RTOG 0617 Update

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How you choose to interpret the data is up to you. However, unless you are a thoracic RO specialist you probably ha no business escalating dose beyond 60 Gy under normal circumstances.

It'll be interesting to see what impact this trial has in practice in a few years. The nccn (minsky et al) says we have no business going above 50.4 in nonoperative esophageal ca. I see 54-59.4 pretty frequently. But I digress....

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How you choose to interpret the data is up to you. However, unless you are a thoracic RO specialist you probably have no business escalating dose beyond 60 Gy under normal circumstances.


This is a pretty bold statement, and I respectfully disagree. First principles suggest that 66 Gy is the dose needed to treat gross disease. Yes, this is a dogma, but why not pick a dogma with some history behind it, rather than an arbitrary value (60 Gy) which happened to be the standard arm in a single, non-replicated, probably poorly run trial?

On a different note, we sometimes forget that our field only graduates 150 residents a year. To say that only a subset of this already pretty small number is qualified to pick a dose for one of the most prevalent cancers seems nonsequitur to me.

Just my two cents.
 
This is a pretty bold statement, and I respectfully disagree. First principles suggest that 66 Gy is the dose needed to treat gross disease. Yes, this is a dogma, but why not pick a dogma with some history behind it, rather than an arbitrary value (60 Gy) which happened to be the standard arm in a single, non-replicated, probably poorly run trial?

On a different note, we sometimes forget that our field only graduates 150 residents a year. To say that only a subset of this already pretty small number is qualified to pick a dose for one of the most prevalent cancers seems nonsequitur to me.

Just my two cents.

I think you would be wise to stop at 60Gy. It's abstract data yes, but its data from an ASCO oral presentation with associated press release. Hopefully we won't have to wait 9 years for a publication ala RTOG 9410.

To address your issue with the dose, 60Gy (not 66Gy) has been the standard dose for many (most) major North American cooperative group trials. Dillman (CALGB) used 60Gy (to isocenter), HOG used 59.4Gy, RTOG 9410 prescribed 63Gy (isocenter), and the frequently quoted SWOG trials have treated to 61.2-64.8Gy (isocenter). Aside from the induction-->CRT vs CRT CALGB trial (Vokes), there are no cooperative group phase III trials going to 66Gy. So when you adjust for prescription method (isocenter vs volume), 60Gy (or slightly less) is a dose supported by the vast majority of trials. I'm not sure that "first principles" ever trumps level I evidence. "First principles" would also suggest you need 64.8Gy for definitive esophageal RT and > 60Gy for GBM, but neither is acceptable practice based on (unexpected) results from randomized trials. "Dogma" and "First principles" will not hold up under scrutiny if you have a high grade toxicity in a patient treated with concurrent chemotherapy to 66Gy.

For those arguing that this was a poorly run trial, I disagree. It is impossible to do rigorous QA for data sets this large. That is the whole purpose of RTOG credentialling, which is much more rigorous than the credentialling for other cooperative groups that conduct radiation trials. Just because you don't like the results doesn't make the trial bad... Don't kill the messenger...
 
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Totally agree with TarHeel. Good trial, unexpected results. People can theorize that it's poor QA or marginal misses. But millimeters in a trial of this size don't lead to 9 month median survival differences. It already says it wasn't due to toxicity, so it's not that. Like people are saying, even if tighter margins, this isn't protons and the 60 Gy coverage likely covered the appropriate volume.

I also don't see why 66 Gy seems better. Do you guys think there is a rise in survival that surpasses 60 Gy, spikes at 66 Gy, and falls as you get to 74 Gy? Not a smart ass question. 60 Gy in 2 Gy fractions or 63 Gy in 1.8 Gy are standard lung cancer doses. Just not sure 66 Gy holds up in court. 60 Gy to PTV is 66 Gy to isocenter.

Anyway, wouldn't go as far as to say a lung specialist only should go higher. But, anyone going higher is basing their decision on phase II trials and AGAINST level one evidence.

Interestingly, we were going to 77.7 Gy/37 Fx in residency routinely, and I don't remember batting an eye, because it was "standard" for us. My first week in practice, I attempted to go to 74 Gy, and was talked out of it by my boss, but still went to 70 Gy. Did it a few more times, but stopped after preliminary results from trial came out.
 
