Hypofractionation for GBM in elderly

[seper]

Is it safe to say that 40Gy/15fx with Temodar is the default choice for a fit 80 y/o patient?

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[medgator]

Haven't seen a gbm in awhile but last I recall wasn't Canadian Fx supposed to be for poor PS pts without tmz?

If someone is a good ecog and underwent a GTR, I would treat them with 60/30+tmz

 

[Burt Radnolds]

I would say there are dual standards for elderly GBM patients. I would favor 60/30 for a high functioning patient, but would speculate you don't lose much (or anything) with 40/15, plus you have good data (Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma. - PubMed - NCBI) to back you for adding tmz in the hypofractionated setting.

 

[Neuronix]

Note that the eligibility for the trial linked above was:

This randomized, phase 3 trial enrolled patients 65 years of age or older who had newly diagnosed glioblastoma (World Health Organization grade IV astrocytoma), which was histologically confirmed after surgery or biopsy performed less than 28 days before randomization. Patients were deemed by their physicians not to be suitable to receive conventional radiotherapy (60 Gy in 30 fractions over a period of 6 weeks) in combination with temozolomide.

So that's what I do. If the patient can't come for 6 weeks or looks pretty bad, I'll use the three week regimen. For a fit 80 year old patient, I would still do 6 weeks w/ concurrent TMZ. It's reasonable to hypofractionate though.

 

[Burt Radnolds]

We are on the same page, as mentioned I would default to longer course for a high PS patient.

However, the median overall survival for MGMT methylated patients with RT+TMZ was a respectable 13.5 months, which for a population of poor performance elderly GBM patients is fairly impressive. "Not suitable for conventional radiotherapy" is a fairly loose study criteria. I can just imagine being a fly on the wall of that consent process and how that discussion could be massaged in a number of ways, including just floating the idea that a shorter option existed and the patient latching onto it.

 

[Neuronix]

I can just imagine being a fly on the wall of that consent process and how that discussion could be massaged in a number of ways, including just floating the idea that a shorter option existed and the patient latching onto it.

Yeah could be. I don't know how these consent processes go in Canada or Europe. For me, if I mention to a patient that there is a 3 week option and a 6 week option, they almost always latch onto the 6 week option. More must be better, right?

 

[Palex80]

We hypofractionate pretty much everyone older than 70 and a sizable portion of the 60-70yo patients too.

Is your patient MGMT positive? If he's not, skip TMZ. TMZ in over 65yo probably adds little to RT anyway.

 

[medgator]

Yeah could be. I don't know how these consent processes go in Canada or Europe. For me, if I mention to a patient that there is a 3 week option and a 6 week option, they almost always latch onto the 6 week option. More must be better, right?

Some think less = less dose and worry about getting "too much radiation"

 

[nkmiami]

I dont treat this way, but just to throw it out there- phase III data for 3d conformal 5 Gy x 5 with 2.5 cm margins- thats why I feel comfortable giving margins that are 10x smaller in the stereotactic setting with similar doses:
http://ascopubs.org/doi/abs/10.1200/jco.2015.62.6606

 

[Krukenberg]

ASTRO has a nice GBM guideline that addresses this question: https://www.practicalradonc.org/article/S1879-8500(16)30003-0/pdf

Important to note that age is an independant predictor of poor prognosis. Patients older than 70 with good PS had the same median survival as poor PS patients. I don’t think just being a “fit elderly patient” warrants conventional fractionation.

 

[Radiator20]

Is it safe to say that 40Gy/15fx with Temodar is the default choice for a fit 80 y/o patient?

In my view, yes. Given a) equivalent disease outcomes for hypofrac vs conventional in elderly, and b) that this patient doesn’t have that much longer to live no matter what, I can’t see taking up the extra weeks of their remaining time for no added benefit. I don’t know that I’d even present conventional fractionation as an option.

 

[medgator]

In my view, yes. Given a) equivalent disease outcomes for hypofrac vs conventional in elderly, and b) that this patient doesn’t have that much longer to live no matter what, I can’t see taking up the extra weeks of their remaining time for no added benefit. I don’t know that I’d even present conventional fractionation as an option.

So do you use age as a cutoff then? (Conventional fx <70)

 

[medgator]

Nccn mentions 34/10 and 50/20 as other options for hypofx in gbm. Anyone use those? Combo with tmz?

