What after neoadjuvant CT-RT for Lung Ca that remained inoperable?

[Kroll2013]

Dear Colleagues,

I hope you are safe.
I need your advice concerning my patient 65 years old, who initially presented (at another institution) for a left lung para-hilar mass, 5cm, involving the left lingular bronchi, N2 on Pet, M0. Biopsy: Poorly differentiated NSCLC, EGFR neg, ALK neg, PD-L1 90%
He received neo-adjuvant CT (CDDP-Navelbine) + RT 45Gy/25fr.
He had a partial response but still inoperable. Last RT session was on october 26/10/20.
What to do ?
Do you recommend SBRT to the residual pet+ hilar lesion, yN0?
Is it safe at this stage ? What regimen?
Is there another option ?

Ty

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[Palex80]

The treatment break is quite long with over 3 months. What did the restaging actually show, you said "residual pet+ hilar lesion, yN0?"
Is only the hilar lesion left and the N2 node disappeared?

 

[FrostyHammer]

This is a great example of why it's nearly always a better decision to treat locally advanced lung cancer definitively than a planned trimodal method.

 

[RADONC4285]

I would hesitate to offer sbrt to a 5 cm mass that's borderline central even in the upfront setting, let alone following ChemoRT to 45 Gy. I would say come up with some sort of conventional fractionation to give additional dose vs just proceeding with immunotherapy

I also agree with above. It's quite rare to actually downsize the patient to become operable. I question the utility of trimodality therapy now that we know 5 year survival approaches 50% with ChemoRT followed by immunotherapy

 

[Kroll2013]

The treatment break is quite long with over 3 months. What did the restaging actually show, you said "residual pet+ hilar lesion, yN0?"
Is only the hilar lesion left and the N2 node disappeared?

yes N0

 

[Kroll2013]

I would hesitate to offer sbrt to a 5 cm mass that's borderline central even in the upfront setting, let alone following ChemoRT to 45 Gy. I would say come up with some sort of conventional fractionation to give additional dose vs just proceeding with immunotherapy

I also agree with above. It's quite rare to actually downsize the patient to become operable. I question the utility of trimodality therapy now that we know 5 year survival approaches 50% with ChemoRT followed by immunotherapy

I totally agree

 

[Kroll2013]

I would hesitate to offer sbrt to a 5 cm mass that's borderline central even in the upfront setting, let alone following ChemoRT to 45 Gy. I would say come up with some sort of conventional fractionation to give additional dose vs just proceeding with immunotherapy

I also agree with above. It's quite rare to actually downsize the patient to become operable. I question the utility of trimodality therapy now that we know 5 year survival approaches 50% with ChemoRT followed by immunotherapy

would a 5*5 regimen be safe and effective? only risk is the primary bronchial tree that normally tolerates till 80 Gy max dose in conventional fractionation.
45 +5*5 slightly above 80Gy Dmax

 

[RADONC4285]

would a 5*5 regimen be safe and effective? only risk is the primary bronchial tree that normally tolerates till 80 Gy max dose in conventional fractionation.
45 +5*5 slightly above 80Gy Dmax

That's likely safe. You're right, if you keep hot spots out of PBT, then your max eqd2 is a little over 80 Gy, which should be fine

 

[Ray D. Ayshun]

Immunotherapy for a few months and restage?

 

[scarbrtj]

Rx of 8.5 Gy times 2 fractions. (I'd do it over two days instead of seven.) This is a modest recommendation yet has a high probability of being very safe if you do it very conformally. But even "modest" radiotherapy can, occasionally, be "curative." Never say never. (Ongoing immunotx an absolute must of course.) 45/25 plus 17/2 has a late BED of about 80 Gy in 40 fractions; this is of course in the ballpark of known safe doses.

 

[Palex80]

I agree with 5 x 5 Gy or perhaps even more with a constraint on the bronchial tree.

I have treated a few central recurrences after 60/2 with chemo. I haven't seen any issues so far.
Time is certainly an issue there, but if you can safely deliver 10 x 5 Gy for a recurrence 1-2 years after 30 x 2 Gy with chemo, then you can certainly do at least 5 x 5 Gy with a 3 month break after 25 x 1.8 Gy with chemo.

 

[evilbooyaa]

Agree with consideration to treat as tolerated based on dose constraints, dependent on previous treatment's DICOMs, EQD2 calculations, and dose selection. I agree with EQD2 of 80Gy at a/b3 sounds reasonable to me as a bronchial tree constraint.