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Not a smart ass question. 60 Gy in 2 Gy fractions or 63 Gy in 1.8 Gy are standard lung cancer doses.

Just to clarify that in RTOG 9410, Curran et al. did 45 [email protected] Gy and then boosted involved disease @ 2 Gy/day to 18 Gy giving the total dose of 63 Gy in 34 Fx (with ENI being done in the first phase of Tx)

http://jnci.oxfordjournals.org/content/103/19/1452.long

I always thought Dillman et al/CALGB used 66 Gy. I think 60-63 is my new dose. The survival numbers from the only Phase III trial using 66 Gy (Vokes CALGB concurrent +/- induction trial) were horrible in both arms. If someone presents with an unresectable Stage III pancoast tumor, are you guys sticking to 60-63?
 
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Sorry I was out last week, and I know this is beating a dead horse, but here are my responses to the above, FWIW:

As far as 60 Gy being the arm in cooperative group trials, let's keep in mind that the dose limit in bygone eras was based on toxicity limitations. You simply couldn't deliver more if you wanted to. In fact, where did 60 Gy originally come from: RTOG 7301 -- yes, as in 1973.

9410 prescribed to 63 Gy using marginally better technologies. I think it's disingenuous to say that "well, the volume must have received 60 since 63 Gy is the isocenter". That maybe true, but then again, it may not be. In any case, someone somewhere in 1994 decided that 60 Gy is probably inadequate as a prescription dose. As far as 66 Gy goes, it has been used in at least two modern trials with modern techniques including the Vokes trial as mentioned and the French trial (http://www.ncbi.nlm.nih.gov/pubmed/16087956?dopt=Abstract). It is a reasonable standard, is consistent with first principles, and has simply not been compared to 60 Gy in randomized fashion.

Also, it is not mere speculation to state that 60 Gy is likely to be inadequate. In fact, there is randomized evidence demonstrating that 60 Gy accrues no survival benefit. This dose (both as XRT only and chemoXRT) was compared against chemotherapy alone by Johnson et al (http://www.ncbi.nlm.nih.gov/pubmed/2161633?dopt=Abstract), and there was no survival benefit. So why would anyone treat a patient to 60 Gy with all the concomitant toxicity for no overall survival benefit? Would it be to prevent local symptoms? If so, then let's call a spade a spade: 60 Gy is aggressive palliation, and not a definitive dose per this randomized trial. That is also level I evidence.

With regard to 0617, why is everyone so unwilling to state (or explain) the obvious: There were more local failures in the high dose arm, ergo tumors were missed. This, to me, should be the very definition of a poorly radiation oncology trial. And the refrain that "it's really tough to run a cooperative trial" is a pretty unsatisfying defense in support of 0617.

The RTOG has run some very important trials and I respect and admire them for it. However, it also has run some poorly designed trials as one would expect from an organization (A) that is made of human beings and (B) that makes decisions in committee. Unremitting, unconditional support for this organization and an unwillingness to say that it errs from time to time is a worse kind of dogma than prescribing to 66 Gy, IMHO.

Finally, the idea that survival gets better until a certain dose (such as 66 Gy or whatever) and then gets worse afterward as toxicities become fatal seems completely reasonable to me. Isn't that the the whole point of the classic two sigmoid curves graph demonstrating the toxic-therapeutic ratio?
 
As far as 66 Gy goes, it has been used in at least two modern trials with modern techniques including the Vokes trial as mentioned and the French trial (http://www.ncbi.nlm.nih.gov/pubmed/16087956?dopt=Abstract). It is a reasonable standard, is consistent with first principles, and has simply not been compared to 60 Gy in randomized fashion.

Looking at median OS, the survival was fairly poor both arms of both trials, particularly in the US-led Vokes study. Can't say that a french trial and a CALGB trial with poor OS in both arms creates any kind of standard for Tx. That being said, I completely agree with your point regarding LC in 0617. The investigators obviously were lax with margins/motion management in the higher-dose arms to end up with a SS decrease in LC In the 74 Gy arm. If dose escalation didn't matter at all, the LC should have been close to similar between both arms.

Unfortunately, for those of us in PP, I think this trial is going to make waves, for at least a while. I'll still consider 66 in select cases, but generally, I am going to be sticking to 60-63. I won't be treating to 70 anymore.

