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Chemotherapy Considerations in Locally Advanced NSCLC

Panelists: Charu Aggarwal, MD, MPH, Hospital of the University of Pennsylvania; Hossein Borghaei, DO, Fox Chase Cancer Center; H. Jack West, MD, Swedish Cancer Institute
Published: Monday, Jan 14, 2019



Transcript:

H. Jack West, MD: I certainly see a lot of patients in a broader community setting where they’re not extremely fit. It can be a challenge but the weekly CARBO [carboplatin]/paclitaxel regimen is one that pretty much any ambulatory patient can pursue. And the fact that it’s weekly gives you the opportunity for regular feedback. Thoughts on what do you think is an appropriate regimen? In the PACIFIC trial, they gave a range, so would you say that there’s kind of a regimen of choice or is it a pretty broad range of what would be acceptable these days? Charu, can I start with you?

Charu Aggarwal, MD, MPH: I would say pre-PACIFIC, I was following the cisplatin/etoposide regimen as a choice much more vigorously, at least in my younger, fitter, healthier patients and reserving carboplatin and paclitaxel weekly with radiation for my older patients. And that wasn’t really based on phase III randomized data. That was just based out of yes, cisplatin/etoposide has been tested in the SWOG [Southwest Oncology Group] study and showed that it was superior. However, I think post-PACIFIC, I do feel comfortable that I can give patients carboplatin and paclitaxel. I certainly don’t want to put patients in a situation where I’m giving them cisplatin and etoposide and preventing them from receiving immunotherapy at the back end. Because we do know that cisplatin is much more toxic than carboplatin, I mean let’s be real.

I do feel comfortable using it, and I think the other question is what to do about consolidation. Do we still use carboplatin and paclitaxel consolidation with the systemic dosing post-chemo-RT [post-chemoradiation therapy]? I’ve frankly given up on doing consolidation. I try and come back in with durvalumab as quickly as I can after completion of chemoradiation. There was never real randomized data to suggest that consolidation chemotherapy benefits people. I mean, there’s been Japanese data that have shown us, actually, that consolidation does not add anything other than toxicity. I would say that I’m much more comfortable using carboplatin and paclitaxel.

H. Jack West, MD: Hoss, I’ll be interested in your thoughts. I was raised in the SWOG system and really have historically preferred cisplatin and etoposide. It’s a very reasonable regimen but not necessarily for everybody and certainly with its challenges. For me, seeing a broader body of data, such as from the RTOG [Radiation Therapy Oncology Group] and various other studies, looking at a weekly CARBO/paclitaxel regimen and showing pretty comparable results has emboldened me that that’s a very reasonable alternative. And that was actually the most commonly used regimen in PACIFIC. So, Hoss, what do you think about CARBO/paclitaxel versus cisplatin versus other regimens? And specifically, one of the issues that I think many devotees of CARBO/paclitaxel have is this issue of, well, weekly CARBO/paclitaxel doesn’t give a systemic dose of chemotherapy and I really relied on consolidation but now I can’t or should I?

Hossein Borghaei, DO: Right. So, actually, that question is packed. You guys have raised several important issues. Let’s start from the top. There’s no randomized data suggesting that any of the regimens that we’re using is better than the other one. So it’s a fallacy to say that CIS [cisplatin]/etoposide or CARBO/PEM [pemetrexed], or CIS/PEM is any better than any of the other ones. We have randomized comparisons for a lot of these regimens, and we’re not seeing major differences. Fact number 2: There has not been a single phase III study showing that any kind of consolidation before PACIFIC had any effects. So, in fact, docetaxel was a little bit more detrimental, if I remember the Hoosier Oncology [Group] phase III studies. So why do you want to do the consolidation?

