RT dose reduction in HPV positive oropharyngeal cancer

[Gfunk6]

Since we had such a great discussion about prostate hypofractionation, I thought we could go over another controversial topic.

David Raben gave an excellent presentation to our residents last year on dose reduction (perhaps to 60 Gy or so with a single cycle of CDDP) for p16 positive oropharyngeal SCC. Logically it makes good sense due to Ang's retrospective finding of better prognosis in these patients.

I'm wondering if any of your institutions are enrolling patients on Phase I/II studies.

I recently had a patient with T2 N1 right tonsil cancer who I felt kind of guilty about going to the standard 70 Gy + 2 cycles CDDP because this was likely over-treatment. Sadly I had no data to proceed otherwise.

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[RadOncDoc21]

I agree with you completely, it is difficult for me to give 70 Gy when the patients is HPV positive. Unfortunately, I don't think I can give anything but 70 with CDDP until there is solid published data supporting dose reduction due to the multiple Phase III RCT supporting this approach. I am unaware of any publshed data reporting on outcomes comparing 70 Gy with CDDP v Dose reduction (RT or chemo) in HPV positive patients. Does anyone know of any studies published to date?

As a side note, I always find it interesting that it is almost always easier to convince patients to accept higher doses on protocol ("we think more dose is increasing your chance of cure") than accept the potential for lower doses ("this lower dose could give you the same chance of cure with potentially lower side effects")

I think it's the fear of recurrence and trying to be "too cute." Whether it is not giving enough margin to spare normal tissue or under dosing, I rather chance side effects vs potentially not curing the cancer. This might change as I continue to learn more about the field.

-R

 

[Palex80]

You can only treat once with a good chance of achieving remission, so I would stick to the standard dose, until new evidence becomes available.

It's sad, but that's how it is. I guess, what you can do is work extra hard on plan optimiazation, eliminating hot spots or perhaps going for hyperfractionated treatment (with the hope that it may limit late toxicity).

 

[medgator]

I agree with you completely, it is difficult for me to give 70 Gy when the patients is HPV positive. Unfortunately, I don't think I can give anything but 70 with CDDP until there is solid published data supporting dose reduction due to the multiple Phase III RCT supporting this approach.

This

 

[temujim]

I recently had a patient with T2 N1 right tonsil cancer who I felt kind of guilty about going to the standard 70 Gy + 2 cycles CDDP because this was likely over-treatment. Sadly I had no data to proceed otherwise.

T2N1? Why not treat with RT alone to 66-70 Gy accelerated in some fashion? RTOG 0022 had 90%+ control rates.

 

[Gfunk6]

T2N1? Why not treat with RT alone to 66-70 Gy accelerated in some fashion? RTOG 0022 had 90%+ control rates.

1. There was some argument over staging this pt N1 or N2a
2. Fear; I'm a first year attending and don't consider myself a H&N expert by any means
3. Lack of randomized data for my own personal comfort level (I would be more "adventurous" with low risk prostate cancer)
4. Playing nice with referring Med Onc; they originally wanted to give neoadjuvant TPF but I managed to talk them out of it

Were I still in residency and on a H&N service, I would have tried to convince my attending to pursue AFX alone.

 

[temujim]

1. There was some argument over staging this pt N1 or N2a
2. Fear; I'm a first year attending and don't consider myself a H&N expert by any means
3. Lack of randomized data for my own personal comfort level (I would be more "adventurous" with low risk prostate cancer)
4. Playing nice with referring Med Onc; they originally wanted to give neoadjuvant TPF but I managed to talk them out of it

Were I still in residency and on a H&N service, I would have tried to convince my attending to pursue AFX alone.

There are retrospective reports out there (MDACC, PMH) for T1-2, N2a and even N2b using radiation alone with good results.