 

[Radiator20]

So do you use age as a cutoff then? (Conventional fx <70)

Seems to me that the definition of "elderly" in GBM is tough. Roa 2004 was >60, Perry was >65, but neither of those matches what I at least intuitively think of as "elderly." I'm not sure there's a single cutoff I'd be dogmatic about, but I do think the trial criteria give a range over which it becomes progressively more appropriate to hypofractionate. So something like 60y always gets conventional, 65y it's a discussion, 70y probably hypofrac. I wonder how others approach this question of age cutoff?

Nccn mentions 34/10 and 50/20 as other options for hypofx in gbm. Anyone use those? Combo with tmz?

I'm not familiar with 50/20, but I would not do Malmstrom 34/10 with TMZ. I think of TMZ as being compatible with the moderate hypofrac of Perry 40/15, but further hypofrac beyond that as being the province of RT alone. Perhaps others approach it differently and/or there's other data I'm not aware of?

 

[evilbooyaa]

Someone who is 80, regardless of clinical performance status, primarily gets offered 40/15 at my instutition with Temodar. The Roa trial did not specify "old, poor PS patients". It specified old patients. I don't know why I would put an 80 year old patient through 6 weeks of radiation. I'm not aware of any data combining TMZ with a 34/10 regimen.

 

[seper]

Thank you all. I like sparing 3 weeks for someone with limited life expectancy. Hypofx should have less acute dermatitis compared to 60/30 Gy, in analogy with the breast data.

 

[Radiator20]

Someone who is 80, regardless of clinical performance status, primarily gets offered 40/15 at my instutition with Temodar

In addition, if PS too poor to tolerate both TMZ + RT, one could consider TMZ alone if MGMT-methylated and more hypofractionated RT alone (potentially 34/10) if MGMT-unmethylated.

 

[Palex80]

I did 5 x 5 Gy to an 80 year old last year with poor PS.
He actually survived 9 months and came back for a second round, I gave him 39.9/2.66 then.

 

[evilbooyaa]

In addition, if PS too poor to tolerate both TMZ + RT, one could consider TMZ alone if MGMT-methylated and more hypofractionated RT alone (potentially 34/10) if MGMT-unmethylated.

Had one patient like that, like 80-85 years old. Came in with GBM post-op, still recovering from surgery, deferred to TMZ alone, he came back with peripheral recurrence 6 months later. Repeat surgery + adjuvant hypofx RT and he did well for another 6 months before recurring.

 

[Haybrant]

For RT alone anything wrong with 300x10 with boost of 3 fractions more in 300s? Was considering this for a poor ps over 70 who is biopsy only, allows me to feel a little better stopping after 2 weeks if necessary

 

[medgator]

For RT alone anything wrong with 300x10 with boost of 3 fractions more in 300s?

I think wbrt was a standard back in the 70s and 80s... interesting how things come back full circle. I've done wbrt in 2 wks before for really poor PS pts

 

[Palex80]

5 x 5 Gy
International Atomic Energy Agency Randomized Phase III Study of Radiation Therapy in Elderly and/or Frail Patients With Newly Diagnosed Glioblasto... - PubMed - NCBI

 

[Radiator20]

For RT alone anything wrong with 300x10 with boost of 3 fractions more in 300s? Was considering this for a poor ps over 70 who is biopsy only, allows me to feel a little better stopping after 2 weeks if necessary

5 x 5 Gy
International Atomic Energy Agency Randomized Phase III Study of Radiation Therapy in Elderly and/or Frail Patients With Newly Diagnosed Glioblasto... - PubMed - NCBI

I agree with Palex. I would not do WBRT (though not sure that’s what you were proposing). Seems to me, in fact, that a poor PS patient is who is likely to do the worst with WBRT.

I am not sure if there is data to support a 3 Gy x 13 regimen such as you propose, but if your concern is getting done in 2 wks, Malmstrom 3.4 Gy x 10 gets you there. And if you want to get done even faster, the Roa/IAEA 25/5 that Palex mentions gets you done in a week. Either of these gets done quickly and is well supported by modern literature for the elderly/poor PS pt (who presumably cannot tolerate TMZ/RT).

 

[Ray D. Ayshun]

We hypofractionate pretty much everyone older than 70 and a sizable portion of the 60-70yo patients too.

Is your patient MGMT positive? If he's not, skip TMZ. TMZ in over 65yo probably adds little to RT anyway.