In the meanwhile, hopefully someone out there is working on a 60 vs 66 trial or a 63 vs 70 trial to answer that question. Quite frankly, outside of 0617, I never saw 74 Gy being used in residency or beyond and, until the 74 Gy arms closed in 2011, I never saw 60 Gy being used either. Most people I know of and trained with treated somewhere with doses of 63-70 Gy. The rationale for why they picked two extremes in doses for 0617 was to be able to really see an effect (hopefully).
 
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74 Gy concurrent with chemo was used in a few phase II trials with decent outcomes, and I think that's why it was chosen.

Nice study, Neoplastic, I never saw that before. I always wonder what benefit RT has in lung cancer. There is a trial that compares 60 Gy to no treatment showing a minimal benefit.

I don't buy the motion argument as the reason for poor local control. There has never been a dose escalation trial with higher local failures. In the esophageal trial, there were more deaths in the high dose arm (before reaching the high dose), but there was not worse local control. It's just a bad outcome. People go to 80 Gy (Michigan, I think), and they don't have undue toxicity or poor local control. 66 is reasonable, but I don't get why you'd think that it isn't just aggressive palliation, either. Basically, all treatment for stage III lung cancer is. Maybe it's better than 60 Gy, but nobody really know if it is. We now know 74 Gy isn't better, but to think its because of marginal misses doesn't really seem right to me. I'm going to check a few of my IMRT plans and see what the dose spray looks like.
 
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I don't buy the motion argument as the reason for poor local control. There has never been a dose escalation trial with higher local failures.

Consider the minksy trial's margins:

The superior and inferior borders of the radiation field were 5 cm beyond the primary tumor. The lateral, anterior, and posterior borders of the field were ≥ 2 cm beyond the borders of the primary tumor. The tumor size was defined by endoscopic ultrasound, barium swallow, or CT scan (whichever was larger). The primary and the regional lymph nodes were included. For tumors of the cervical esophagus, the supraclavicular lymph nodes were included. A separate photon or electron boost to the supraclavicular lymph nodes was allowed to bring the total dose to 50.4 Gy.High-dose target volume (14.4 Gy).

Patients randomized to the high-dose arm received a cone down of 14.4 Gy to a total dose of 64.8 Gy. The intent of the cone down was to treat the primary tumor only, not the regional primary lymph nodes. The superior and inferior borders of the field were decreased to 2 cm beyond the tumor. The lateral anterior and posterior borders were the same as the initial target volume.

vs what was allowed in RTOG 0617

Definition of the PTV:
Free-breathing non-ITV approach (i.e. standard CT simulation without 4DCT or fusion of
inhalation and exhalation scans):

There are two components to the PTV expansion. the internal motion (IM margin) which
should be at least 1 cm in the inferior-superior direction, and 0.5 cm in the axial plane
and an additional set-up margin (SU margin) of 0.5 cm. Thus, the total PTV includes the
CTV plus a total margin of at least 1.5 cm to the superior-inferior dimensions and at least
1.0 cm in the axial plane.

A significant diff IMO and if you consider subclinical dose spread out over 7.5 weeks in the high-dose arm, I think it's a very reasonable explanation. No 4DCT was mandated and margins were allowed to be fairly tight without that
 
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So, why are you sure that every patient on 74 Gy had small margins and every patient on 60 Gy had big margins? We don't know that, and there isn't any reason to be certain of that, other than rampant speculation. If it is in fact true, then I still think it would be worthwhile to look at dose spray. 14 Gy is an amount that I'm fairly sure (not certain), would cover the immediate 1 cm, which would make up for tight margins, which would rule out that explanation. Even though there is no evidence for that explanation other than conjecture.
 
"A significant diff IMO"??

The 0617 margins were 0.5-1 on GTV or ITV for CTV.
As you quoted, you then had at least 1.5 in S/I and 1 radially added for PTV.
That means at LEAST 2 cm S/I and 1.5 cm radially. At MOST, 2.5 S/I and 2 radially. This is to define PTV, NOT field border.
Block edges are usually 7 mm to get coverage in my experience but lets call it 5mm for minimum field edge.
Now block edges are at least 2.5 cm S/I and 2 cm radially and at most 3 cm S/I and 2.5 cm radially. Thus, the field borders are not significantly different from field borders in Minsky trial and probably larger. Of course, protocol violations may abound!