There will probably never be randomized data (+/- systemic therapy) for the T1-2N0-1 oropharynx subgroup. Results are too good with RT alone (which is why they are excluded from RTOG 1016 trial). I have heard of talk of TORS vs RT for this group, though if it happens the primary outcome would likely be toxicity rather than control.

NCCN will provide you cover - it recommends definitive RT alone. Hopefully that will assuage your med onc. But props for talking them out of TPF!

 

[Gfunk6]

There are retrospective reports out there (MDACC, PMH) for T1-2, N2a and even N2b using radiation alone with good results.

There will probably never be randomized data (+/- systemic therapy) for the T1-2N0-1 oropharynx subgroup. Results are too good with RT alone (which is why they are excluded from RTOG 1016 trial). I have heard of talk of TORS vs RT for this group, though if it happens the primary outcome would likely be toxicity rather than control.

NCCN will provide you cover - it recommends definitive RT alone. Hopefully that will assuage your med onc. But props for talking them out of TPF!

Good points all. Once I have a bit more experience under my belt, I think I will be more comfortable discussing AFX alone in patients with <= Stage III oropharyngeal SCC.

 

[Palex80]

But props for talking them out of TPF!

Every time I hear of neoadjuvant TPF I recall this nice article:

http://jco.ascopubs.org/content/27/1/9.full

The title is just so cute!

 

[Houston500]

would love to dose reduce H/N RT. Managing them on treatment may be a lot easier then....

 

[medgator]

But props for talking them out of TPF!

it'd be more funny if it weren't so true. I'm amazed how much I've seen med oncs in the community jump on tpf induction for the low nodal volume, favorable risk patients.

 

[seper]

1) Treatment de-escalation for HPV+ OPC must proceed only via controlled trials. There are 2 trials already underway (testing 70 Gy + cetuximab and 60 Gy with cisplatin, I believe).
2) Pts with HPV+ OPC, but with history of smoking, should not be considered for treatment de-escalation. In my personal opinion, these should include second hand smokers and marijuana users.

 

[deleted4401]

I agree with GFunk - there certainly is cover and we learned in residency that RT alone can be enough, but there is still data for CRT for these patients and if the patient sees a medonc, more likely than not they will be offered radiosensitization, b/c NCCN says it is an option (2B). I don't argue about this, but if I see them first, I may not send to medonc.

But, yeah even in non-HPV if chemoRT is overtreatment, then it really is for HPV+, but what can you do without data?

I treat them all with UCSF fractionation if CRT. If no chemo, then 0022. Scared of 2.2 Gy fractions with chemo, but for some reason 2.12 sounds okay. Ha.

S

 

[ShirleyT]

Interesting thread. Reminds me about a patient I treated 2 years ago with HPV positive disease. T4 N2C oropharynx with bulky level 4 nodes and took induction chemo. Prechemo disease went to 70/33 except the level 4 nodes went to 63/33 with plans for a planned neck dissection after chemorads due to brachial plexus. Well the patient had a one week break during treatment due to transportation issues and then refused his last treatment and then refused the planned neck dissection. But amazing he is still in CR.

 

[Ursus Martimus]

It is known that the immune system can mount a response to hpv cancers. But with rt, lymphocytes are so radiosensitive. The lymphocytes in treatment field a likely irradiated. To shift the paradigm all together I wonder what chemotherapy alone strategy would render. Probably a good project for someone with a preclinical model of hpv head and neck cancer.

 

[kimplera]

too bad no-one has such a pre-clinical model...

 

[Gfunk6]

I finally found the trial I was thinking of after listening to Ken Hu's Spring Refresher talk last year.

ECOG 1308 Taxol/Carboplatin/Cetuximab induction

if CR then 54 Gy + Cetuximab
if PR then 70 Gy + Cetuximab

 

[TarHeelRadOnc]

I finally found the trial I was thinking of after listening to Ken Hu's Spring Refresher talk last year.

ECOG 1308 Taxol/Carboplatin/Cetuximab induction

if CR then 54 Gy + Cetuximab
if PR then 70 Gy + Cetuximab

54Gy is bold... good luck with that...

