Radiation Oncology Perception vs Reality

[excalibur86]

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[Neuronix]

replaced by magic bullets?

Definitely this. Pew pew.

 

[Gfunk6]

Read the FAQ, this question is specifically addressed.

This topic has been hashed and re-hashed on this forum. Most recently here.

 

[deleted4401]

Damnit, with iPhone I'm sometimes able to beat Gfunk on this but was busy this evening. Drat!

 

[study pray love]

Hello,

I am currently a second year medical student interested in radiation oncology. I did research in the field during my first year summer and shadowed a ton in the RadOnc department at my school. That being said, I wanted to clarify some perceptions I had about the field.

I recently had the Oncology module in my classes and I became under the impression that the future of cancer research is chemotherapy/molecular targeted therapy. RT was always presented as a "necessary evil", something that we use in the clinic that is certainly therapeutically effective, but also replete with toxic side effects, and therefore something to generally avoid if possible. I know RT use to treat many cancers has declined over the past 50 years due better chemotherapies and surgical techniques. Also when I attend talks on the future of cancer therapy, rarely do I see any mention of RT - it's always about some new drug or gene that's the focus of discussion.

I was wondering if you guys could shed some light on this. Will RT someday be an outmoded form of therapy, or replaced by magic bullets? Will RT fit in to the future mode of cancer therapy? I know prognostication is rather difficult, but maybe you guys have a better perspective on this than I do. Thanks.

I am interested in radiation oncology so I read the book, "The Best News About Radiation Therapy" to get an idea of what radiation onc is all about. It was easy reading and informative. Here is the amazon link:http://www.amazon.com/Best-News-About-Radiation-Therapy/dp/159077051X.

Also, in the words of the radiation oncologist I shadowed, "Until we have the magic bullet, radiation and chemotherapy are the mainstay. Someday, hopefully, they will both become obsolete."

 

[Raygun77]

I think your course may have focused optimistically on newer biologic therapies and much less on newer radiotherapy techniques because of it's designers- likely medical oncologists in research.

It is a shame that rad oncs don't take a more active academic work load in medical student teaching. In my course I had all of one lecture by a rad onc, giving a very broad overview (replete with the big stats, e.g. 50% of cancer patients will get RT, and then runnning through the different techniques. I'm sure it went over the heads of most of the other students).

It'll take rad oncs putting their hands up to teach and help design the syllabus, both clinically and pre-clinically. FYI, i think the scope of radiotherapy has dramatically increased thanks to technology, but also modern chemotherapy and biologics that are making, for the first time, 'stage 4 cancer' potentially curable. radiation oncology, like oncology as a whole, is very research heavy, yet the research still can't keep up with all of the (usually technological) advances. A shame because it means a lot of potential improvements have to wait some time to be 'proven'. If the research and talent pool is anything to go by, though, the future of the field is bright (IMO).

 

[Palex80]

Concering the "magic bullet" and the latest developments in the field of medical oncology:

There are only 2 types of solid tumors, where "magic bullets" have provided a survival benefit for the patients in the curative setting.

breast cancer with trastuzumab

and

heand and neck cancer with cetuximab (when given concurrently with radiation therapy)


All other "magic bullets" are either useful in the curative setting for hematologic malignancies (like imatinib for CML; yes I know it works in GIST tumors too, but that's an orphan disease) or are only active in the palliative setting (like bevacizumab, which has been tested for half a dozen diseases in the curative setting and has only showed some activity for certain diseases in the palliative setting instead).


In short:
The vast majority of today's "magic bullets" work in order to prolong the survival of patients in the palliative, not the curative setting. More patients surviving longer in the palliative setting means more patients survivng long enough to develop bone & brain mets, meaning more radiation therapy needed.

 

[Seldon1985]

And honestly, even cetuximab isn't exactly a magic bullet... Yes, it is a molecularly targeted agent with 10% differential in survival w concurrent xrt, but we're not talking about eradicating head and neck SCC or even HPV+ SCC...

 

[Reaganite]

Perception.

Reality.