 

[Ray D. Ayshun]

So what's getting treated? Just the primary?

 

[beamotherapy]

With PDL1 of 90% I would push for immunotherapy first and then only do re-RT if there was non-responding local disease and no distant disease

 

[FrostyHammer]

With PDL1 of 90% I would push for immunotherapy first and then only do re-RT if there was non-responding local disease and no distant disease

Got any evidence based indications to spend that kind of money? Or is it another recommendation for off-label hemorrhaging of healthcare dollars?

 

[Ray D. Ayshun]

Got any evidence based indications to spend that kind of money? Or is it another recommendation for off-label hemorrhaging of healthcare dollars?

We've already left evidence-based in the present case. The plan to treat the residual mass 5x5 seems neither palliative nor definitive. Its not clear to me what the intent of more rt is here beyond just treating the imaging. His mediastinum has not been adequately treated. Is there no way to get further from the original course to allow an actual attempt at true re-rt? Seems immunotherapy may allow for that here. The patient should be able to foot the bill after his successful lawsuit against the "other institution."

 

[radiation]

I think immunotherapy very reasonable here. Patient got concurrent chemoradiation to a dose of 45 gy (PACIFIC allowed for as low as 54gy) and if he got a little more radiation, nobody would blink if he went straight to IO after completion of chemorads (PACIFIC allowed up to 42 days after XRT). 3 months is a little long so I don't know if it will be as effective. But single agent or combo IO I think is certainly reasonable here and has more data than re-RT.

Whats the max SUV of the node? Could it be a false positive? Is it easy to biopsy?

 

[FrostyHammer]

We've already left evidence-based in the present case. The plan to treat the residual mass 5x5 seems neither palliative nor definitive. Its not clear to me what the intent of more rt is here beyond just treating the imaging. His mediastinum has not been adequately treated. Is there no way to get further from the original course to allow an actual attempt at true re-rt? Seems immunotherapy may allow for that here. The patient should be able to foot the bill after his successful lawsuit against the "other institution."

Yes but the price tag for a little extra RT vs the price tag for immunotherapy... I'm sure there's no need to even do the math.

 

[FrostyHammer]

I think immunotherapy very reasonable here. Patient got concurrent chemoradiation to a dose of 45 gy (PACIFIC allowed for as low as 54gy) and if he got a little more radiation, nobody would blink if he went straight to IO after completion of chemorads (PACIFIC allowed up to 42 days after XRT). 3 months is a little long so I don't know if it will be as effective. But single agent or combo IO I think is certainly reasonable here and has more data than re-RT.

Whats the max SUV of the node? Could it be a false positive? Is it easy to biopsy?

Bingo - you said it. 3 months delay may not make it effective and a waste of healthcare dollars. Remember, one of the hypothesis generating unspecified subgroup analyses of PACIFIC that people are seriously talking about is that IO seemed to only benefit if given within 14 days of RT. Many people thinking that it means IO is best to give in an "acutely inflamed" environment, which makes mechanistic sense. 3 month delay? Not so much.

 

[Ray D. Ayshun]

Yes but the price tag for a little extra RT vs the price tag for immunotherapy... I'm sure there's no need to even do the math.

My argument is that a little extra RT to a portion of the original treatment volume serves no real purpose, and only burns the bridge for real re-RT. My question really is, if this patient can make it to, say, this October without distant progression, would it be possible to reirradiate him with definitive intent? Maybe not. Even if you wedge in the 5x5 pallfinitive regimen, does he still get io afterwards?

 

[FrostyHammer]

My argument is that a little extra RT to a portion of the original treatment volume serves no real purpose, and only burns the bridge for real re-RT. My question really is, if this patient can make it to, say, this October without distant progression, would it be possible to reirradiate him with definitive intent? Maybe not. Even if you wedge in the 5x5 pallfinitive regimen, does he still get io afterwards?

Honestly, if this patient makes it to any time with any level of non-distant progression as detected on imaging, then there's an evidence-based level 1 indication to give immunotherapy for previously treated relapsed NSCLC. In that case, re-RT it's basically a mood point because of that level 1 indication. So I don't think any bridges would be burned if he would be treated with RT now. If there was a concern for burning the bridges in the future, it's probably best to deliver RT to a more aggressive dose than 5x5. I would personally attempt for a dose that, when accounting for the initial RT, would give you an EQD-2 of at least 70 Gy. If one wants to be extra cognizant, he/she can hypothetically take into account the 3-month delay and expected loss of local control and translate that into how much additional dose would be required (aka a scarbtj type of exercise) while maintaining OAR limits.