 

[RadRadRad]

yeah. don't know about this one. and so many other variations from the standard of care that even if it fails will be hard to know why.
1. Is induction chemo superior to upfront CRT
2. IF choosing induction is TPCetuximab equivalent to TPF
3. For HPV+ oropharynx is cetux/RT equivalent to CDDP/RT for the combined portion of tx
4. Is Cetuximab/RT even useful if not using altered fractionation
5. Can dose be reduced to 54Gy

 

[Gfunk6]

IT HAS BEGUN!

http://www.redjournal.org/article/S0360-3016(15)03190-9/abstract?rss=yes

p16 positive H&N cancer treated with 60 Gy and weekly CDDP. 86% pCR rate.

Phase III trial in the works . . .

 

[ramsesthenice]

Follow up phase II without neck dissection is accruing well. They got very good buy in from the surgeons and medical oncologists. At least for the ones they can keep away from induction trials...

 

[OTN]

I'm going to 100% need Phase III data before I change my practice. The NSCLC dose escalation Phase III trial was a pretty good demonstration of how Phase II data doesn't always translate into Phase III success.

 

[seper]

I wonder if XRT alone to 70 Gy/7 weeks is better de-escalation than 60 Gy + cis.

 

[ramsesthenice]

I wonder if XRT alone to 70 Gy/7 weeks is better de-escalation than 60 Gy + cis.

Interesting question. If you can convince a couple surgeons and med oncs to buy into a trial like this then please quit your job as a doctor and start teaching mind control classes. And sign me up for one. I get accused of trying to kill people for suggesting 70Gy RT alone for T1N0 OP patients. Data be damned.

 

[medgator]

I wonder if XRT alone to 70 Gy/7 weeks is better de-escalation than 60 Gy + cis.

I doubt it. There is something synergistic about chemoradiation to a lower dose IMO than just going to a higher dose of XRT. Call it my gut reaction, but I think the esophagus 85-01 study is a testament to what happens between lower dose XRT with chemo vs higher dose XRT alone.

Obviously, we'll never know without the Phase III study that has those arms. Maybe they could throw erbitux in there too while they are it as another arm.

 

[Neuronix]

NRG-HN002 (https://www.nrgoncology.org/Clinical-Trials/NRG-HN002) is a randomized phase II asking a very similar question: 60 Gy (6 weeks) + weekly cis vs. 60 Gy in DAHANCA fractionation (6 fx/wk for total of 5 weeks).

We omit chemo but do DAHANCA style hypofractionated RT for virtually all T2N1 or less head and neck (excepting the usual players: nasopharynx, larynx, etc).

 

[seper]

How would you treat p16+ T2N0 base of tongue cancer in a nonsmoker?

 

[ramsesthenice]

70 Gy, No chemo. Not ready to make the switch yet with such short follow up. I think we will get there, but Im not quite ready to go 60 Gy no chemo without longer-term follow up.

 

[seper]

I would agree, 66-70 Gy RT alone. The question is, whether to accelerate it at 6 fractions peer week or not?

 

[ramsesthenice]

I would agree, 66-70 Gy RT alone. The question is, whether to accelerate it at 6 fractions peer week or not?

Wouldn't be wrong. Your not giving chemo so there is merit to the idea. At the same time, local control with standard fractionation for T2N0 p16+ tumors is well north of 90%. It's hard to imagine accelerated fractionation providing a measurable or reliable difference. Just my thought.

 

[medgator]

Wouldn't be wrong. Your not giving chemo so there is merit to the idea. At the same time, local control with standard fractionation for T2N0 p16+ tumors is well north of 90%. It's hard to imagine accelerated fractionation providing a measurable or reliable difference. Just my thought.