 

[Palex80]

http://www.youtube.com/watch?v=k1nM9RRD4FU

 

[Gfunk6]

http://www.youtube.com/watch?v=k1nM9RRD4FU

"Death is not a contraindication to radiation therapy. . . at least now she will lie still."

 

[Scatter]

Perception.

Reality.

Hells Yeah!

Nota Bene: in the Bonner trial the majority of pts on the Ctx arm were treated with altered fractionation of some sort (I think mostly concommitant boost and hyperfrac).

Just double checked. CB in 56% and hyperfrac in 18%. In other words, 3/4 pts rec'ed altered fractionation of the sort that's previously been proven to be better than once daily fractionation.

 

[medgator]

Hells Yeah!

Nota Bene: in the Bonner trial the majority of pts on the Ctx arm were treated with altered fractionation of some sort (I think mostly concommitant boost and hyperfrac).

Just double checked. CB in 56% and hyperfrac in 18%. In other words, 3/4 pts rec'ed altered fractionation of the sort that's previously been proven to be better.

26% got standard 70 Gy/35 Fx. One big criticism of that trial as no one really believes that's an acceptable SOC for radiation therapy alone for Stage III/IV HNSCC

 

[Scatter]

26% got standard 70 Gy/35 Fx. One big criticism of that trial as no one really believes that's an acceptable SOC for radiation therapy alone for Stage III/IV HNSCC

Exectamundo.

 

[Gfunk6]

Concurrent Cetuximab vs CDDP for locally advanced H&N cancer is an interesting issue. The results of RTOG 1016 should (hopefully) put this issue to rest. Although retrospective data between Cetuximab + XRT vs CDDP + XRT are conflicting, i know that many major academic centers still prefer CDDP > Cetuximab (MSKCC & UCSF come to mind).

 

[deleted4401]

Yeah, I think most people only switch to the 'Erb if patient has renal dysfunction or significant hearing issues, or as in this part of the country, when we have a mannitol shortage. Yup, that's right. No mannitol in Maryland, so having to switch to 'Erb or carbo/taxol. What a pain.

 

[Gfunk6]

Maybe Bristol Myers Squibb and Eli Lilly sabotaged the mannitol production facilities.

 

[medgator]

Yeah, I think most people only switch to the 'Erb if patient has renal dysfunction or significant hearing issues, or as in this part of the country, when we have a mannitol shortage. Yup, that's right. No mannitol in Maryland, so having to switch to 'Erb or carbo/taxol. What a pain.

Maybe Bristol Myers Squibb and Eli Lilly sabotaged the mannitol production facilities.

It's not just mannitol. All sorts of generic-label drugs have been in shortage within the past several months including propofol, methotrexate, leucovorin and Doxil.

http://www.nytimes.com/2012/02/22/h...rts-amid-shortage-of-2-cancer-drugs.html?_r=0

http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050792.htm

 

[Sheldor]

Quick comment for M3's and below who stumble on this thread:

When I first read the thread title I thought this would be about the perceptions of the field versus the reality once you start rotating through it as a M4, a resident and eventually an attending. As someone who knew relatively early in my medical education that I wanted to pursue Radiation Oncology I had a lot of time to read this forum and other online resources about the field, but I feel like even here the perception can get a tad warped.

The point distilled: This is, by far, the best field in medicine. Important, it IS, still medicine. Its easy to focus on what is foreign before rotating, such as physics, etc. However, not only are Rad Onc's still using skills learned in medical school to be a good physician, they become quite adept at symptom management. So, if you think you may be interested in the field definitely rotate through because I think you will be very, very surprised.

 

[Palex80]

Wait, wait, wait, boys!

The Bonner trial has its shortcomings, but the altered fractionation regimes allowed in the trial are not a proven bias concerning Cetuximab's efficacy.

