Hypofractionation for prostate cancer [Cleveland Clinic protocol]

[Gfunk6]

How often (if at all) do you guys use Cleveland Clinic hypofractionation or the equivlaent for treating prostate cancer?

It seems that I am using it much more frequently than my colleagues. In fact, I *always* use it for low-risk and low-intermediate risk disease unless there is a compelling reason not to (unable to achieve hypofractionation OAR dose constraints, prior h/o urethral trauma, etc.). Whenever I treat pelvic LNs for higher-risk disease, I stick with standard (2.0 Gy/day) fractionation.

I just don't see why a lower risk patient needs to come in for 38-44 fractions when it can be done in 28 fractions with equivalent efficacy and toxicity. Plus prostate IGRT is really over the top nowadays so missing the target seems to be a non-issue. Am I missing something? Other than greater reimbursement . . .

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[deleted4401]

I don't think it's wrong to hypofractionate for prostate cancer, in fact, it's probably biologically a good idea.

However, for curative cases of any cancer, I don't stray from NCCN guidelines, since I'm in community practice. They don't currently mention hypofractionation (Cleveland Clinic style or extreme Cyber type doses) and recommend traditional doses. On protocol or at an academic center, I'd loosen up a bit, but I stick to the traditional doses. Any complication, even if it isn't the physician's fault, could be attributed to something that isn't considered "standard". Prostate cancer is a disease that arguably doesn't need to be treated, and so I keep it very simple, until the NCCN catches up.

Simul

 

[Gfunk6]

Good points from both of you, thanks. There was a recent publication in the Red Journal showing final results of a Phase III randomized trial in the US/Australia (link: http://www.redjournal.org/article/S0360-3016(10)03031-2/abstract) between hypofractionation and standard fractionation for prostate cancer. They showed a bPFS advantage in the hypofrac arm w/ no increase in toxicity. Granted these doses are far less than what we are proposing, but for my comfort level this evidence is compelling.

 

[Houston500]

Good points from both of you, thanks. There was a recent publication in the Red Journal showing final results of a Phase III randomized trial in the US/Australia (link: http://www.redjournal.org/article/S0360-3016(10)03031-2/abstract) between hypofractionation and standard fractionation for prostate cancer. They showed a bPFS advantage in the hypofrac arm w/ no increase in toxicity. Granted these doses are far less than what we are proposing, but for my comfort level this evidence is compelling.

This study enrolled only 217 patients. Besides the obviously low doses used, they were planned with TWO-dimensional or old 3D techniques using a 4-field box setup and prescribed to the isocenter. Needless to say, I would not use this study as a basis to support the standard use of hypofractionation in prostate cancer, though that doesn't mean I wouldn't offer it to select patients of mine, either.

 

[Gfunk6]

Point well taken. However this is a problem with prostate randomized data in general. By the time trials reach enrollment, mature and are published, the techniques are outdated. We have to extrapolate something.

 

[Cancerdancer]

There always seems to be a bias against hypofractionation, with the claims that the data can't be extrapolated. Your point is well-taken. In general our community is OK extrapolating when it means more treatment (dose-escalated IMRT w/ ADT for high-risk prostate isn't supported by data either, but people don't stop at 66 Gy or drop the ADT) but very hesitant to accept less treatment.

God bless ASTRO for putting out a consensus statement on breast hypofractionation, but you'll still see people creatively misinterpret it to say things like 'per the guidelines we can't hypofractionate DCIS, or separation > 25 cm, or women < 50' when the statement said no such thing. Again, usually bias for more treatments/fractions.

My academic center always hypofractionates prostate 70/28, for the record And with some nudging, we're starting to for DCIS as well...

 

[Houston500]

Don't take this the wrong way, but you are missing the point. Extrapolating is fine, but you still have to be critical in picking what evidence you choose to support your clinical decisions. There is a difference between "outdated" and "obsolete". This australian study, by design and result, is the later and I am not sure if it can be used as a compelling evidence in support of hypo fractionation. The biochemical control rates In both arms are horrible regardless that one appears better than the other. The phase 2 Cleveland study has far more strength than this phase 3 trial.

 

[Cancerdancer]

OK, fair.

