Great Debates in Oncology: The Use of Adjuvant/Neoadjuvant Chemotherapy in Soft-Tissue Sarcoma - Round 3

Dr Van Tine: I think the both of you have done a really good job going back and forth, and so I’d like to evolve this topic one more time and get more specifically into what patient characteristics should be considered with determining the appropriateness of adjuvant/neoadjuvant therapy for localized sarcoma.

And I think this time we should begin with Robin.

Dr Jones: Thanks, Brian. So, I think, in many ways this almost reiterates the previous discussion. I think one of the things I really like about the histology tailored trial is that the inclusion/exclusion criteria were very strict in terms of the, particularly the tumor grade, tumor size, location, and histological subtypes included in the trial. So, I think it’s very important that we recognize that there are tumors that are very high risk for the development of recurrent disease and I think in this population it’s very important to have this discussion regarding the pros and cons of neoadjuvant/adjuvant chemotherapy.

As Jon mentioned earlier on, some patients decide that they don’t want to have chemotherapy because the supporting evidence is not to the standard that they would like, plus there is the small but very important risk of long-term complications, such as secondary leukemias, cardiac and renal toxicity.

I think as well, as Jon mentioned, ifosfamide is a toxic drug. It’s a very effective drug, a very important drug, but it clearly is a drug that we need to be thoughtful and careful administering to individual people. And clearly, we need to take into consideration performance status, comorbidities, age, concurrent medication, when weighing up the pros and cons of neoadjuvant or adjuvant chemotherapy. So, I think we need to be conscious of all of these things when discussing the role of neoadjuvant/adjuvant chemotherapy.

Dr Trent: Yeah, Robin, great points and I fully agree and, Robin, the considerations of the patient are ultimately the most important factor in our discussion today.

So, we do see patients that have these high-grade, high-risk sarcomas and we have to help them and we have to participate in the discussions. We have to provide our recommendations in the context of the best data available, but at the end of the day, the patient may decide they want to proceed with the beneficial chemotherapy, or they want to take the risk of no chemotherapy, and they have to also make decisions about potential side effects, and I often—I’d be interested to hear how you 2 approach it—when I do make a decision about neoadjuvant or adjuvant chemotherapy, we also discuss that the patient ultimately has the decision to stop at any time.

If I’m recommending 6 cycles of doxorubicin plus ifosfamide as the plan, then they may take 1 cycle and say, “Hey, this is just not for me.” And that’s perfectly reasonable, and I encourage them to make that decision if they want to, and I will support them, their decision, either way. And so, it’s, it ultimately comes down to the patient and important factors of the patient. Robin mentioned pretty much all of those that we take into consideration when we’re assessing the ability of a patient to tolerate a given chemotherapy.

There’s one thing that I’d like to mention also in the neoadjuvant/adjuvant and using some of the novel therapies in the adjuvant setting such as trabectedin, eribulin, even pazopanib. And I think we can also make the case that olaratumab should be studied in the adjuvant setting; it’s a recently improved anti-PDGF receptor antibody that, when added to doxorubicin in the metastatic setting, provides a nearly 1 year addition of survival, and if the phase 3 study supports that observation, then that’s a very active drug that one would be compelled to study in the context of a clinical trial potentially, and anthracycline, or an anthracycline plus ifosfamide in combination with olaratumab in the adjuvant or neoadjuvant setting in order to take advantage of that 1 year survival activity.

So, I think we need to do some of these novel agents, we need to mix them into histology specific therapy. I wonder whether or not longer durations of therapy are needed in the appropriate patients. I wonder, at the end of the day, whether survival is also the best end point. Are there any surrogate end points for neoadjuvant or adjuvant therapy, or biomarkers that might one day replace survival?

Survival… It just takes a long time to get to that end point and patients need more, better therapies today.