FWIW, in the Perry NEJM article, this was mentioned re MGMT status comparing RT/TMZ to RT alone:

Although the greatest benefit was observed in patients with methylated MGMT status (median survival, 13.5 months with radiotherapy plus temozolomide vs. 7.7 months with radiotherapy alone; hazard ratio, 0.53; 95% CI, 0.38 to 0.73; P<0.001), a clinically meaningful overall survival advantage, which did not reach statistical significance, was also observed in patients with unmethylated MGMT status (median survival, 10.0 months vs. 7.9 months; hazard ratio, 0.75; 95% CI, 0.56 to 1.01; P = 0.055; P = 0.08 for interaction)

Has me wondering if larger fraction size in this trial may make concurrent TMZ more efficacious than with standard fraction size in patients with unmethylated MGMT, though there's probably data escaping me now proving this assumption incorrect.

 

[evilbooyaa]

For RT alone anything wrong with 300x10 with boost of 3 fractions more in 300s? Was considering this for a poor ps over 70 who is biopsy only, allows me to feel a little better stopping after 2 weeks if necessary

Eh. 3 x 13 Not supported by data. I'd do 3.4 x 10 if you were really concerned about that. I honestly don't know that I'm ever going to do 5 x 5 in this clinical scenario.

 

[Radiator20]

Eh. 3 x 13 Not supported by data. I'd do 3.4 x 10 if you were really concerned about that. I honestly don't know that I'm ever going to do 5 x 5 in this clinical scenario.

Likewise, I’ve never seen 5 x 5 actually used. That said, not totally sure I understand why not. Mind sharing why you are reluctant?

 

[evilbooyaa]

Likewise, I’ve never seen 5 x 5 actually used. That said, not totally sure I understand why not. Mind sharing why you are reluctant?

Meh, don't have a EBM reason behind it. I'd probably have to do it once before I became comfortable offering it, and would likely lean for that in an elderly AND frail person, rather than one or the either, if they were say MGMT unmethylated. Haven't run into that specific scenario as of yet.

There's a small nagging voice in the back of my mind, going "If A is the standard, and B is non-inferior to A, C is non-inferior to B, and D is non-inferior to C, then is D non-inferior to A?"

 

[Palex80]

Do 8 x 8.5 Gy! Takes 1.5 weeks.

Phase 2 trial of hypofractionated high-dose intensity modulated radiation therapy with concurrent and adjuvant temozolomide for newly diagnosed gli... - PubMed - NCBI

Radionecrosis for the win!

 

[evilbooyaa]

Do 8 x 8.5 Gy! Takes 1.5 weeks.

Phase 2 trial of hypofractionated high-dose intensity modulated radiation therapy with concurrent and adjuvant temozolomide for newly diagnosed gli... - PubMed - NCBI

Radionecrosis for the win!

20 out of 46 patients developing necrosis. Good one, Palex.

 

[nkmiami]

20 out of 46 patients developing necrosis. Good one, Palex.

Isn’t it impressive that many pts did not get radionecrosis at these doses. Intuitively I think we would all expect higher rates? 1.5 cm rim of normal brain getting 40gy in 8 fractions. We agonize abt expanding 1-3 mm margin on 6 gy x5

 

[Haybrant]

Ya, not whole brain. 300x10 to the flair w margin and cone down 900 more to the GTV w margin. This is for a unresected patient. What should be covered in the 3.4x10 patient? Thanks

 

[Ray D. Ayshun]

Ya, not whole brain. 300x10 to the flair w margin and cone down 900 more to the GTV w margin. This is for a unresected patient. What should be covered in the 3.4x10 patient? Thanks

Didnt look up 34 gy trial, but in sticking with your 3gy/fx question, theres this schema.

Short-course radiotherapy in elderly and frail patients with glioblastoma multiforme. A phase II study
Jeremic, Branislav; Shibamoto, Yuta; Grujicic, Danica; Milicic, Biljana; et al. Journal of Neuro - Oncology; New York Vol. 44, Iss. 1, (Aug 1999): 85-90.

45 gy in 15 fx to gtv plus 2 cm. Seemed to work pretty well. Ive only seen 40/15 and 5x5, and 3.4 x 10 w bev for reirradiation, but not 45/15. Could get him through two weeks and try for 3, which would get close to your original 39 gy target.

 

[Radiator20]

Didnt look up 34 gy trial, but in sticking with your 3gy/fx question, theres this schema.

Short-course radiotherapy in elderly and frail patients with glioblastoma multiforme. A phase II study
Jeremic, Branislav; Shibamoto, Yuta; Grujicic, Danica; Milicic, Biljana; et al. Journal of Neuro - Oncology; New York Vol. 44, Iss. 1, (Aug 1999): 85-90.