However, what it does show is that hypofractionation, with a median f/u of 90 months, can result in similar late toxicity rates, with similar, if not enhanced, biochemical control rates.

I still stick by my point though. We all jumped on adding hormones to intermediate risk patients based on D'Amico's paper of a whopping 206 patients, of whom a fair number were high-risk.

And yet our discussion of hypofractionation focuses on the wrong paper, b/c papers showing less (fractions) might be better are subject to a different level of scrutiny. The randomized trial of hypofractionated RT vs 80 Gy standard fractionation demonstrated a significantly enhanced biochemical control rate with no worsened toxicities...yet doesn't even get mentioned in this thread.

PMID 20047800

Perhaps what the Australian study should teach us is that we should trust in Jack Fowler, out to 90 months. He was the senior author of the Italian study referenced above as well...

 

[Palex80]

The randomized trial of hypofractionated RT vs 80 Gy standard fractionation demonstrated a significantly enhanced biochemical control rate with no worsened toxicities...yet doesn't even get mentioned in this thread.

PMID 20047800

The follow up of the Italian trial is too short to really make valid statements on late toxicities in my opinion. The second problem are the numbers. Randomizing 168 patients is simply not enough to make a valid statement concerning toxicity, as far as statistical power is concerned.
I will however agree with most of you in one thing: Hypofractionation seems like a viable option for prostate cancer patients and can be offered. It also seems that hypofractionation may actually be the only way to deliver doses equivalent to more than 80 Gy in normal fractionation to the prostate, without risking late toxicity. There are even people talking about hypofractionated IMRT-IGRT beeing the "killer" of proton treatment for prostate cancer.

We don't offer hypofractionated prostate treatment yet in my insitution, but we also don't offer hypofractionation for women younger than 55 receiving adjuvant whole breast irradiation. Why we don't do that? Cause we still have concerns concerning very late toxicity (cosmesis).

 

[Reaganite]

The follow up of the Italian trial is too short to really make valid statements on late toxicities in my opinion. The second problem are the numbers. Randomizing 168 patients is simply not enough to make a valid statement concerning toxicity, as far as statistical power is concerned.
I will however agree with most of you in one thing: Hypofractionation seems like a viable option for prostate cancer patients and can be offered. It also seems that hypofractionation may actually be the only way to deliver doses equivalent to more than 80 Gy in normal fractionation to the prostate, without risking late toxicity. There are even people talking about hypofractionated IMRT-IGRT beeing the "killer" of proton treatment for prostate cancer.

We don't offer hypofractionated prostate treatment yet in my insitution, but we also don't offer hypofractionation for women younger than 55 receiving adjuvant whole breast irradiation. Why we don't do that? Cause we still have concerns concerning very late toxicity (cosmesis).

Why would hypofractionated imrt-igrt be the "killer" of proton treatment for prostate ca? Hypofractionation and igrt can be applied to protons as well.

 

[deleted4401]

This is a very good discussion because it's less about evidence and more about philosophy.
I had a very spirited discussion with my group about hypofractionating for DCIS. I offered it to patients, and was called out on it. They said we agree with your logic, but you are a private practitioner and it's not guideline based treatment. If I wanted to offer it, I needed to write up a consent form for it.

The fact is, American medicine is a different beast. It's not completely about evidence or even what's right for the patient. It's about what is considered usual and customary by an average practitioner. That's how juries decide.

Honestly- if there were no NCCN guidelines and I could never be sued and all treatments were reimbursed the same, I would recommend extreme hypofractionation for all low risk prostate cancer. It makes sense and it works. But, that's not considered standard of care, so I don't mention it.

And yes, if hypofx is approved for prostate ca, proton centers will lose tons of money. The investors were not very bright in my opinion.

 

[Palex80]

Why would hypofractionated imrt-igrt be the "killer" of proton treatment for prostate ca? Hypofractionation and igrt can be applied to protons as well.

Well the main argument I have been hearing from the "proton boys" regarding proton-RT for prostate cancer is that with protons you can increase the dose to the prostate and thus lead to higher tumor control rates. The second argument used was that protons may lead to less toxicity than photons.

Both arguments were made using data from older trials, comparing protons with "old-school" photon-RT. In the modern photon-era, I see very little benefit with protons.

