be good for the patient to take off an entire extremity? You have to think about the functional and cosmetic consequences of the resection.

Oftentimes, if we have bulky nodal disease that may be approaching the femoral artery, femoral vein, axillary artery, or brachial plexus, in collaboration with the medical oncologist and our multidisciplinary tumor board, we’ll employ a neoadjuvant strategy to try to downsize the disease with the plan of going back for 6 months later and planning on surgery—unless there’s an absolute complete response and you can’t tell that there’s any disease there. But, in general, the discussion with the patient with a regional disease is, can I resect it? If it can’t be resected, then you start employing strategies, like limb infusions, for extremity in-transit disease; T-VEC (talimogene laherparepvec) intralesional injections, or systemic therapies.

Keith T. Flaherty, MD: So, we’ll come back to that topic before about regionally appropriate therapies, and T-VEC, of course, being the new kid on the block, I think is an interesting point. Maybe this is a time to think about, for those who undergo resection who are clearly high risk for recurrence—bulky nodal lesions particularly, or even a patient with a couple of in-transits, but still resectable—ipilimumab, in the United States, as a new treatment option. Before I go to my United States colleagues on how they think about ipilimumab at 10 mg/kg in the adjuvant setting, maybe a little more neutral perspective from Georgina, where, in Australia, it’s not a licensed adjuvant approach. What do you make of the data with so-called high-dose ipilimumab in the adjuvant setting?

Georgina Long, BSc, MBBS, FRACP: The phase III trial—which was reported, I think, last year or the year before actually—of ipilimumab versus placebo in patients with stage 3 resected, the bulkiest or the greatest burden of disease would have only been 1 mm in a lymph node, right up to resectable stage 3b and 3c. That’s the patient population we’re talking about in this trial. Randomized ipilimumab at 10 mg/kg versus placebo showed a relapse-free survival benefit with a hazard ratio of 0.75. That’s 25% reduction in the risk of recurrence. However, we don’t have overall survival benefit. And in that trial, there were some deaths due to treatment. It’s very toxic, 10 mg/kg of ipilimumab.

It’s not approved for use in Australia, or I don’t think in any parts of the world except the United States. So, it’s not an option for us. But even if it was, I don’t think there would be much uptake by many Australian medical oncologists given the toxicity, given the lack of overall survival with no overall survival evidence as yet—but that’s coming. That might change with an overall survival benefit, because the big question we now have with all these drugs in stage 4 is, exposing patients earlier where 50% are actually cured with surgery, are we saving them any time? If we institute treatment at stage 4, are we curing them then? We do believe we’re curing patients in stage 4. Is it really worth all this risk benefit? So, these are the issues. At this point, I don’t think many medical oncologists outside the United States would actually take up ipilimumab, even if it was available, with the current evidence, given the toxicity and the benefit.

Transcript Edited for Clarity