Transcript:Brian A. Van Tine, MD, PhD: If we’re going to talk about toxicity, we’re probably the last people on the ifosfamide mountain. We’re at the top of the mountain using high-dose ifosfamide, and I think most of the world has moved on. This is still an incredibly important drug for what we use, but it’s incredibly difficult to use. A lot of private practices are no longer financially able to do it because of what it does in terms of chemotherapy chair time. It can be incredibly dangerous.

I think one of the crowning achievements of a very prestigious career, just absolutely stunning, was what Dr. Ian Judson really did in the EORTC trial, where he finally tried to make an attempt at asking, “What is our standard of care?” I think I couldn’t ask a more appropriate person, Dr. Jones, who has moved into that position, to comment on the Judson trial, which I think we’re all going to be holding onto for quite a long time until the drugs change. And talk about a little bit, just briefly, about the doxorubicin versus doxorubicin with ifosfamide.

Robin L. Jones, MD, MRCP: Thank you. In summary this is a randomized trial for patients 60 or less in age, randomizing patients in the first-line setting of metastatic disease to receive either doxorubicin or doxorubicin plus ifosfamide. The primary endpoint for the trial was overall survival. The bottom line is that there was no statistically significant difference in overall survival between the two arms. But the combination arm had a statistically higher response rate and statistically longer progression-free survival.

So, coming back to Dr. Patel’s point regarding personalized therapy in oncology and in sarcoma in general: I think that this is a great trial, but we still have to personalize treatment in terms of selection of either doxorubicin or doxorubicin and ifosfamide. And clearly, for patients with rapidly progressive disease, with inoperable locally advanced disease or patients that have big symptoms from their tumor burden, we’d consider doxorubicin and ifosfamide as a treatment option.

Andrew J. Wagner, MD, PhD: Robin, I completely agree, but I’m a little upset with you because you’re not listening to me. So, you mentioned improvement in response rate and improvement in progression-free survival, or increase in response rate, increase in progression-free survival. You left out increase in toxicity. So, there were more toxicity with the combination than the single agents.

Robin L. Jones, MD, MRCP: I was going to lead on to that. So, in response …

R. Lor Randall, MD, FACS: Get the gloves!

Robin L. Jones, MD, MRCP: That’s the crux of things. So, moving on from patients with rapidly progressive disease who’ve got a lot of symptoms, who we can clearly improve their quality of life by giving quite a toxic schedule. But for patients with small volume metastatic disease, I would say that doxorubicin, in terms of the quality-of-life component of multidisciplinary care, would be the option to consider.

Andrew J. Wagner, MD, PhD: Yeah, I agree. And it goes back to what Shreyas was saying, which is you need to …

Robin L. Jones, MD, MRCP: Personalized meds.

Andrew J. Wagner, MD, PhD: Right. You need to direct it to the patient.

Shreyaskumar R. Patel, MD: Again, I think for the sake of discussion, I have to make this point: that the worst toxicity that comes to a young, otherwise healthy person who would be considered a candidate for the doublet therapy would be recurrent tumor, progressive tumor, and death. So, admittedly the two drugs are more toxic, as expected. I don’t think anybody can or should try to hide that. But when you select the patients appropriately, the toxicities become manageable.

I think this trial also represents a major problem with a frequentist designed trial. If you really look at the statistical design, the investigators wanted to find the 1-year survival difference of 10% in favor of the 2-drug arm. Right? They expected that Adriamycin or doxorubicin will do 50% and the two drugs will do 60%.

What happened when the results came out? Doxorubicin gave 51%—shame on it! And the two drugs did perform as expected at 60%. Now, if you talk to clinicians, none of us will say that a 9% difference, instead of the expected 10%, is unimportant and therefore the trial is negative. Yet, the frequentist design makes the authors say this is a negative trial. It’s not a negative trial in that setting.

So, the point being that acknowledging that the two drugs are more toxic, acknowledging that it has limitations and cost issues and a variety of other things, I think there can and are patients who would be appropriate candidates for this doublet therapy. And this is where the personalizing happens.

Robin L. Jones, MD, MRCP: And the authors state that in the manuscript.

Shreyaskumar R. Patel, MD: Exactly.

Robin L. Jones, MD, MRCP: So, Andy and I are in total agreement.

Andrew J. Wagner, MD, PhD: Believe it or not, I was going to make the same point you did. As one who likes to do less chemotherapy than that, I think that you’re completely right in that the conclusion that it was not statistically significant is an artifact of the design of the study. Metrics are put in place a priori for the study and that you come up with something that doesn’t quite hit the 0.05 level, it’s okay.

There’s a suggestion of improvement, it’s definitely there, and I agree, too, with you that we don’t want patients to have earlier progression. We’re not curing anybody with this regimen. So it’s really a question of earlier progression and potentially earlier death. The part that does concern me, though, is the increased rate of febrile neutropenia, which is something that can be life-threatening.

We have to balance risks, and that is not age-dependent necessarily. Although a younger patient is more likely to be able to tolerate the combination chemotherapy from a physical standpoint, it’s a little bit less predictable about the febrile neutropenia. And just one more point is that we all have patients. I have a 74-year-old woman who I’ve treated with this regimen and she continued to work full time. She comes to see me from 8 hours away and hangs drapes as a job. So, people can do great with the combination.

Robin L. Jones, MD, MRCP: This trial was for patients less than 60, so again …

Andrew J. Wagner, MD, PhD: She wouldn’t be in that study. But my point is that …

Robin L. Jones, MD, MRCP: It’s that personalization of treatment that’s very, very important. And again, I fully take your point regarding quality of life, but we have to individualize treatment.

Shreyaskumar R. Patel, MD: I think in experienced hands, as all of us would agree, that if our goals are trying to improve outcomes in a stepwise fashion, we have got to take the so-called best regimen for the right patient population, add something onto it that’s tolerable if you will, and that’s the only way we’re going to make progress.

Andrew J. Wagner, MD, PhD: Just maybe we can use an examples —actually just a brief example, Brian. I’m sorry. I know you want to move on. But if you had a patient with four or five, one and one-half centimeter lung nodules that are slowly progressing over time, I’d be much less likely to use combination chemotherapy with that patient than someone who has bulky or symptomatic disease.

Jonathan C. Trent, MD: Unless the intent was to cure the patient.

Brian A. Van Tine, MD, PhD: You know, I think one of the things that …

Jonathan C. Trent, MD: With oligometastatic disease, there are a small number of metastatic sarcoma patients that can be cured with combination chemotherapy, metastasectomy.

R. Lor Randall, MD, FACS: Metastasectomy.

Robin L. Jones, MD, MRCP: But again I would almost argue that: is that due to the underlying biology of the disease rather than the use of one drug versus two drugs and the other modalities that are employed?

Brian A. Van Tine, MD, PhD: I feel like I’m having trouble controlling a presidential debate. I feel like we could actually talk about this for a good 3 hours and still get nowhere because this is why we have regional differences in the use of Adriamycin and ifosfamide.

Transcript Edited for Clarity