Dr Jones: One of the interesting things regarding the histology tailored trial is that the sort of standard that they used was 3 cycles of epirubicin and ifosfamide, and the Italians had previously done a trial in high-risk patients, or patients with high-risk tumors of 3 versus 5 cycles of anthracycline plus ifosfamide, suggesting that they were equal in terms of efficacy, but clearly, the 2 cycles were easier to tolerate. So, I think Jon is absolutely spot on that we need to do more trials in the neoadjuvant setting, and more sort of thoughtful trials in the way of specific histological subtypes, and as I say, with the incorporation of putative molecular and functional imaging markers of benefit.

So, I think it’s a very interesting time in terms of drug development for sarcomas, and there are lots of potential trials that we could perform in the localized disease setting.

Dr Van Tine: I’d like to thank both of you, and I’d like to give you both an opportunity for a 1-minute summary and concluding statement based on everything you’ve said over the last hour.

And would we like to start with Jon?

Dr Trent: So, we discussed a lot of data today. As with any clinical trial, there are going to be criticisms and critiques, there are going to be highlights, and there are going to be questions about the trial design. But at the end of the day, we really have about 4 or 5 large, randomized clinical trials, sarcoma meta-analysis, or combined analysis. It’s really what we have and we have to review that data, interpret it the best that we can, and come away with the conclusions that we believe are, we can apply to optimize the therapy and survival of our patients who have these high-grade, large sarcomas.

That’s the goal at the end of the day, and I think we all—Brian Van Tine, Robin Jones, myself—all have exactly the same goals. And we may interpret the data a little differently, and my approach and the patients that I see at Sylvester Comprehensive Cancer Center are interested in chemotherapy. They come here often because they are looking for chemotherapy, and although the data are not pristine, the interpretation of the data can be in the favor of adjuvant or neoadjuvant chemotherapy. And as I said earlier, we perform neoadjuvant chemotherapy whenever we can, and prefer that (just like Robin) over adjuvant chemotherapy.

Another point I would like to make is that patients should always be considered for clinical trials. It’s the only way we’re going to advance the field. The only way we’re going to get better data is to continue our clinical research such that we can one day get closer towards a cure.

I’d like to end by thanking you for listening, thanking you for taking time out of your busy day, and I’d be delighted if you have a question, you can e-mail me at jtrent@med.miami.edu or you can follow me on Twitter at @jtrentmdphd.

I look forward to hearing from you, and thank you, Brian, for inviting me to participate.

Dr Van Tine: And Dr Jones?

Dr Jones: So, again, I’d like to say thank you for the invitation. I’ve really enjoyed this session. I’ll be concise in terms of my summing up. I think, currently, there are no conclusive data from randomized trials to suggest that adjuvant chemotherapy is beneficial. As we discussed, there are potential long-term toxicities from anthracyclines and alkylating agents, although the risk of these is small.

Having said that, I think the recent histology tailored chemotherapy trial performed by the Italian, French, and Spanish sarcoma groups is very interesting. I commend those investigators for performing this trial in a really well-defined group of patients with high-risk disease (ie, large extremity and trunk soft-tissue sarcomas of high grade and deep anatomic location). And I think that this is really good, and it shows that we can perform large clinical trials in the neoadjuvant setting.

And, as Jon mentioned, the future should be clinical trial participation, and we should look at better ways of identifying patients who will benefit from neoadjuvant or adjuvant chemotherapy and try to identify better systemic therapies in order to eliminate the development of metastatic disease. So, to sort of reiterate that point, it’s really important that everybody—all sarcoma patients—are offered the chance to participate in a clinical trial.

So, with that I’ll say thank you and, similarly, if you want to contact me my e-mail is robin.jones4@nhs.net, and thanks again for the opportunity to take part.

Dr Van Tine: I’d like to thank both of you. It’s neat to bring together world leaders to have a discussion about the treatment of sarcoma, and just as I believe, as I’ve been listening, I think it becomes fairly obvious why the guidelines say the patients should be managed, but not necessarily treated, by people with extensive experience in this.

And so, with that I would like to conclude, and since you both threw out your e-mails I feel obligated to do the same, so mine is bvantine@wustl.edu, and so I’m happy also to hear from any of you.

And so, with that we will conclude, and I thank everybody for their time.