There is that rtog data going at 2.2/day to the primary to 66. I'd do 2.12/daily to 70, 1.7/daily to the elective nodal chains

 

[seper]

Thanks for pointing RTOG 0022 out. Some people do use this scheme in clinical practice. Personally, I think p16+ stage II tumor does not merit accelerated treatment.

 

[medgator]

Thanks for pointing RTOG 0022 out. Some people do use this scheme in clinical practice. Personally, I think p16+ stage II tumor does not merit accelerated treatment.

Yeah it's a personal call. I'd feel comfortable with modest acceleration 70 Gy/33 fractions as above for a 3.5 cm oropharynx CA until there is better data on treatment de-escalation. I know some people also feel comfortable treating T2N1 Tonsil cancers without chemo, but I personally would add chemo and do standard Fx.

 

[temujim]

Re-analysis of DAHANCA 6/7 showed even p16+ benefited from acceleration. Wasn't broken down by stage though.

 

[seper]

thank you. very pertinent

 

[cdf95cro]

70 Gy, No chemo. Not ready to make the switch yet with such short follow up. I think we will get there, but Im not quite ready to go 60 Gy no chemo without longer-term follow up.

We do this frequently at MDACC for HPV+/p16+ "small" T1-2, low risk N1-2c (e.g. all nodes <2cm, no low neck nodes, no RP nodes) OPC cases.

For T1-2 tonsils we often treat primary w 66/30 fx w RT alone, taking nodes from 66-70 depending on size; most oters get 69.96 in 2.12 Gy sans chemotherapy, all in 5 fx/week.

Multi-disciplinary eval is key however; need full buy-in from surgeon and med onc that this is indeed a low-risk OPC. For instance, w pharyngeal wall involvment. deep GP sulcus, or soft palate extension we often tend towards adding weekly CDDP.

Historically, Adam Garden's data are pretty compelling that these pts can be effectively cured w RT alone:
http://www.ncbi.nlm.nih.gov/pubmed/15022283
http://www.ncbi.nlm.nih.gov/pubmed/15183477
http://www.ncbi.nlm.nih.gov/pubmed/23360540


Wouldn't go to 60Gy off-trial quite yet..but will be opening Sue Yom's RTOG study shortly.

 

[Gfunk6]

Results of E1308 published last week in JCO.

70% of patients in single-arm study had CR to 54 Gy with two year PFS 84% among all comers. Phase III trial in works - I suppose they will omit locally advanced patients (T4 or N3) as these groups did not do as well with reduced dose.

http://meetinglibrary.asco.org/content/133616-144

 

[OTN]

We do this frequently at MDACC for HPV+/p16+ "small" T1-2, low risk N1-2c (e.g. all nodes <2cm, no low neck nodes, no RP nodes) OPC cases.

For T1-2 tonsils we often treat primary w 66/30 fx w RT alone, taking nodes from 66-70 depending on size; most oters get 69.96 in 2.12 Gy sans chemotherapy, all in 5 fx/week.

Multi-disciplinary eval is key however; need full buy-in from surgeon and med onc that this is indeed a low-risk OPC. For instance, w pharyngeal wall involvment. deep GP sulcus, or soft palate extension we often tend towards adding weekly CDDP.

Historically, Adam Garden's data are pretty compelling that these pts can be effectively cured w RT alone:
http://www.ncbi.nlm.nih.gov/pubmed/15022283
http://www.ncbi.nlm.nih.gov/pubmed/15183477
http://www.ncbi.nlm.nih.gov/pubmed/23360540


Wouldn't go to 60Gy off-trial quite yet..but will be opening Sue Yom's RTOG study shortly.

The first trial quotes a 79% 5-year LRC rate for T2 tumors- not as good as I would have hoped. Does that argue for or against concurrent chemo? I might argue the former...

 

[medgator]

The first trial quotes a 79% 5-year LRC rate for T2 tumors- not as good as I would have hoped. Does that argue for or against concurrent chemo? I might argue the former...