45 gy in 15 fx to gtv plus 2 cm. Seemed to work pretty well. Ive only seen 40/15 and 5x5, and 3.4 x 10 w bev for reirradiation, but not 45/15. Could get him through two weeks and try for 3, which would get close to your original 39 gy target.

Interesting, was not aware of this study. That said, 47 pts from 1987-1993, and I'm just not sure the advantage of treating this elderly/frail pt for a longer course and to a higher dose, when there is better evidence for a shorter course to lower dose (34/10). Plus, if he gets through 2 wks and crashes and burns, you've undertreated him, whereas with 34/10 you're already done.

Ya, not whole brain. 300x10 to the flair w margin and cone down 900 more to the GTV w margin. This is for a unresected patient. What should be covered in the 3.4x10 patient? Thanks

I don't believe Malmstrom specifies in the paper. Given that they're European I would imagine enhancing + 2 cm. Personally, I would also ensure FLAIR was getting covered (but would not put an additional margin on FLAIR). Defer to anyone else if they know for sure what Malmstrom did.

In addition, if he's MGMT methylated, I'd consider TMZ alone.

 

[Ray D. Ayshun]

Interesting, was not aware of this study. That said, 47 pts from 1987-1993, and I'm just not sure the advantage of treating this elderly/frail pt for a longer course and to a higher dose, when there is better evidence for a shorter course to lower dose (34/10). Plus, if he gets through 2 wks and crashes and burns, you've undertreated him, whereas with 34/10 you're already done.



I don't believe Malmstrom specifies in the paper. Given that they're European I would imagine enhancing + 2 cm. Personally, I would also ensure FLAIR was getting covered (but would not put an additional margin on FLAIR). Defer to anyone else if they know for sure what Malmstrom did.

In addition, if he's MGMT methylated, I'd consider TMZ alone.

I dont disagree. ive never used or seen 45/15 or 34/10 in the up-front setting. If theres genuine concern about the patient crashing and burning during a 2 week course, and also evidence supporting a one week course, then maybe 5 gy x 5 is the right choice.

 

[Neuronix]

Isn’t it impressive that many pts did not get radionecrosis at these doses. Intuitively I think we would all expect higher rates? 1.5 cm rim of normal brain getting 40gy in 8 fractions. We agonize abt expanding 1-3 mm margin on 6 gy x5

This is because we generally accept up to 10% rate of RT necrosis (from RTOG 9005), though many of us would like that even lower if possible. That is a 43% rate of RT necrosis, which I think that most would consider unacceptably high.

 

[Palex80]

This is because we generally accept up to 10% rate of RT necrosis (from RTOG 9005), though many of us would like that even lower if possible. That is a 43% rate of RT necrosis, which I think that most would consider unacceptably high.

But the ones with the necrosis lived longer!


35/3.5 is also an option...

A randomized trial comparing 35Gy in ten fractions with 60Gy in 30 fractions of cerebral irradiation for glioblastoma multiforme and older patients... - PubMed - NCBI

 

[Ray D. Ayshun]

I looked up how they planned hypofractionated patients in the malmstrom trial, and they referred to this trial, which offers even more oprions.

Radiother Oncol. 1994 Nov;33(2):113-6.
Hypofractionated radiotherapy as palliative treatment in poor prognosis patients with high grade glioma.
Thomas R1, James N, Guerrero D, Ashley S, Gregor A, Brada M.
Author information

Abstract
We report the palliative effectiveness of a hypofractionated radiotherapy regimen in patients with poor prognosis high grade glioma. Thirty-eight elderly, and/or disabled patients received radiotherapy to a dose of 30 Gy in 6 fractions over 2 weeks to a planning target volume defined by the enhancing tumour and a 2-cm margin. The median survival was 6 months with a 1-year survival rate of 23%. Treatment was without acute toxicity. One month after radiotherapy, functional status, assessed using a verbally administered Barthel index, improved in 38% and remained stable in a further 39% of surviving patients. At 3 months 39% of surviving patients had improved and a further 12% remained stable. We conclude that in the poor prognostic group of patients with high grade glioma hypofractionated partial brain radiotherapy is well tolerated, convenient and provides effective palliation in a proportion of patients. Comparison with conventional radiotherapy or symptomatic care alone require further evaluation in randomised studies.

 

[evilbooyaa]

All the hypofractionation trials are T1 enhancing + 2cm. No FLAIR + margin nonsense (which honestly, I don't like doing even for Stupp regimen given how they did their radiation)

 

[Neuronix]

Stupp did not do FLAIR + margin either.