 

[w00tz]

Yes but the price tag for a little extra RT vs the price tag for immunotherapy... I'm sure there's no need to even do the math.

This patient will get immunotherapy sooner or later...

 

[Palex80]

So what's getting treated? Just the primary?

This is a very good question. What we have sometimes done for SBRT of central lesions or those with N1 involvement is to encompass the next N2 station into a PTV with a lower dose when they were not positive on PET/EBUS, but could be involved anyway. This is something which can easily be done for the 4R/L station whent treating the hilus.
So, if the N2-station that was positive in this patient was close to the N1 disease and responded to the neoadjuvant part of the treatment (as it seems to have happened), one could opt to irradiate this N2 station during SBRT.
If one was planning to deliver 5 x 5 Gy to the residual N1, perhaps prescribing 5 x 3.5-4 Gy to the N2 node is an option. This is not an ablative dose, but 5 x 3.5-4 Gy could be enough to kill of any microscopic involvement in that N2 node.

 

[Palex80]

Bingo - you said it. 3 months delay may not make it effective and a waste of healthcare dollars. Remember, one of the hypothesis generating unspecified subgroup analyses of PACIFIC that people are seriously talking about is that IO seemed to only benefit if given within 14 days of RT. Many people thinking that it means IO is best to give in an "acutely inflamed" environment, which makes mechanistic sense. 3 month delay? Not so much.

This belief is based on a non-planned, post-hoc analysis of the PACIFIC data. It's not a proven fact. It could very well be that patients that get their immunotherapy "faster" after completion of CRT are:
a) the fitter ones
b) taken care of in a better hospital setting

Please, do remember how PACIFIC was designed. Patients were screened and randomized AFTER showing CR/PR/SD following CRT. Restaging, screening, consenting and starting immunotherapy within 14 days after completion of CRT is not trivial.

I think all patients should get immunotherapy following CRT for stage III NSCLC, as long as they show CR/PR/SD, time is not a factor.

 

[scarbrtj]

he/she can hypothetically take into account the 3-month delay and expected loss of local control and translate that into how much additional dose would be required (aka a scarbtj type of exercise) while maintaining OAR limits

Haha it should be an "everybody" type exercise. OTOH that 3 month delay makes things really, really subjective. In theory one subtracts ~0.5 BED-Gy10 per (elapsed, including weekends) day of treatment (assuming we know the alpha component of alpha/beta). A 5 week treatment, and 3 month break, plus maybe a week more treatment, mean the treatment package is so chronologically long that the BED-Gy10 is nearly zero, or negative... a reductio ad absurdum.

 

[Lamount]

If patient has good performance status, can give a boost to the area. Others have suggested 80 Gy EQD2... I am a little more aggressive with my bronchial constraints. Based on this paper, I allow
Max dose 100 Gy (EQD2 a/b =3)
D1 < 90 Gy.
(which is actually conservative by their numbers)

Based on your clinical situation, you may be able to get in another 35-40 Gy in 15 fractions, depending on anatomy. This may help offset some of the re-population issues

 

[FrostyHammer]

This patient will get immunotherapy sooner or later...

No guarantees ever, but with immunotherapy the kicker is that they are often left on it indefinitely (especially if off-label), so it can get quite pricey if you start it up-front versus wait. may not seem like a big deal but financially it clearly is.

 

[FrostyHammer]

This belief is based on a non-planned, post-hoc analysis of the PACIFIC data. It's not a proven fact. It could very well be that patients that get their immunotherapy "faster" after completion of CRT are:
a) the fitter ones
b) taken care of in a better hospital setting

Please, do remember how PACIFIC was designed. Patients were screened and randomized AFTER showing CR/PR/SD following CRT. Restaging, screening, consenting and starting immunotherapy within 14 days after completion of CRT is not trivial.

I think all patients should get immunotherapy following CRT for stage III NSCLC, as long as they show CR/PR/SD, time is not a factor.

Totally agree, Palex - I was just making a note of the mechanistic fact as a potential explanation which is academically intriguing and being explored further now as a result of those findings.

