Does this head & neck patient need chemo?

Started by Pewl
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Pewl

The Dude Abides
15+ Year Member
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56 year old male with a pT1pN2bMx left base of tongue SCCA. He presented with a firm mass in the left JGD region. He underwent a left base of tongue resection and left neck dissection. There were +5/64 nodes positive (+2 in level II and +3 in level 3, all less than 3cm and no extranodal extension. The tumor itself was 1.5cm. P16 positive, No PNI or LVSI but the lateral margin was positive. The ENT went back and re-excised that margin and "swears" he got all of it. Path is pending.

How many of you would recommend chemo in this scenario if the new margin becomes negative? Obviously, if the positive margin were still present then chemo would be a slam dunk. But, N2b disease without ENE isn't really a clear indication for chemo. Is there any solid data out there for this situation?
 
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Yes P16 positive. I will need to look into that from the outside records. If it were re-excised during that same surgery and found to be negative then essentially it was a surgery with negative margins. However, if they went back and resected it a few weeks later... it might be a different story.
 
There are two good papers looking into this question:

http://www.ncbi.nlm.nih.gov/pubmed/16161069
by Bernier

and

http://www.ncbi.nlm.nih.gov/pubmed/9744457
by Cooper


Bernier's paper is superior in the methodology, since it's a metaanalysis of the latest two randomized trials. Bernier principally says, that you need chemo in the adjuvant H&N setting if you have ECE of the lymph nodes or an incomplete resection. Cooper on the other hand identifies the presence of two or more metastatic lymph nodes (pN2b) as a factor, which justifies chemo.

In our clinic we stick to the Bernier criteria, but I have seen others going for chemo in high risk and otherwise fit patients with pN2b disease as well.

One interesting question regarding your patient would be, if you could add cisplatin based chemotherapy and lower the total dose delivered to the primary tumor area (for example down to 60 Gy from the usually given 64-66 Gy), because the patient is HPV16 positive and thus may benefit from cisplatin chemotherapy? By lowering the total delivered to the critical area of the base of the tongue you may expect a reduced risk for late toxicity, especially regarding swallowing function?
 
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One interesting question regarding your patient would be, if you could add cisplatin based chemotherapy and lower the total dose delivered to the primary tumor area (for example down to 60 Gy from the usually given 64-66 Gy), because the patient is HPV16 positive and thus may benefit from cisplatin chemotherapy?

Some would argue that situation is best suited for cetuximab. There's an rtog study (1016) looking at hpv positivity and using either erbitux or cisplatin

Getting back to this case,I think you could go either way. Add the chemo if the margin is questionable
 
As an aside, why do surgery in this patient in the first place? I don't really see the value to surgery with a BOT primary and usually push for definitive chemoRT. I know some institutions are strong proponents of surgery including transoral laser but havent seen much good data to support the addition of sugery to CRT.

Potentially less morbidity. Particularly if you can go from TOR --> post-op XRT and avoid chemotherapy entirely. Also you will generally get lower doses of radiation.
 
I was going to say, I think when institutions get a laser, they start doing surgery for oropharynx CA. But, for even clinical early stage patients, I think Mayo's data indicated 60% needed post-op RT or CRT. I don't know ... It's downstream for us, if we aren't included in the initial treatment plan discussion.

In any case, agree with everyone - +SM and ECE are the indications, everything else, well you make the call. NCCN says to consider CRT if they have the other risk factors (N2b, T3/T4, PNI, LVSI, etc.), b/c the EORTC trial included them AND it had a survival benefit. I just saw something kind of interesting, though - if they are pT1N0-1 with a positive margin, chemoRT was not recommended by the panel.

I think one of the most important things to consider in addition to the tumor factors is age, as the advantage is far greater in the <50-60 subset compared to those older (based on that meta-analysis). I'd agree with concurrent treatment for this patient, if he was in good health and a non-smoker, based on the N2b disease. Do you believe the surgeon about the margin? If you do, then 60 Gy is fine, I think.

Palex - that Cooper paper more or less was hypothesis generating as to who should be selected for an upcoming RTOG trial, which was performed (9501), and essentially negative for N2b patients. I don't know what value it has now, now that we know the results of the EORTC and the RTOG trials.

In my community, my feeling is that most medoncs would give the juice.
S
 
What's a better paper than the EORTC paper (Bernier) and the RTOG paper (Cooper), you might ask?

Well, how about a combined EORTC / RTOG paper!

IMHO, this is the "go-to" paper when it comes to post-op chemo/RT decisions.