Now, the weekly CARBO/Taxol [paclitaxel] poses a special issue, right? Why we do the 2 big doses of CARBO/Taxol afterwards is because of metastatic spread, the cancer cells being around. You want to make sure you have some systemic therapy, but that’s all pre-PACIFIC data. The reality is that we live in a little bit of a data-free zone right now because PACIFIC did not look at that specific question. And let’s keep in mind the 28% of patients who got on PACIFIC, if I again recall correctly, got induction chemotherapy with full-dose chemotherapy before they went to the concurrent arm of the study.

So what does all of this mean for my practice? I still like to give full-dose chemotherapy if I can because I sort of believe in that metastatic elimination, so I like CIS/etoposide. I’ve used it a lot. For my nonsquamous patient population, I kind of like the platinum/pemetrexed approach. I don’t see anything wrong with that. It gives you 2 or 3 full doses. But if I do weekly CARBO/Taxol, I’m with you, I don’t feel the need to give the 2 big doses after chemo-RT, and I’d rather start the DURVA [durvalumab] earlier. Would I fault somebody? Let’s assume you want to do the weekly CARBO/Taxol and you still want to give the full dose. Well, that takes 6 weeks. You’re still within roughly the window of PACIFIC because you’re in that magical 42-day time period that they allow.

The issue that we all have is that we are interpreting the PACIFIC trial as indicating that the sooner you start the DURVA, the better the outcome, when in reality it might be that the patients who got started on DURVA sooner had better performance status, had less burden of disease, they tolerated the concurrent part of everything a little bit easier. That’s why they got the DURVA a little bit earlier. So there was a natural selection.

H. Jack West, MD: So to step back, there has been a post hoc analysis that looked at time initiating DURVA after completion of chemoradiation and showing that the best results were in the patients, the relatively small subset in the initial iteration of the trial who started within 2 weeks. That was not broadly feasible, and they had to widen the eligibility to a 6 week interval. So, yeah, I agree with you that a lot has been made of this “best results in the patients earlier.” But that’s not a clear cause and effect. It’s not a randomized finding.

Hossein Borghaei, DO: Exactly.

H. Jack West, MD: There’s very good reason to think that those patients are not the same patients who required 5, 6 weeks to be at that point.

Transcript Edited for Clarity 

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Transcript:

H. Jack West, MD: I certainly see a lot of patients in a broader community setting where they’re not extremely fit. It can be a challenge but the weekly CARBO [carboplatin]/paclitaxel regimen is one that pretty much any ambulatory patient can pursue. And the fact that it’s weekly gives you the opportunity for regular feedback. Thoughts on what do you think is an appropriate regimen? In the PACIFIC trial, they gave a range, so would you say that there’s kind of a regimen of choice or is it a pretty broad range of what would be acceptable these days? Charu, can I start with you?

Charu Aggarwal, MD, MPH: I would say pre-PACIFIC, I was following the cisplatin/etoposide regimen as a choice much more vigorously, at least in my younger, fitter, healthier patients and reserving carboplatin and paclitaxel weekly with radiation for my older patients. And that wasn’t really based on phase III randomized data. That was just based out of yes, cisplatin/etoposide has been tested in the SWOG [Southwest Oncology Group] study and showed that it was superior. However, I think post-PACIFIC, I do feel comfortable that I can give patients carboplatin and paclitaxel. I certainly don’t want to put patients in a situation where I’m giving them cisplatin and etoposide and preventing them from receiving immunotherapy at the back end. Because we do know that cisplatin is much more toxic than carboplatin, I mean let’s be real.

I do feel comfortable using it, and I think the other question is what to do about consolidation. Do we still use carboplatin and paclitaxel consolidation with the systemic dosing post-chemo-RT [post-chemoradiation therapy]? I’ve frankly given up on doing consolidation. I try and come back in with durvalumab as quickly as I can after completion of chemoradiation. There was never real randomized data to suggest that consolidation chemotherapy benefits people. I mean, there’s been Japanese data that have shown us, actually, that consolidation does not add anything other than toxicity. I would say that I’m much more comfortable using carboplatin and paclitaxel.