 

[radiation]

What if we reframed it this way - is total biologic dose given with any re-RT regimen in this situation higher or lower than a cumulative EQD2 of 74 gy? If we all agree that 74 gy is too toxic, then I think its not a huge leap to think that the TCP and NCTP curves are just too close in this area and further RT is just as likely to hurt than to help.

If you look at the pts getting combo IO with TPS >50%, the results are pretty impressive and almost all of them beat the dose escalated arm of RTOG 0617.

Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer - PubMed

First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.

pubmed.ncbi.nlm.nih.gov

 

[Palex80]

What if we reframed it this way - is total biologic dose given with any re-RT regimen in this situation higher or lower than a cumulative EQD2 of 74 gy? If we all agree that 74 gy is too toxic, then I think its not a huge leap to think that the TCP and NCTP curves are just too close in this area and further RT is just as likely to hurt than to help.

If you look at the pts getting combo IO with TPS >50%, the results are pretty impressive and almost all of them beat the dose escalated arm of RTOG 0617.

Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer - PubMed

First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.

pubmed.ncbi.nlm.nih.gov

View attachment 328622

I do not think it's that simple.
74 Gy delivered to the primary tumor from the start + large parts of the mediastinum can be more toxic that 45 Gy delivered to the same volume, followed by a SBRT boost to a smaller, residual tumor with a highly conformal technique.
We do not know what the reasons for the failure of RTOG 0617 were and we may actually never find out, many things have been suggested (heart dose, tighter margins in dose escalated arm, immunosuppression, suboptimal techniques...).

 

[FrostyHammer]

What if we reframed it this way - is total biologic dose given with any re-RT regimen in this situation higher or lower than a cumulative EQD2 of 74 gy? If we all agree that 74 gy is too toxic, then I think its not a huge leap to think that the TCP and NCTP curves are just too close in this area and further RT is just as likely to hurt than to help.

If you look at the pts getting combo IO with TPS >50%, the results are pretty impressive and almost all of them beat the dose escalated arm of RTOG 0617.

Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer - PubMed

First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.

pubmed.ncbi.nlm.nih.gov

View attachment 328622

74 Gy is most definitely not too toxic if you're using IMRT. Half of patients in 0617 got 3D. Try delivering 74 Gy with 3D and you'll see why...yipes.

 

[radiation]

 

[scarbrtj]

View attachment 328787

Of all the trials we have quoted thus far in this thread, this one could be the most similar, strangely enough, to the OP's case. However, PETs of course have notorious false positive rates. (Or at least the false positives are much more common than false negatives.) Furthermore, from first rad bio principles cancer cells which have been irradiated do take at least as long as their next mitotic phase to "die" from the radiation. For some lung cancers, it's been published that it may be 50-100 days between mitoses. Thus it would be highly, highly (~100%?) probable that there would be non-dead (but on their way to death at next cell division, or the one after that... ie they've lost clonogenic potential from the RT) cells mid-radiation treatment. And those non-dead "dead man walking" cells will light up on PET. But now a positive PET *really* means nothing. At that point from a sensitivity/specificity (statistical) view, now the PET has a much higher chance of false positives. So this trial neither helps nor hurts either the dose-escalaters or the dose-lowerers IMHO. A kind of dumb trial but what do I know.

 

[Lamount]

Of all the trials we have quoted thus far in this thread, this one could be the most similar, strangely enough, to the OP's case. However, PETs of course have notorious false positive rates. (Or at least the false positives are much more common than false negatives.) Furthermore, from first rad bio principles cancer cells which have been irradiated do take at least as long as their next mitotic phase to "die" from the radiation. For some lung cancers, it's been published that it may be 50-100 days between mitoses. Thus it would be highly, highly (~100%?) probable that there would be non-dead (but on their way to death at next cell division, or the one after that... ie they've lost clonogenic potential from the RT) cells mid-radiation treatment. And those non-dead "dead man walking" cells will light up on PET. But now a positive PET *really* means nothing. At that point from a sensitivity/specificity (statistical) view, now the PET has a much higher chance of false positives. So this trial neither helps nor hurts either the dose-escalaters or the dose-lowerers IMHO. A kind of dumb trial but what do I know.

...to say nothing of the fact that radiation causes inflammation, which is FDG avid. I always hate it when someone gets a PET soon after RT because I don’t know what to make of it. Maybe FLT would be more helpful.