Yes, all 3 fractionation schedules were allowed in the Bonner trial:
once per day normfractionated, twice per day hyperfractionated and twice per day concomitant boost.
The reason (the authors have mentioned), why this was done, was that at the time the trial was desinged the RTOG 9003 definitive data were not out, so all 3 fractionation schedules were valid (just split-course sucks, but we knew that before )


Now, in the Bonner trial, which was a randomized trial +/- cetuximab together with definitive irradiation, this is what happened (i am quoting the original paper):

The analysis included the following numbers of patients: 55, 37, and 120 patients undergoing once-daily, twice-daily, and concomitant-boost therapy, respectively, in the group assigned to radiotherapy alone and 50, 38, and 117 patients, respectively, in the group assigned to radiotherapy plus cetuximab.

So in both arms of the trial we had similar distribution of patients undergoing either normfractioned, hyperfractionated or concomitant boost radiation therapy. Thus the results concerning the outcome of the study (favoring the cetuximab arm) cannot be attibuted to an uneven distribution of fractionation schedules among the two arms of the study.

An unplanned, exploratory, not-well-powered subgroup analysis of the data showed that especially the patients with concomitant boost benefited the most from cetuximab.

This was, again, an unplanned, exploratory, not-well-powered subgroup analysis. Its results could be interpreted by saying that Cetuximab seems to develop it's greatest potential in the presence of a concomitant boost fractionation.

What we have done in our clinic is simple:

1. Every stage III/IV HNSCC-patient schedule for definitive treatment get's cisplatin, if he/she can tolerate it. We use normfractionated treatment for these patients.
2. If a patient cannot tolerate cisplatin, then he/she get's Cetuximab. We perform concomitant boost then.


Claiming that the Cetuximab-arm of the trial performed better, because more patients in the Cetuximab arm were treated with concomitant boost, than in the radiotherapy alone arm is wrong.
And even if that was the case, I may remind you that the final RTOG 9003-update (ASTRO 2005) did not show any overall survival benefit for any of the 4 arms of the trial.

 

[Scatter]

Concurrent Cetuximab vs CDDP for locally advanced H&N cancer is an interesting issue. The results of RTOG 1016 should (hopefully) put this issue to rest. Although retrospective data between Cetuximab + XRT vs CDDP + XRT are conflicting, i know that many major academic centers still prefer CDDP > Cetuximab (MSKCC & UCSF come to mind).

Not sure about this, because we now know that p16 and EGFR overexpression are inversely correlated. So, giving Cetuximab to an HPV+ patient is sort of like targeted therapy without the target. However, I don't think the RT+Cetux arm will fare that much worse, because these pts would likely do well even with RT alone (not sure about de-escalated dose, though). It'll be very interesting to find out, the trial is accruing well. It'd be interesting to look at outcomes of pts from the Bonner trial (ca. 50% had EGFR overexpressed, i.e., essentially p16 negative tumors) based on p16 status. CDDP is still king in my book.

 

[deleted254819]

Not sure about this, because we now know that p16 and EGFR overexpression are inversely correlated. So, giving Cetuximab to an HPV+ patient is sort of like targeted therapy without the target. However, I don't think the RT+Cetux arm will fare that much worse, because these pts would likely do well even with RT alone (not sure about de-escalated dose, though). It'll be very interesting to find out, the trial is accruing well. It'd be interesting to look at outcomes of pts from the Bonner trial (ca. 50% had EGFR overexpressed, i.e., essentially p16 negative tumors) based on p16 status. CDDP is still king in my book.

Cmon people, just look at the Forest Plots of the Bonner study update (lancet onc 2010). The breakdown of patients who benefited is completely consistent with the characteristics of HPV positive oropharynx patients (i.e. oropharynx, lower T-stage, node+, treated in US, male, younger, etc... even concomitant boost fractionation is a surrogate for being treated in the US, where the incidence of HPV+ OPSCC is much higher than in Eastern Europe, where the non-US patients were accrued).

