Panelists:Ezra Cohen, MD, FRCPSC, FASCO, UC San Diego; Joshua M. Bauml, MD, University of Pennsylvania; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center; Barbara A. Burtness, MD, Yale University School of Medicine
Ezra Cohen, MD: I want to move on from induction chemotherapy and talk about some of the data that came out at this year’s ASCO meeting around how to refine chemotherapy radiation; where we’re going forward, perhaps revisiting some standards. Josh, tell us some of the data that excited you out of this year’s ASCO meeting.
Joshua M. Bauml, MD: The one that excited me the most surrounded cisplatin dosing. So, we’ve discussed cisplatin 100 mg/m2 bolus dosing. That’s a big dose of cisplatin. The toxicity is substantial. And so, what many people have been doing is using a weekly dose of cisplatin along with radiation—and we’re doing that with scant data, I think I could say, generously.
Jared Weiss, MD: Scant to negative.
Joshua M. Bauml, MD: Scant to nonexistent.I think under the table, there are some data.There are phase II data in single arm studies showing that it’s effective. But when you put those up against phase III randomized studies, it’s really hard. The problem is when you have a patient who has significant morbidities, significant comorbidity going in, and you’re a little hesitant about giving them 100 mg/m2 cisplatin along with radiation. I think that some of those data regarding weekly dosing, usually at 40 mg/m2, are quite appealing, especially given the fact that the underlying mechanism of action purported for cisplatin with radiation is as a radiation sensitizer. So, it makes biologic sense, even, to spread out the cisplatin to have it in the system throughout the radiation. Here, I’m obviously waving hands a little bit, but there’s a reason to think this might work.
Jared Weiss, MD: Figuratively and literally.
Joshua M. Bauml, MD: Exactly. So, there were 2 studies at ASCO this year that looked at this with trials. I want to talk first about one done in China in nasopharyngeal cancer. And in that study, they randomized patients to weekly 40 mg/m2 of cisplatin or 2 doses of high-dose cisplatin, 100 mg/m2, which is not the standard of care, traditionally. It’s usually 3 doses. In any case, they found that the overall survival, locoregional control, and any cancer outcome you look at were identical between the 2 groups. What was interesting about that study, though, was that they found the toxicity was greater for weekly dosing. Now this was an abstract, so I don’t know how frequently they checked CBCs in the every-3-week dosing. So, they noticed more cytopenias in the weekly dosing. I’m wondering if there were more CBCs done in that group as well, but I don’t know at this juncture. That study was done in nasopharyngeal cancer, again in China—so, EBV, a different patient population.
The other study, which was done in India, purported to look at chemoradiation just in general in head and neck cancer. But over 90% of the patients on that study were receiving adjuvant chemoradiotherapy for oral cavity cancer. The reason why that’s relevant, and why it’s specified that the study was done in India, is that the exposures of lead to oral cavity cancers in India are quite different than the exposures that occur in the United States. Specifically, the use of betel nuts and smokeless tobacco is at a much higher rate in that population. They found that while the overall survival was the same between high-dose and weekly dosing—which, by the way, used 30 mg/m2, not 40 mg/m2—the locoregional control was significantly worse with the weekly dosing. Where does this leave me in terms of the use of weekly dosing? I’m just as confused as when I walked in. And so, I think that there are significant limitations to both of these studies, but it’s really hard to imagine a robust phase III study that’s really going to answer this question. I think that efforts to look at retrospective large series would be an appropriate next step to really get at this from an American, United States population.
Barbara A. Burtness, MD: Although those series may contain the bias that we all give the 100 mg/m2 when we can, and we give the 40 mg/m2 when we don’t think we can give the 100 mg/m2.
Jared Weiss, MD: The other thing to note is that a lot of the United States are not using 40 mg/m2 as their standard. I agree with both of your comments, that when weekly is used, it should be the preferred regimen. But having spoken to a lot of community doctors, I think it’s more often the 30 mg/m2 that they’re using, which is a legitimately de-intensified regimen, for better and for worse.
Ezra Cohen, MD: So, Jared, you would advocate, if you’re going to use weekly, use the 40 mg/m2?
Jared Weiss, MD: Yes. So, in my mind, if you have a patient whose risk is high enough that you really think you need chemotherapy added in, your main goal in using weekly is not necessarily to de-escalate, but rather to have only 1 week of the drug stuck in the patient if you start to get into trouble. You can adjust dose or bail as the patient needs on a weekly basis, instead of an every-3-week basis. And you see them a lot more and provide more supportive care.
Barbara A. Burtness, MD: The peak dose may be somewhat tied to autotoxicity and nephrotoxicity. So, for the person who’s got the borderline audiogram or the hypertensive patient who’s on 3 drugs…
Jared Weiss, MD: But I’m not advocating a de-escalation, just a breaking up.
Barbara A. Burtness, MD: So, one of the interesting things about the Noronha presentation was this implication, again, that high-dose Q3 week was not as toxic as the weekly schedule. But it came out in the presentation that they had provided significantly more supportive care for the 100 mg/m2, because they were so concerned that it wouldn’t be feasible: more hospitalization for hydration and so forth.
Joshua M. Bauml, MD: In the 100 mg/m2, the adverse events, I believe, were higher than they were in weekly, which is what I’d expect from a clinical perspective, but they were not unmanageable.
Barbara A. Burtness, MD: And they were different.
Joshua M. Bauml, MD: Yes, they were different.
Ezra Cohen, MD: So, Barbara, I would completely agree with you. One thing that is definitively coming out, in terms of toxicity, is that the high-dose cisplatin does have high rates of autotoxicity and likely higher rates of nephrotoxicity, because that’s related to Cmax of the drug and you’re going to get a higher Cmax with 100 mg/m2. I’ll tell you my take on the 2 studies that you were talking about. One is that 40 mg/m2 to me seems to be actually more toxic than the every-3-weeks without a significant signal that it’s more efficacious, while the 30 mg/m2, as you alluded to, Jared, appears to be less efficacious. In a patient who we’re trying to cure, maybe that’s not the optimal dose. And to me, personally, I came out of the meeting thinking that this was an advocacy for the every-3-week 100 mg/m2. That’s a bit of editorializing.