With hypofractionation we may be able to achieve higher biochemical control rates than with standard fractionated photon-RT.
Through IMRT/IGRT we are already able to limit dose to the critical structures and shrink the PTV.

Surely, hypofractionated-proton-RT may theoretically provide even better biochemical control rates, but the problem is than local control in the prostate is already very high with modern dose-escalated photon-RT, so that there will only probably be very little room for improvement, that may actually matter.

As far as side effects and IGRT of proton-RT is concerned, I have serious concerns concerning its feasibility with modern spot-scanning techniques on a moving target like the the prostate.

 

[medgator]

Surely, hypofractionated-proton-RT may theoretically provide even better biochemical control rates, but the problem is than local control in the prostate is already very high with modern dose-escalated photon-RT, so that there will only probably be very little room for improvement, that may actually matter.

Especially when you consider a cost-benefit analysis

 

[CyberKnife19]

At my institution, we currently have a Phase I/II hypo-fracionation trail as follows w/BED 2 Gy equivalents in parentheses (assuming a/b = 1.5 Gy)

1. 64.7 Gy/22 Fx (82.6)
2. 58.08 Gy/16 Fx (85.1)
3. 51.6 Gy/12 Fx (85.5)

I won't steal the thunder of my fellow resident conducting the trial, but the rates of GI and GU toxicity are looking pretty good...stay tuned.

 

[Gfunk6]

38 Gy in four fractions w/ Cyberknife (alpha/beta > 250)

Very short follow-up obviously, but the dose is modeled on prostate HDR monotherapy.

I hope NCCN adopts some form of hypofractionation into their guidelines soon. Eight weeks of radiation for low-risk prostate cancer with fiducials, IMRT, and daily IGRT seems a tad excessive.

 

[seper]

I heard there are data now supporting 42.6 Gy/16 fx for DCIS. Can anybody elaborate?

This is a very good discussion because it's less about evidence and more about philosophy.
I had a very spirited discussion with my group about hypofractionating for DCIS. I offered it to patients, and was called out on it. They said we agree with your logic, but you are a private practitioner and it's not guideline based treatment. If I wanted to offer it, I needed to write up a consent form for it.

The fact is, American medicine is a different beast. It's not completely about evidence or even what's right for the patient. It's about what is considered usual and customary by an average practitioner. That's how juries decide.

Honestly- if there were no NCCN guidelines and I could never be sued and all treatments were reimbursed the same, I would recommend extreme hypofractionation for all low risk prostate cancer. It makes sense and it works. But, that's not considered standard of care, so I don't mention it.

And yes, if hypofx is approved for prostate ca, proton centers will lose tons of money. The investors were not very bright in my opinion.

 

[seper]

Huh?

 

[Gfunk6]

pmid: 20147717

This is the long-term Whelan data for invasive breast cancer. Seper was asking about DCIS.

 

[deleted4401]

Whelan's group has a series of their DCIS patients. I believe NYU (Fomenti) has a series, as well as a few other places. They seem to do just fine, but these are retrospective and single-institution. Interestingly, like in the Whelan trial for invasive disease, there was concern about higher LR with high grade disease (which I don't get at all). Another thing is that Whelan trial for invasive disease, they did not exclude those with associated DCIS. So, there are good arguments for it, but from a purist perspective, it isn't really SOC, and the new consensus guidelines (from the Webinar this Autumn) did not feel there wasn't enough data to warrant including or excluding DCIS patients, and its up to the treating physician.

S

 

[medgator]

38 Gy in four fractions w/ Cyberknife (alpha/beta > 250)

Very short follow-up obviously, but the dose is modeled on prostate HDR monotherapy.

I hope NCCN adopts some form of hypofractionation into their guidelines soon. Eight weeks of radiation for low-risk prostate cancer with fiducials, IMRT, and daily IGRT seems a tad excessive.

slightly different than the fractionation scheme used in the study published from Stanford, (7.25 Gy x 5 Fractions)

http://www.ncbi.nlm.nih.gov/pubmed/18755555

 

[Cancerdancer]

I heard there are data now supporting 42.6 Gy/16 fx for DCIS. Can anybody elaborate?

PMID 20803608 and
20400190

 

[seper]

thx
it's starting to look very good