Non-oropharyngeal HNSCC and HPV

[Palex80]

I was wondering what your take is concerning HPV in non-oropharyngeal HNSCC.
Data seem to point out towards better prognosis, but I have not found any deescalation trials looking at non-oropharyngeal HNSCC.

I saw a new patient with an oral cavity HNSCC post surgery who has never smoked. HPV status had not been determined so far and the pathologist suggested to determine it. I am wondering if this result would influence my management. The indication for RT is clear in this patient due to size and depth of invasion, but what about the dose?

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[kimplera]

would not change dose off trial. Data on HPV in non-oropharyngeal is mixed and while they likely have improved outcomes i highly doubt we will see any de-escalation studies in the near future.

 

[medgator]

would not change dose off trial. Data on HPV in non-oropharyngeal is mixed and while they likely have improved outcomes i highly doubt we will see any de-escalation studies in the near future.

Too many of my HPV pts have a decent enough of smoking history for me to consider that any time soon. I think the cut off for the trials was 10 pk/yrs?

 

[kimplera]

Too many of my HPV pts have a decent enough of smoking history for me to consider that any time soon. I think the cut off for the trials was 10 pk/yrs?

Depends on the study but in general yes

 

[seper]

There are of course retrospective data on influence of p16 status on outcomes of RT, but it is premature to use in clinic IMO

 

[evilbooyaa]

I've seen studies that suggest it is NOT prognostic in larynx, hypopharynx, and oral cavity, can anyone link studies suggesting it is prognostic?

Some of THE worst outcomes I have ever seen in oral cavity cancer have been one exact cohort. (n=5ish) - caucasian women, essentially non-smokers, between ages of 40-60, with an oral tongue cancer.

So no, I would not de-escalate therapy in HPV+ non-OPhx cancer. I personally still don't de-escalate therapy even in HPV+ OPhx cancer outside of the rare adjuvant post-TORS patient as per E3311...

 

[jondunn]

I personally still don't de-escalate therapy even in HPV+ OPhx cancer...

yeah no one really should yet, nor do I think anyone is, off trial. Chera said he occasionaly does, but he does based on his own trial.

 

[Burt Radnolds]

I've seen studies that suggest it is NOT prognostic in larynx, hypopharynx, and oral cavity, can anyone link studies suggesting it is prognostic?

Some of THE worst outcomes I have ever seen in oral cavity cancer have been one exact cohort. (n=5ish) - caucasian women, essentially non-smokers, between ages of 40-60, with an oral tongue cancer.

So no, I would not de-escalate therapy in HPV+ non-OPhx cancer. I personally still don't de-escalate therapy even in HPV+ OPhx cancer outside of the rare adjuvant post-TORS patient as per E3311...

p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma - PubMed

Similar to results in patients with OPSCC, patients with p16-negative non-OPSCC have worse outcomes than patients with p16-positive non-OPSCC, and HPV may also have a role in outcome in a subset of non-OPSCC. However, further development of a p16 IHC scoring system in non-OPSCC and improvement...

pubmed.ncbi.nlm.nih.gov

 

[temujim]

I've seen studies that suggest it is NOT prognostic in larynx, hypopharynx, and oral cavity, can anyone link studies suggesting it is prognostic?

Some of THE worst outcomes I have ever seen in oral cavity cancer have been one exact cohort. (n=5ish) - caucasian women, essentially non-smokers, between ages of 40-60, with an oral tongue cancer.

So no, I would not de-escalate therapy in HPV+ non-OPhx cancer. I personally still don't de-escalate therapy even in HPV+ OPhx cancer outside of the rare adjuvant post-TORS patient as per E3311...

E3311 wasn't powered to prove 50 = 60. No matter what the HN surgeons say. I would hesitate de-escalating even in that intermediate risk adjuvant setting.

 

[radoncopotamus]

E3311 wasn't powered to prove 50 = 60. No matter what the HN surgeons say. I would hesitate de-escalating even in that intermediate risk adjuvant setting.

There were 200 patients randomized to 50 vs 60 without a hint of difference. It is reasonable to be hesitant to adopt but also reasonable to adopt I think.

 

[temujim]

There were 200 patients randomized to 50 vs 60 without a hint of difference. It is reasonable to be hesitant to adopt but also reasonable to adopt I think.