If you are are actually concerned about the original 5 cm field border, that is because it is a different disease thought to spread in submucosal lymphatics very differently than NSCLC. As stated before, the dose in this trial is 9 Gy higher than the Minsky and the 65 Gy wash should be pretty large if we were to try to compare the two trials, which I concede is silly as they are different diseases.

"No 4DCT was mandated and margins were allowed to be fairly tight without that"

My understanding early in my training was that 2cm to block edge on gross tumor was the standard for 3D planning before formal definitions of GTV, CTV, PTV. I may be wrong and don't feel like reviewing old M&M sections of trials. If my memory is correct, then the margins aren't really "tight" over historical approaches and are probably larger, especially if any ITV is used.
 
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My understanding early in my training was that 2cm to block edge on gross tumor was the standard for 3D planning before formal definitions of GTV, CTV, PTV. I may be wrong and don't feel like reviewing old M&M sections of trials. If my memory is correct, then the margins aren't really "tight" over historical approaches and are probably larger, especially if any ITV is used.

Fair enough.... the question then arises about trial compliance.

I guess we'll have to hope for the manuscript to shed some slightly on a such a huge SS difference in LC in the higher-dose arm. Hopefully it won't take 10+ years like 9410 did.
 
Good discussion...a couple points:

1) As to the question of 66 v. 60, remember that 6 Gy potentially represents a 3 log-kill improvement. And though I have no proof that 66 Gy is the ideal, escalated dose to provide overall survival benefit, I do have evidence that 60 Gy does not provide such a benefit via a randomized, cooperative, prospective trial. I think the "ideal dose" is probably somewhere between 60 and 74, and hence I think 66 Gy is a good dose until a better trial is run.

2) With regard to why 0617 has weird local control results, I've heard only two plausible possibilities:
a) the higher local failures were caused by marginal misses due to margin problems or compliance issues, as others have noted
b) the stratification and randomization were poorly designed or somehow compromised

Either way, calling this a "good trial" and accepting the results at face value (as the ASCO president has done) seems ill-advised.
 
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I wonder if there were significantly more patients treated with IMRT in the 74 Gy arm-- that coupled, with 'tighter' margins, led to inferior local control.

Wouldn't it be crazy if they just have the high and low dose arms flipped in the stats analysis? Sounds crazy, but RTOG has made mistakes with statistical analyses in the past (I believe the D'Amico dose-escalation trial).
 
b) the stratification and randomization were poorly designed or somehow compromised

Either way, calling this a "good trial" and accepting the results at face value (as the ASCO president has done) seems ill-advised.

Agreed. While results of a randomized trial can't simply be dismissed because they don't agree with the hypothesis, its important to recall that randomization/stratification aren't perfect. Even a well stratified trial can be undone by happenstance. Do enough head-to-head trials with your pocket change and at some point you'll conclude that a dime is more likely to come up heads than a quarter (must have something to do with the edge thickness).
 
Totally non-scientific study that I did:

Took a few lung IMRT plans that went to 60 Gy. Changed the prescription to 74 Gy. Then pretending I was too tight on the PTV (which is never true, my volumes are transcontinental), increased the volume of it by 0.5cm in 3 dimensions. Then, checked how much of that new expanded PTV was getting 60 Gy. >93-95%. Almost the entire volume got 97% of dose. Obviously there are many caveats to this, but you can just tell that the fall off from 74 Gy to 60 Gy is not steep. Plus, like someone said above, the instructions on the trial had big volumes, even if you used the smallest that they recommended.

The big flaw is that I think that if I did 74 Gy for any of my plans, I would have allowed lesser coverage around the spinal cord, b/c it is damn hard to maintain tolerance when going this high. Also, I would have used the tightest expansions recommended, which is not what I do now.

Sticking with the theory that 1 out of 20 studies have to have wrong results :) And, that I have done the last research project of my life. I think ARS will definitely accept this.
 
12% of radiation oncologists are palliating lung cancer with 60 Gy/30 fx. No wonder the feds came after us. Sheesh.
 
Looks like the other part of 0617 will also turn out to be negative........

