Insights From: Victor Villalobos, MD, PhD, University of Colorado School of Medicine; Saketh Guntupalli, MD, University of Colorado School of Medicine; Shreyaskumar R. Patel, MD, University of Texas MD Anderson Cancer Center; Anthony P. Conley, MD, University of Texas MD Anderson Cancer Center
Victor Villalobos, MD, PhD: In the gynecologic oncology field for sarcomas, what is your approach for the treatment of metastatic disease?
Saketh Guntupalli, MD: The first question we ask is, is this someone we can surgically debulk? I still believe that surgery is an incredibly important component of the armamentarium for the treatment of sarcomas. The important things to look at are those that we talked about before: performance status, ability to surgically resect, and ability to get all of the disease. I think that’s important. If we do that, and we’re looking at what adjuvant treatment is, after that, I certainly think that in the upfront setting, for most gynecologic oncologists, they would probably say gemcitabine and Taxotere [docetaxel]. That comes from what we think is very, very good data, out of Memorial Sloan Kettering, that looked at and found that there was a benefit in giving this doublet in patients with sarcomas.
The problem is, what happens later when they recur and they become metastatic again? That kind of goes into some of the new data that we see. I know that gemcitabine and Taxotere (docetaxel) have been compared, head-to-head, with single agent Adriamycin (doxorubicin). In looking at that, they found that there wasn’t a statistically significant difference between those 2 groups. And, Adriamycin had less toxicities. If you really look at that data, critically, those curves separate out quite nicely at 24 to 28 weeks, post-treatment. Once you look and see that, I think you find that Adriamycin is probably a little bit easier to give, with less side effects, than the doublet. So, we’re reaching this new area where we’re rethinking how we treat some of these disease processes. From there, we have some other options.
Victor Villalobos, MD, PhD: Going back to that paper, it’s a GeDDiS paper?
Saketh Guntupalli, MD: Right.
Victor Villalobos, MD, PhD: I had a couple issues with that paper, frankly, with the doses that they chose. Gemcitabine is likely the more active of the 2 drugs, and is also the easier of the 2 drugs. They chose a lower dose, 675 mg/m2. Typically, we give 900 mg/m2 over 90 minutes. They’ve maintained the higher dose of the docetaxel, 75 mg/m2, which is actually much more toxic and probably has less activity, although it does have some synergy. Do you think that the results would have been different if they chose a full dose of gemcitabine versus the lower dose? Or, maybe, even had the ability to modulate the dose of the docetaxel to lower doses to make it more tolerable?
Saketh Guntupalli, MD: Certainly, there are issues with every study. This was a phase II study, and you can kind of argue...
Victor Villalobos, MD, PhD: But it was randomized.
Saketh Guntupalli, MD: Yes, it’s randomized. But I do agree. I think that the dose of Taxotere was higher than what we would normally use in this setting. So, that might prejudice the data, somewhat, to have more side effects in the doublet arm as compared to the single arm. But still, I think the data is reasonably good. There was a significant difference in the number of patients that had to come off protocol. It was much higher in the gemcitabine and Taxotere arm, as compared to the single agent Adriamycin arm. And, those survival curves are reasonably good.
Victor Villalobos, MD, PhD: Overlapping, yes.
Saketh Guntupalli, MD: Yes, and then they kind of separate out, favoring the doxorubicin arm. So, while statistically not significant, if you really look at it and look at what a sarcoma patient is going to do, broadly, particularly, the ones that are going to respond, we do have to manage side effects. I think that’s really important.
Victor Villalobos, MD, PhD: What dosing do you use for gemcitabine and docetaxel?
Saketh Guntupalli, MD: Normally, we don’t use that combination in other gynecologic cancers, often. But 900 mg/m2, as you said, for the gemcitabine. We do tend to use a little bit of a lower dose, around 50 mg/m2 to 60 mg/m2, for the docetaxel. But that’s in other gynecologic cancers. I think that the higher dosing is probably what’s driving the toxicity in that study.
Victor Villalobos, MD, PhD: Has that study changed the way you practice?
Saketh Guntupalli, MD: Well, I have had a sarcoma case, already, in which I talked to the patient about giving adjuvant treatment. This was for a different situation then what we had been talking about previously. I did give her single agent Adriamycin, because that particular patient was coming from very far away. Logistically, it would have been difficult to give a doublet to her, just from the length of time it took to get that treatment. The other consideration was, this particular patient had a lot of comorbidities. And, exacerbating comorbidities in a patient that already has a cancer, I think, is something to weigh. So, we talked about the data and we elected to use the single agent.
Victor Villalobos, MD, PhD: There is some new data with a new molecule out there called olaratumab, which, to a certain degree, makes the GeDDiS trial obsolete if that phase III data comes out better. I don’t see that there’s any inherent problem with giving gemcitabine and docetaxel first. Nor do I see a problem with getting doxorubicin first. And, frankly, it may be tailored to the patient’s comorbidities. If someone already has severe neuropathy from diabetes, I’m going to lean away from the docetaxel, frankly.
Saketh Guntupalli, MD: Or, if somebody has CHF (congestive heart failure), or cardiomyopathy, you’re not going give them Adriamycin.
Victor Villalobos, MD, PhD: The benefit of gemcitabine/docetaxel is that if you find the proper dose, that the patient can tolerate, they can continue it indefinitely as long as they’re doing well. Whereas, with doxorubicin, you’re dose limited by the cumulative cardiac toxicity.
Saketh Guntupalli, MD: In that study, technically, there was no significant difference between either group. So, your comment, that you could really use either/or in the upfront setting, is correct. If you look at it rigorously, from a statistical point of view, there wasn’t a difference. What is nice is that we do have options, now. You can look at the patient and say, “Based on your comorbidities, based on what we think we could do, we have the option for both. We have something that likely works in both situations.”
Victor Villalobos, MD, PhD: For patients that received gemcitabine and docetaxel in the first-line therapy setting, far fewer of them actually received doxorubicin in the second-line setting.
Victor Villalobos, MD, PhD: I’m wondering how that affected the overall survival?
Saketh Guntupalli, MD: Oh, absolutely.
Victor Villalobos, MD, PhD: I’m willing to think that people are afraid of doxorubicin, to a certain degree. It’s a toxic drug, but people tolerate it quite well, frankly. I wonder if people that actually got gemcitabine/docetaxel may have been less enthusiastic about going on to doxorubicin, second-line?
Saketh Guntupalli, MD: That’s a very interesting point that you make, specific to gynecologic cancers. Because, previously, if you looked at how we treated endometrial cancer 20 years ago, or 25 years ago, that was actually one of the standard regimens for endometrial cancer: to incorporate doxorubicin into the treatment regimens. But as that has fallen out of favor, and we have randomized data to show that doublets like carboplatin and Taxol (paclitaxel) are as effective, a generation of gynecologic oncologists who give chemotherapy are not as familiar with giving Adriamycin. Therefore, they are almost concerned about it or are afraid to give it. We have to educate people, by working with our medical oncology colleagues, to know that these drugs do have efficacy and, yes, they’re toxic but those toxicities can be managed.
Victor Villalobos, MD, PhD: And, lastly and importantly, response to one class of therapy does not necessarily predict response or nonresponse to another class.
Saketh Guntupalli, MD: That’s very true.
Victor Villalobos, MD, PhD: Look at the patient we shared together. This patient had progressed within 3 to 4 cycles of gemcitabine and docetaxel. This patient had been on doxorubicin, and did great. I would give them all the benefit of the doubt and try both, at some point. I think it matters less about the timing of them.