Combined EORTC / RTOG Analysis
Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501).
Bernier J, Head Neck. 2005 Oct;27(10):843-50.
http://www.ncbi.nlm.nih.gov/pubmed/16161069?dopt=Abstract

BACKGROUND:
In 2004, level I evidence was established for the postoperative adjuvant treatment of patients with selected high-risk locally advanced head and neck cancers, with the publication of the results of two trials conducted in Europe (European Organization Research and Treatment of Cancer; EORTC) and the United States (Radiation Therapy Oncology Group; RTOG). Adjuvant chemotherapy-enhanced radiation therapy (CERT) was shown to be more efficacious than postoperative radiotherapy for these tumors in terms of locoregional control and disease-free survival. However, additional studies were needed to identify precisely which patients were most suitable for such intense treatment.

METHODS:
Both studies compared the addition of concomitant relatively high doses of cisplatin (on days 1, 22, and 43) to radiotherapy vs radiotherapy alone given after surgery in patients with high-risk cancers of the oral cavity, oropharynx, larynx, or hypopharynx. A comparative analysis of the selection criteria, clinical and pathologic risk factors, and treatment outcomes was carried out using data pooled from these two trials.

RESULTS:
Extracapsular extension (ECE) and/or microscopically involved surgical margins were the only risk factors for which the impact of CERT was significant in both trials. There was also a trend in favor of CERT in the group of patients who had stage III-IV disease, perineural infiltration, vascular embolisms, and/or clinically enlarged level IV-V lymph nodes secondary to tumors arising in the oral cavity or oropharynx. Patients who had two or more histopathologically involved lymph nodes without ECE as their only risk factor did not seem to benefit from the addition of chemotherapy in this analysis.

CONCLUSIONS:
Subject to the usual caveats of retrospective subgroup analysis, our data suggest that in locally advanced head and neck cancer, microscopically involved resection margins and extracapsular spread of tumor from neck nodes are the most significant prognostic factors for poor outcome. The addition of concomitant cisplatin to postoperative radiotherapy improves outcome in patients with one or both of these risk factors who are medically fit to receive chemotherapy.
 
What's a better paper than the EORTC paper (Bernier) and the RTOG paper (Cooper), you might ask?

Well, how about a combined EORTC / RTOG paper!

IMHO, this is the "go-to" paper when it comes to post-op chemo/RT decisions.

This is the paper I was thinking about after seeing the patient. For sure the combined paper shows ECE and positive margins as slam dunk indications for chemo. But, what if that margin were left for say a few weeks before being re-excised. Is that the same as a negative margin obtained on the day of surgery?

As far as why he received upfront surgery, I do think that when a transoral laser is available many ENT's will go for upfront resection. Many still require post-op RT+/- chemo but the chemo could be potentially avoided?
 
The question is why do the transoral laser? On protocol absolutely it makes sense but off protocol what data is there to suggest it improves outcomes, toxicity, or QOL compared with definitive CRT?

I completely agree, but as you said:

Its pretty much a moot point since we are downstream of the surgeons and they do what they want.

In the community, I haven't seen as much uptake of TORS
 
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Yes, we get the patient after the surgeons get their hands on them. The data suggests RT+/- chemo as upfront base of tongue treatment. I think the ENT's at our institution are just a little more gungho about surgery, is all. We're definitely downstream!
 
What's a better paper than the EORTC paper (Bernier) and the RTOG paper (Cooper), you might ask?

Well, how about a combined EORTC / RTOG paper!

IMHO, this is the "go-to" paper when it comes to post-op chemo/RT decisions.

Combined EORTC / RTOG Analysis
Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501).
Bernier J, Head Neck. 2005 Oct;27(10):843-50.
http://www.ncbi.nlm.nih.gov/pubmed/16161069?dopt=Abstract

Ehhhmmm... That was the paper, that I quoted already. :laugh::laugh::laugh:



I just saw something kind of interesting, though - if they are pT1N0-1 with a positive margin, chemoRT was not recommended by the panel.

Well, yes and it makes sense actually. You wouldn't treat a cT1-2 cN0 SCC of the head and neck region with RCT, would you? RT alone is fine for these patients.
 
Agreed. But T2N0-N1 they did recommend it. Seemed a bit arbritrary.
 
Well, yes and it makes sense actually. You wouldn't treat a cT1-2 cN0 SCC of the head and neck region with RCT, would you? RT alone is fine for these patients.