Cetuximab adds no benefit in stage III unresectable lung cancer

Cetuximab does not improve overall survival when used alongside chemoradiotherapy in patients with unresectable stage III lung cancer, based on data from a randomized, phase III comparison trial.

Cetuximab also appeared to be associated with an increase in therapy-related toxicities, based on data presented during a plenary session of a world conference on lung cancer.

Median survival in patients randomized to cetuximab was 23.1 months, compared with 23.5 months in patients not taking cetuximab; overall survival at 18 months was 60.8% versus 60.2% on the cetuximab and noncetuximab arms, respectively (P = .484; hazard ratio, 0.99), based on data from 465 patients.

There were 167 therapy-related grade 3 nonhematologic adverse events reported in the cetuximab group, compared with 115 in the no-cetuximab group (P<.0001).

There was no significant interaction between radiation dose and cetuximab, although preliminary analysis did suggest that cetuximab may have more beneficial effect in patients with high-EGFR expression.
 
that's an important finding.
heart dose>V20>V5
 
Handy reference if you get a peer to peer request for imrt approval from an insurance company:

http://jco.ascopubs.org/content/early/2016/09/28/JCO.2016.69.1378?cmpid=jco_pap_3Oct2016

0617 allowed for a V20 of 37%. I had one peer to peer with a patient who had a V20 of 35% on the 3D plan and something like 23% on an IMRT. V5 and MLD was acceptable on each. I was told because RTOG protocols allowed it, I should be treating the 3D. It took me about 15 minutes of yelling about Grade 3 or higher (including fatal) pneumonitis rates before he finally yielded. UHC, BTW.
 
Great to see the manuscript... I've changed my practice to push IMRT and prioritize heart dose since the abstract last year.
 
Handy reference if you get a peer to peer request for imrt approval from an insurance company:

http://jco.ascopubs.org/content/early/2016/09/28/JCO.2016.69.1378?cmpid=jco_pap_3Oct2016
Annnnnnd I just did another peer to peer last week for an N2 lung for a patient with Cigna who outsources their authorization process to Evicore. I haven't had to deal with this from any other insurance company within the last year I would say.

I pretty much ripped the rad onc on the other end of the line for not knowing the imrt data which is published in the jco as per my above link.

Are you guys still getting peer to peer requests for 3D vs imrt comparison plans in pts with stage III lung ca? The lung and heart doses were reasonable, of course the cord was at 60 Gy with the 3D :)

It's such a waste of everyone's time
 
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Peer to peer reviews are pretty obnoxious in general. Some of them keep insisting to me that they are radiation oncologists, and I feel like asking back: "Are you sure????"
 
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In defense of the peer reviewer (can't believe I am saying that- and no I am not one) they often have to follow the policy guidelines which may give explicit criteria for necessity. For advanced NSCLC I think you can often justify it with a plan comparison. Just because an abstract says IMRT should be considered routine doesn't make it so. If IMRT doesn't result in an appreciable or clinically significant reduction of normal tissue dose exposure then it probably isn't necessary. I find myself needing IMRT much more than not and usually don't have issues getting it approved other than having to generate 2 plans.


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In defense of the peer reviewer (can't believe I am saying that- and no I am not one) they often have to follow the policy guidelines which may give explicit criteria for necessity. For advanced NSCLC I think you can often justify it with a plan comparison. Just because an abstract says IMRT should be considered routine doesn't make it so. If IMRT doesn't result in an appreciable or clinically significant reduction of normal tissue dose exposure then it probably isn't necessary. I find myself needing IMRT much more than not and usually don't have issues getting it approved other than having to generate 2 plans.


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The abstract has been published fyi as a full manuscript, link above.

The conclusion:

IMRT was associated with lower rates of severe pneumonitis and cardiac doses in NRG Oncology clinical trial RTOG 0617, which supports routine use of IMRT for locally advanced NSCLC

Like I said, I think since that data came out in the last 1-2 years, I've seen a lot less p2p phone calls to obtain imrt authorizations in stage 3 lung, but Cigna/evicore remain exceptions... It's worse than Medicaid.

Cigna does a lot of other stuff as well, like pretty much never approving igrt for any palliative case.. They even tried to deny 3D on a pelvic bone met, I told them it was appropriate to document ptv, coverage, hot spots, nearby organ dose etc. Bone met palliation is pretty much 2D and 10 fractions or less with Cigna.
 
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