Trying to play cute with HNSCC can be be very risky imo. I wouldn't even touch a descalation protocol in the community until we see >5 years of FU.

 

[Burt Radnolds]

What are your all elective doses in HPV+ HNSCC? I personally find 63Gy intermediate risk to be overkill if you have high quality examination and imaging (CT contrast, PET). It can also trash your ability to spare some structures. I think dropping to 5950 is completely appropriate, and honestly I am comfortable omitting it all together and doing just 70 and 56Gy in many cases.

 

[BobbyHeenan]

What are your all elective doses in HPV+ HNSCC? I personally find 63Gy intermediate risk to be overkill if you have high quality examination and imaging (CT contrast, PET). It can also trash your ability to spare some structures. I think dropping to 5950 is completely appropriate, and honestly I am comfortable omitting it all together and doing just 70 and 56Gy in many cases.

I usually don't do the intermediate level dosing either for the reasons you've described. One of my partners does it every time though, where she trained they did it the majority of the time. Of my main head/neck attendings in training only about half of them used the intermediate level and the other half did 70/56 only for the majority of definitive head and neck squamous cell cases.

For my oral boards I did 70/56 on all intact head/neck cases (supraglottic larynx and tonsil. GTV plus 1-1.5 cm = CTV70) and my examiner seemed fine with it and never questioned it. I believe RTOG 1016 did not recommend any 63 Gy intermediate dose as well, as GTV = 0.5-1.5 cm is what they recommend for CTV1 with CTV2 being 56 Gy @ 1.6 Gy.

 

[scarbrtj]

Hey guys, keep in mind that re: XRT dosing for p16+ tumors (likely the authors did not know that these patients were HPV+ at the time!), this being the first published literature I'm aware of (https://www.ncbi.nlm.nih.gov/pubmed/7215078), doses of 30 Gy were adequate for long-term local control. There's reason to think the biology of a H&N p16+ SCC is different than an anal p16+ SCC... but reasons also to think the biology might be similar. Embrace biology

 

[scarbrtj]

Trying to play cute with HNSCC can be be very risky imo. I wouldn't even touch a descalation protocol in the community until we see >5 years of FU.

Play cute, lol. I like that. We have to be aware though that non-cute radiation oncology techniques came to us by and large via historical precedents, Edicts of Experts, and limited testing via validation against other approaches. I'm sure you know that. There are probably many valid ways to treat things. Sometimes we get stuck inside our own bubble.

 

[Phantom1]

Play cute, lol. I like that. We have to be aware though that non-cute radiation oncology techniques came to us by and large via historical precedents, Edicts of Experts, and limited testing via validation against other approaches. I'm sure you know that. There are probably many valid ways to treat things. Sometimes we get stuck inside our own bubble.

I disagree, we can certainly get caught inside our own bubble, but I think with dose de-escalated IMRT in head and neck cancer there is a fine line where we are risking loco-regional recurrences to minimize side effects. Old school doses and margins were used for a reason, be it empirical or evidence based. Lets say we could do the trial to find the exact minimum dose required to cure a specific set of trial patients, would there be any margin of safety dose wise for real life if patients miss treatments, or due to holidays? I think one of the biggest errors that we are making in Rad Onc today is #1 over-imaging for setup (kV daily, fluoro, or multiple CBCT's daily if needed to correct for large shift) which may lead to more 2nd malignancies 15 years from now, and then #2 assuming that what you see on your CT sim is exactly where the tumor is going to be to the mm, on treatment day. CTV to PTV expansions also help to account for some tumor growth between sim and treatment start. Are we using margins so tight that patient's can fly through treatment with little to no side effects (and less time effort needed by us managing them on treatment), but then are at increased risk of failure? Dont get me wrong I am all for de-escalation trials, but let the results play out.