For these RT alone T1-2N0 patients would you consider altered fractionation, specifically hyperfractionation? I think the most recent update of RTOG 90-03 from ASTRO this past year showed improved local control only in the hyperfractionated arm, no longer in the concomitant boost arm.
 
For these RT alone T1-2N0 patients would you consider altered fractionation, specifically hyperfractionation? I think the most recent update of RTOG 90-03 from ASTRO this past year showed improved local control only in the hyperfractionated arm, no longer in the concomitant boost arm.

Or you could slightly hypofractionate (2.2 Gy x 33 = 66 Gy) based on the results of RTOG 0022.
 
That's true. I think RTOG 9003 was largely more advanced cases. RTOG 0022 used IMRT alone and showed excellent control.in early stage oropharynx
 
That's true. I think RTOG 9003 was largely more advanced cases. RTOG 0022 used IMRT alone and showed excellent control.in early stage oropharynx

People using hypofractionation for post op cases? 0022 all intact, right?
 
You are right, 0022 is for intact only. I guess I lost track of the conversation, I thought it had migrated from post-op back to intact.

Going back to hyperfractionated then, have you guys done that for post-op?
 
I will sometimes do some hypofrac in postop if there is a positive margin. Then I will give 60 Gy in 30 fx to surgical bed, 54 Gy to undissected lymphatics and then i will make a 64-66 Gy in 30 fx very small volume and I usually ask the surgeon to help me outline where to put that volume to make it as small as possible. I get nervous with a large hypofrac in postop since there is morbidity with adding radiation after extensive surgery, plus i don't have good data to back it up i will admit.
 
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Going back to hyperfractionated then, have you guys done that for post-op?

Only for patients who are starting adjuvant RT at a late timepoint with a predicted overall treatment time from resection to end of RT > 13 weeks, according to that ancient Ang paper...

I simply give 1.5 - 1.6 Gy bid in those cases, usually during the boost phase.



I will use hyperfractionation for RT alone in high-risk RT-only cases (so no chemo), like cT2 cN0 base of tongue or hypopharynx tumors, although I won't do it for tonsils.
 
I will use hyperfractionation for RT alone in high-risk RT-only cases (so no chemo), like cT2 cN0 base of tongue or hypopharynx tumors, although I won't do it for tonsils.


In your practice do you offer IMRT to these T20N0 intact patients as well? Since the more recent RTOG 0022 suggests it to be effective as well?
 
In your practice do you offer IMRT to these T20N0 intact patients as well? Since the more recent RTOG 0022 suggests it to be effective as well?

We use hyperfractionation usually or concomitant boost. The problem with IMRT is, that we still have only step-and-shoot, so doing 60 fractions of step-and-shoot IMRT can be... frustrating.
I can^t wait to get sliding window, to perform fast IMRT for these patients. Right now, we usually do IMRT for our concomitant boost patients, when we treat the first big volume with electine nodal RT.
 
We do step and shoot. It's not that bad. What machine are you using? After CBCT, 5-7 fields take 10-15 minutes. Is that unreasonably long?

We use hyperfractionation usually or concomitant boost. The problem with IMRT is, that we still have only step-and-shoot, so doing 60 fractions of step-and-shoot IMRT can be... frustrating.
I can^t wait to get sliding window, to perform fast IMRT for these patients. Right now, we usually do IMRT for our concomitant boost patients, when we treat the first big volume with electine nodal RT.
 
We use ELEKTA Synergy machines. The physics tell me our leaves and our treatment software are the issue, they seem to take ages to move to the right position.
The problem is, that our machines are full at the moment. Thus it's difficult for me to give bid treatment, knowing that another patient may have wait for a slot or be referred to another institute (with perhaps not such good treatment quality).
If you do CBCT and need another 15 min for 7 beams, this means a 25 minute window twice per day. So you are using up 50 min of the machine time for just a single patient. That's long. 🙂


We are getting the new Agility leaves and new software soon, so things should speed up by then. I am not a huge fan of VMAT, I find fixed beam sliding window techniques pretty nice too.
 
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We have 30-35 patients per machine, so with 4 LINACs running, we have about 120-140 patients/day.
 
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Speaking of transoral surgery + adjuvant therapy vs definitive CRT:

http://archotol.jamanetwork.com/article.aspx?articleid=1485601#qundefined

20 in each group, retrospective, worse toxicity in definitive arm at 6 and 12 months. Who knows what this means?

Heavily biased probably. The patients, who were able to be resected may have been the ones with less fixated tumors, which are easier to resect. They may have also had a better swallowing function before resection, than the ones who received def. RCT.