H. Jack West, MD: Hoss, I’ll be interested in your thoughts. I was raised in the SWOG system and really have historically preferred cisplatin and etoposide. It’s a very reasonable regimen but not necessarily for everybody and certainly with its challenges. For me, seeing a broader body of data, such as from the RTOG [Radiation Therapy Oncology Group] and various other studies, looking at a weekly CARBO/paclitaxel regimen and showing pretty comparable results has emboldened me that that’s a very reasonable alternative. And that was actually the most commonly used regimen in PACIFIC. So, Hoss, what do you think about CARBO/paclitaxel versus cisplatin versus other regimens? And specifically, one of the issues that I think many devotees of CARBO/paclitaxel have is this issue of, well, weekly CARBO/paclitaxel doesn’t give a systemic dose of chemotherapy and I really relied on consolidation but now I can’t or should I?

Hossein Borghaei, DO: Right. So, actually, that question is packed. You guys have raised several important issues. Let’s start from the top. There’s no randomized data suggesting that any of the regimens that we’re using is better than the other one. So it’s a fallacy to say that CIS [cisplatin]/etoposide or CARBO/PEM [pemetrexed], or CIS/PEM is any better than any of the other ones. We have randomized comparisons for a lot of these regimens, and we’re not seeing major differences. Fact number 2: There has not been a single phase III study showing that any kind of consolidation before PACIFIC had any effects. So, in fact, docetaxel was a little bit more detrimental, if I remember the Hoosier Oncology [Group] phase III studies. So why do you want to do the consolidation?

Now, the weekly CARBO/Taxol [paclitaxel] poses a special issue, right? Why we do the 2 big doses of CARBO/Taxol afterwards is because of metastatic spread, the cancer cells being around. You want to make sure you have some systemic therapy, but that’s all pre-PACIFIC data. The reality is that we live in a little bit of a data-free zone right now because PACIFIC did not look at that specific question. And let’s keep in mind the 28% of patients who got on PACIFIC, if I again recall correctly, got induction chemotherapy with full-dose chemotherapy before they went to the concurrent arm of the study.

So what does all of this mean for my practice? I still like to give full-dose chemotherapy if I can because I sort of believe in that metastatic elimination, so I like CIS/etoposide. I’ve used it a lot. For my nonsquamous patient population, I kind of like the platinum/pemetrexed approach. I don’t see anything wrong with that. It gives you 2 or 3 full doses. But if I do weekly CARBO/Taxol, I’m with you, I don’t feel the need to give the 2 big doses after chemo-RT, and I’d rather start the DURVA [durvalumab] earlier. Would I fault somebody? Let’s assume you want to do the weekly CARBO/Taxol and you still want to give the full dose. Well, that takes 6 weeks. You’re still within roughly the window of PACIFIC because you’re in that magical 42-day time period that they allow.

The issue that we all have is that we are interpreting the PACIFIC trial as indicating that the sooner you start the DURVA, the better the outcome, when in reality it might be that the patients who got started on DURVA sooner had better performance status, had less burden of disease, they tolerated the concurrent part of everything a little bit easier. That’s why they got the DURVA a little bit earlier. So there was a natural selection.

H. Jack West, MD: So to step back, there has been a post hoc analysis that looked at time initiating DURVA after completion of chemoradiation and showing that the best results were in the patients, the relatively small subset in the initial iteration of the trial who started within 2 weeks. That was not broadly feasible, and they had to widen the eligibility to a 6 week interval. So, yeah, I agree with you that a lot has been made of this “best results in the patients earlier.” But that’s not a clear cause and effect. It’s not a randomized finding.

Hossein Borghaei, DO: Exactly.

H. Jack West, MD: There’s very good reason to think that those patients are not the same patients who required 5, 6 weeks to be at that point.

Transcript Edited for Clarity 
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