Based on this data, it's reasonable to assume that the ONLY patients that may benefit from adding cetuximab to RT are HPV+ oropharynx patients. Ironically, cetuximab is usually used in patients who have comorbidities that preclude cytotoxic chemotherapy use, which are the same patients that are most likely to be HPV negative (i.e. older smokers with OPSCC or non-oropharynx smoking-related HNSCC). For these patients, cetuximab=water, so we use altered fractionation as if they were getting RT alone (for the proven benefit in this setting) while letting med onc keep pushing cetuximab

 

[medgator]

Cmon people, just look at the Forest Plots of the Bonner study update (lancet onc 2010). The breakdown of patients who benefited is completely consistent with the characteristics of HPV positive oropharynx patients (i.e. oropharynx, lower T-stage, node+, treated in US, male, younger, etc... even concomitant boost fractionation is a surrogate for being treated in the US, where the incidence of HPV+ OPSCC is much higher than in Eastern Europe, where the non-US patients were accrued).

Based on this data, it's reasonable to assume that the ONLY patients that may benefit from adding cetuximab to RT are HPV+ oropharynx patients. Ironically, cetuximab is usually used in patients who have comorbidities that preclude cytotoxic chemotherapy use, which are the same patients that are most likely to be HPV negative (i.e. older smokers with OPSCC or non-oropharynx smoking-related HNSCC). For these patients, cetuximab=water, so we use altered fractionation as if they were getting RT alone (for the proven benefit in this setting) while letting med onc keep pushing cetuximab

Just look for the rash

http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70311-0/abstract

 

[Palex80]

Cmon people, just look at the Forest Plots of the Bonner study update (lancet onc 2010). The breakdown of patients who benefited is completely consistent with the characteristics of HPV positive oropharynx patients (i.e. oropharynx, lower T-stage, node+, treated in US, male, younger, etc... even concomitant boost fractionation is a surrogate for being treated in the US, where the incidence of HPV+ OPSCC is much higher than in Eastern Europe, where the non-US patients were accrued).

1. HPV testing was not performed in the Bonner trial. You are making assumptions, based on no evidence from this trial.

2. Oropharynx benefited the most, but hypopharynx and larynx are also on the left side of the plot. One can argue, that there were only very few larynx patients in the trial, so it's just bad luck, while hypopharynx patients generally perform poorely. Whatever you give them (+/- cetuximab) doesn't change their poor prognosis a lot.

3. "lower T-stage". T4 sucks, we all know that. But most the patients we treat don't have a T4.

4. "treated in the US". One can make the argument, that radiotherapy delivery outside of the US was not that good. Thus Cetuximab didn't manage to make much of a difference, since the radiotherapy was bad. Plus, hyperfractionation and concomitant boost are US-specific, like you said.

5. "age". We know that most of our older patients benefit less from chemo in HNSCC than our younger patients. This is the case pretty much everywhere in oncology. Not much of a surprise here.

For these patients, cetuximab=water, so we use altered fractionation as if they were getting RT alone (for the proven benefit in this setting) while letting med onc keep pushing cetuximab

Which is actually against evidence.


You are adressing unplanned, subgroup analyses, not powered enough to detect these kind of differences. Sorry, but you need to make a new trial to prove your point.
We should be careful about drawing conclusions from not-powered enough subgroup analyses in radiation oncology. We have done this before and it ended in a mess, with people still fighting about it: RTOG 9413

Luckily, I've heard that the Scandinavians are currently trying to run or are running a randomized trial with +/- Cetuximab which is NON-pharma sponsored.

 

[deleted254819]

Agree with virtually all of your points. Unfortunately, the use of Cetuximab has become widespread in poor performance status patients who have cisplatin contraindications despite the evidence being limited to a single randomized trial. Since this is the only level 1 data, it is indeed what one must make reasonable inferences from, despite the limitations and underpowered/unplanned nature of the subsequent subgroup analyses. In fact, Bristol-Myers Squibb refused to release baseline smoking data for patients treated on this study, which could have served as a surrogate for HPV status (i.e. as all non-smoker OPSCC cases are HPV negative) and allowed for this potentially revealing subgroup analysis.

I'll be eager to see future randomized analyses once they are mature, but for now inference is all we've got. Based on this, our institutional preference of late has been to use cetuximab only with standard fractionated RT on-protocol for HPV+ non-smokers, and to accelerate RT with cetuximab in those older, non-chemo candidates who seemed to benefit the least in the Bonner unplanned subgroup analysis.