 

[Old rad onc]

I disagree, we can certainly get caught inside our own bubble, but I think with dose de-escalated IMRT in head and neck cancer there is a fine line where we are risking loco-regional recurrences to minimize side effects. Old school doses and margins were used for a reason, be it empirical or evidence based. Lets say we could do the trial to find the exact minimum dose required to cure a specific set of trial patients, would there be any margin of safety dose wise for real life if patients miss treatments, or due to holidays? I think one of the biggest errors that we are making in Rad Onc today is #1 over-imaging for setup (kV daily, fluoro, or multiple CBCT's daily if needed to correct for large shift) which may lead to more 2nd malignancies 15 years from now, and then #2 assuming that what you see on your CT sim is exactly where the tumor is going to be to the mm, on treatment day. CTV to PTV expansions also help to account for some tumor growth between sim and treatment start. Are we using margins so tight that patient's can fly through treatment with little to no side effects (and less time effort needed by us managing them on treatment), but then are at increased risk of failure? Dont get me wrong I am all for de-escalation trials, but let the results play out.

Agree. You only get one good chance to treat head and neck. I want to see 5 year data on lower doses. The recurrences in places like base of tongue have few options but radical surgery which usually has a fairly low salvage rate. Agree with Medgator that these cancers are not to be fooled with. Wait for phase 3 trials before altering doses.

 

[medgator]

Play cute, lol. I like that. We have to be aware though that non-cute radiation oncology techniques came to us by and large via historical precedents, Edicts of Experts, and limited testing via validation against other approaches. I'm sure you know that. There are probably many valid ways to treat things. Sometimes we get stuck inside our own bubble.

And sometimes you get another chance to cure a h&n patient if you mess up the first time.

Oh wait, no you don't....

 

[Palex80]

I am highly reluctant to believe that 3x TPF followed by 54 Gy radiation therapy + cetuximab is a better approach than an upfront radiochemotherapy or radio-cetuximab to 70 Gy.
That is an awful lot of chemotherapy for these patients and we know that the benefit of an induction treatment before a combined radiochemotherapy (and probably radio-cetuximab) is minimal, based on two big randomized trials.

What I would rather see are more "chemoselection" trials using one-two cycles of cisplatin-monotherapy. Responding patients then get radiation therapy alone to a moderate dose, while those not responding are treated with surgery. That would be true deescalation of treatment.
"Avoiding" 16 Gy of radiation therapy, which are replaced by the 3 cycles of TPF is not a good trade off, in my opinion.

 

[Reaganite]

Agree. How much of the 1-2 cycles in the community already happens anyway? Almost every patient I see stops after 2 cycles of Cis anyway due to neutropenia...and I haven't seen a recurrence yet.

 

[temujim]

Currently for HPV+ do 66-68 Gy for gross disease and 41.4 Gy to elective neck (if a sequential plan) or 54.12 - 54.4 Gy to elective neck (if an SIB plan). No intermediate dose levels unless there's a borderline lymph node that bothers me.

Have put a lot of patients on HN-002. Looks good so far. But, yeah need longer term data before moving to those doses. Though, for the few M1 at presentation, 60 Gy + cisplatin has provided long term locoregional control.

Induction chemo is the wrong path to go IMO, to reduce dose or select patients for particular treatments. Would seem an incredibly expensive and toxic test.

What are your all elective doses in HPV+ HNSCC? I personally find 63Gy intermediate risk to be overkill if you have high quality examination and imaging (CT contrast, PET). It can also trash your ability to spare some structures. I think dropping to 5950 is completely appropriate, and honestly I am comfortable omitting it all together and doing just 70 and 56Gy in many cases.

 

[medgator]

Agree. How much of the 1-2 cycles in the community already happens anyway? Almost every patient I see stops after 2 cycles of Cis anyway due to neutropenia...and I haven't seen a recurrence yet.

Surprisingly,, many of my patients get through all 3,emend seems to work well, plus aggressive hydration the week after each cycle.

Plus I PEG all of them upfront if they are getting concurrent chemo/xrt