If you want to take an underpowered phase II trial as evidence to de-escalate, that's your business. Can only assume you're treating the same definitive patients to 60 Gy +/- cisplatin based on better data. And seeing as how over 100 patients on two phase II ORATOR trials has shown that RT > TORS, your surgeons probably aren't cutting (or roboting?) either.

 

[radoncopotamus]

If you want to take an underpowered phase II trial as evidence to de-escalate, that's your business. Can only assume you're treating the same definitive patients to 60 Gy +/- cisplatin based on better data. And seeing as how over 100 patients on two phase II ORATOR trials has shown that RT > TORS, your surgeons probably aren't cutting (or roboting?) either.

If you want to take an underpowered phase II trial as evidence to de-escalate, that's your business. Can only assume you're treating the same definitive patients to 60 Gy +/- cisplatin based on better data. And seeing as how over 100 patients on two phase II ORATOR trials has shown that RT > TORS, your surgeons probably aren't cutting (or roboting?) either.

What would be your non inferiority bar for 50 vs 60 Gy?

 

[gmsquid]

P16 is not the same as HPV positive, it’s only considered so in opx, and it may not be 100% true. In fact a lot of cutaneous sccs are p16 positive, so hpv dna testing should be done in the setting of unknown primary. There is some data to suggest that p16 positive non opx cancers have better prognosis, but not large series. Regardless deescalation in hpv related opx cancers is investigational.

 

[evilbooyaa]

p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma - PubMed

Similar to results in patients with OPSCC, patients with p16-negative non-OPSCC have worse outcomes than patients with p16-positive non-OPSCC, and HPV may also have a role in outcome in a subset of non-OPSCC. However, further development of a p16 IHC scoring system in non-OPSCC and improvement...

pubmed.ncbi.nlm.nih.gov

P16+ in OPhx is a surrogate for HPV+, where the concordance is upwards of 90%+, and HPV+ is actually what drives the better survival outcome, but p16 is easier to test for.

From that paper itself (Table 2), the concordance rates for HPV+ is much lower.

Of 53 OC, Larynx, and Hypopharynx patients who were p16+, only 20 were also HPV+ (or 37.7% concordant). So I'm not really sure what to make of data like that, unless we're suggesting that p16+ is prognostic on its own regardless of the HPV+ status?

As you can see by Fig. 1E and F, pretty much all the advantage is seen in folks that are both HPV+ and P16+ (and not just one or the either). Unless we're going to start checking BOTH of those in non-Ophx (which we can) then OK, otherwise I don't see the rationale for considering de-escalation based purely on p16.

 

[RickyScott]

I've seen studies that suggest it is NOT prognostic in larynx, hypopharynx, and oral cavity, can anyone link studies suggesting it is prognostic?

Some of THE worst outcomes I have ever seen in oral cavity cancer have been one exact cohort. (n=5ish) - caucasian women, essentially non-smokers, between ages of 40-60, with an oral tongue cancer.

So no, I would not de-escalate therapy in HPV+ non-OPhx cancer. I personally still don't de-escalate therapy even in HPV+ OPhx cancer outside of the rare adjuvant post-TORS patient as per E3311...

P16 can be present in many cancers where its expression has nothing to do with hpv, like serous endometrial etc

 

[RSAOaky]

There were 200 patients randomized to 50 vs 60 without a hint of difference. It is reasonable to be hesitant to adopt but also reasonable to adopt I think.

I agree with this logic. I think this post by Daniel Ma is a particularly well thought out and poignant discussion on the topic of de-escalation. I have de-escalated per E3311 when appropriate and the 10 Gy really does make a difference in acute and long-term toxicity. There is no signal to suggest any difference in outcomes and if there is one, it is so unlikely to be substantial that the number of patients need to prove equivalence would preclude a Phase III trial from being performed. At some point you have to accept that a big improvement in morbidity for EVERYONE is worth a SMALL TO NONEXISTENT DECREMENT in mortality for few. We're willing to do so much to patients w/ H&N cancer based on retrospective studies and unplanned post-hoc analyses of trials using archaic pathologic/surgical/imaging/radiation techniques, but we become chicken ****s when a well designed Phase II trial shows equivalence because it's not Phase III.

 

[evilbooyaa]

P16 can be present in many cancers where its expression has nothing to do with hpv, like serous endometrial etc

OK... but the interest in H&N is because of HPV, right? We don't analyse p16 expression (besides just basic IHC) and make treatment decisions based on expression of p16. Is P16 positivity considered a good prognostic factor in other, non H&N, non-gynecological, non-anal/penile cancers?

 

[RickyScott]

OK... but the interest in H&N is because of HPV, right? We don't analyse p16 expression (besides just basic IHC) and make treatment decisions based on expression of p16. Is P16 positivity considered a good prognostic factor in other, non H&N, non-gynecological, non-anal/penile cancers?

I can only speak for my hospital, but we typically get p16 without hpv insitu hyb in head and neck and that in this circumstance p16 is more accurate than hpv in situ hybridization (which only checks for some forms 16,18,32 of the virus). My understanding is that P16 overexpression due to blocking RB by hpv is a good prognostic sign because the tumor lacks ability to repair DNA damage since it lacks functional RB.

When p16+ is overexpressed for some other reason, I dont think that is a good prognostic sign.

 

[jondunn]

OK... but the interest in H&N is because of HPV, right?

oropharynx. wouldn't say H/N.

 

[temujim]

I agree with this logic. I think this post by Daniel Ma is a particularly well thought out and poignant discussion on the topic of de-escalation. I have de-escalated per E3311 when appropriate and the 10 Gy really does make a difference in acute and long-term toxicity. There is no signal to suggest any difference in outcomes and if there is one, it is so unlikely to be substantial that the number of patients need to prove equivalence would preclude a Phase III trial from being performed. At some point you have to accept that a big improvement in morbidity for EVERYONE is worth a SMALL TO NONEXISTENT DECREMENT in mortality for few. We're willing to do so much to patients w/ H&N cancer based on retrospective studies and unplanned post-hoc analyses of trials using archaic pathologic/surgical/imaging/radiation techniques, but we become chicken ****s when a well designed Phase II trial shows equivalence because it's not Phase III.

Except there are 2 well designed randomized phase II trials showing RT is better than TORS. So stop being chicken ****s and tell your H&N surgeons to pound sand and put their robots away.

 

[evilbooyaa]

oropharynx. wouldn't say H/N.

OPhx is the OG of p16+ as a prognostic marker, but this thread (and the paper I'm citing) suggests people are interested in the exact same question in all H&N sites. I just don't see it, based on the evidence at this time.

 

[RSAOaky]

Except there are 2 well designed randomized phase II trials showing RT is better than TORS. So stop being chicken ****s and tell your H&N surgeons to pound sand and put their robots away.

Not debating TORS vs RT here, I agree with you. Anecdotally and based on the limited data we have, dysphasia is worse. However, TORS is here to stay. Much like they have since the dawn of time, surgeons will do whatever they want to do regardless of how chicken **** their radiation oncologists are. If you want to swing your huge balls around trying to tell a bunch of egomaniacs what to do they’ll just go find someone who doesn’t, so you may as well do what you can do to minimize your cumulative toxicity.

 

[temujim]

Not debating TORS vs RT here, I agree with you. Anecdotally and based on the limited data we have, dysphasia is worse. However, TORS is here to stay. Much like they have since the dawn of time, surgeons will do whatever they want to do regardless of how chicken **** their radiation oncologists are. If you want to swing your huge balls around trying to tell a bunch of egomaniacs what to do they’ll just go find someone who doesn’t, so you may as well do what you can do to minimize your cumulative toxicity.

That's my point -- the same level of evidence supports 60 Gy in the definitive setting. Is that what you do? NRG HN005 a waste of time?

The primary purpose of E3311 was to select an arm for a phase III trial. Will it ever be done? Probably not. Who knows.

And yeah the H&N surgeons in my area don't do TORS in the upfront setting. YMMV.

 

[medgator]

And yeah the H&N surgeons in my area don't do TORS in the upfront setting. YMMV.

Fortunate that we have to refer out for tors, have a good understanding with the ENTs locally about trying to avoid inappropriate trimodality in patients by not sending them those type of cases