To do WBRT or not to do WBRT

[Palex80]

Here's an interesting case, I would like to discuss with you fellows:

A 60 year old patient is diagnosed with a cT3 cN0 cM1 Pancoast-SCC of the lung. He has a solitary brain metastasis of 1,8 cm, which has resulted into a single seizure so far.
6 years ago he was irradiated for Stage IVa HNSCC and has already received 50,4 Gy to the supraclavicular fossa. He is in complete remission.

Since it's only a solitary brain metastasis and the patient is in good state, it was decided to follow an aggressive approach.
As a first measure a radiosurgery is carried out for the brain metastasis.

Since he has already received 50,4 Gy to the supraclavicular fossa for his HNSCC, there is a problem with giving him a neoadjuvant irradiation for his Pancoast tumor. Therefore it is decided that he should receive neoadjuvant chemotherapy alone and then undergo surgery for the Pancoast tumor.


Here is the question:
Would you give him WBRT?

I probably would, bearing in mind that the whole treatment is aggressive. 1. If he develops new brain metastases that grow from microscopic cell deposits which are already there, then the whole therapy would have be in vain.
2. We are treating a patient with an active primary tumor. This is not a solitary brain metastasis arising 2 years after treatment of the primary tumor. Therefore the potential for further microscopic metastases is great.
3. Bearing in mind that the metastasis measures 1,8 cm, one can speculate that it has been there for quite some time, so this tumor has been making metastases for quite a while too.
4. The data on such an aggressive approach for the treatment of NSCLCs with solitary metastases in the brain are based on patients treatment with surgery both for the primary tumor and the brain metastasis. However the bulk of these patients also received postoperative WBRT based on the Patchell study. When performing radiosurgery alone, one can guarantee a similar local control rate for the treated metastasis as with resection+WBRT, but the distant control rate in the brain is lower.

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[Gfunk6]

Well based on RTOG 9508, there was an overall survival advantage in RPA Class I (Lung) when SRS was added to WBRT. His age qualifies him for Class I and I assume his KPS is 70+. However his primary needs to be controlled and I think the jury is still out on that.

Nevertheless, I would offer WBRT as his primary has probably seeded multiple micro-mets already. However, we are very anti-WBRT at my institution and I think it would also be reasonable to follow him with brain imaging and offer him salvage WBRT or RS down the road should it become necessary. For a trial justifying the latter approach see Eric Chang's paper in Lancet Oncology 2009 (PMID: 19801201).

 

[Gfunk6]

Gfunk, would you offer SRS alone if this was your oral boards or would you stick with what has been shown in the RTOG trial?

I would play it safe and say WBRT w/ SRS and base my answer on RTOG 9508.

SRS alone is better then SRS + WBRT according to Eric Chang's paper based on assessment of neuro-cognitive function (using Hopkins Verbal Learning Test). SRS was actually markedly superior in the same study over SRS + WBRT with OS as an endpoint but the study was definitely underpowered to reach such a conclusion. Other papers like the Japanese studies or Sneed's mult-institutional retrospective study (as you cited) also show that SRS alone can be used effectively with equivalent PFS endpoints. But really, I'm of the opinion that Chang's study is deeply flawed and Sneed's study (while compelling) is difficult to choose over existing Level I evidence.

In general on oral boards, I think, it is safer to go with the easy answers. If you give too nuanced an answer and try to justify with literature you may be digging yourself a grave. Your examiners are, after all, experts in their respective field.

 

[deleted4401]

You could see the smirk on Chang's face when he presented that outrageous data. An overall survival benefit! Waiting for the paper ...

I think now there is level one evidence, though flawed, to say SRS alone is legitimate. If good KPS, only extrapulmonary site of dz, I think that I'd say on boards to add Patchell style WBRT, going slowish (2.0 - 2.5 Gy Fx to 37 to 40ish), b/c that's what I'd actually recommend (though I have feeling my NSG colleagues would veto me).

-S

 

[user_name]

I don't know if it is accessible by web, but the point-counterpoint by Chang and Patchell at Radium Society in Vancouver was awesome. Chang went first and explained his study in thorough but dry detail. Patchell went second and ripped the study apart. What some may not know about Patchell is that he is actually a neurologist, not neurosurgeon. He did a convincing job pointing out that the wrong neurocognitive tests were chosen. He also pointed out that the 4 month point (if I remember correctly) was the maximum in decline in most neurocog outcomes from XRT and biased the outcome. Chang did a good job pointing out a MS of a few months precludes a later time point.

Anyway, I found it funny that a neurologist (who would care more about neurocog one would think) was begging a radonc (who would care less?) to give WBRT. Worth a review if you can find it.

Also, Patchell was way more entertaining and bombastic. He won the audience vote at the end even though Chang gave the more scientific argument. Maybe it would be different outcome at ASTRO with less residents and private practice docs, but I don't know.

 

[Brim]

Has there ever been a strict definition of what constitutes a "controlled primary" for the purpose of RPA classification? I've looked for the answer, but it's eluded me.

 

[TarHeelRadOnc]

I would play it safe and say WBRT w/ SRS and base my answer on RTOG 9508.

SRS alone is better then SRS + WBRT according to Eric Chang's paper based on assessment of neuro-cognitive function (using Hopkins Verbal Learning Test). SRS was actually markedly superior in the same study over SRS + WBRT with OS as an endpoint but the study was definitely underpowered to reach such a conclusion. Other papers like the Japanese studies or Sneed's mult-institutional retrospective study (as you cited) also show that SRS alone can be used effectively with equivalent PFS endpoints. But really, I'm of the opinion that Chang's study is deeply flawed and Sneed's study (while compelling) is difficult to choose over existing Level I evidence.

In general on oral boards, I think, it is safer to go with the easy answers. If you give too nuanced an answer and try to justify with literature you may be digging yourself a grave. Your examiners are, after all, experts in their respective field.

I would be careful the way you quote RTOG 95-08. This is this most misquoted trial in the literature, in my experience. Remember that patients in this study were NOT stratified by primary tumor site or by RPA status (The first RPA study [Gaspar et al] wasn't published until 1997... after the start of RTOG 95-08). The only significant predictor of improved survival with SRS+WBRT vs WBRT alone was solitary brain metastases. After Bonferroni corrections, statistical significance for non-stratified variables was defined as p<0.0056. As such, lung primary and RPA class I disease were NOT associated with a survival benefit with the addition of SRS (p=0.051 and p=0.044, respectively). Moreover, I don't think that the RTOG 95-08 study actually addresses the question that Palex is asking.

The bettter study, IMO, is the recently reported EORTC study (ASCO 2009/ASTRO 2009). Interestingly, this study confirmed what many of us have thought all along: (1) that radiosurgery alone is associated with substantially better LC than surgery alone (LF 30% vs 60%) and (2) the benefit of WBRT is less pronounced in patients treated with SRS than with surgery. The only trials showing a neurologic cause specific survival benefit with the addition of WBRT to local therapy (SRS or surgery) are trials that included surgery as the local therapy (Patchell et al. 100% surgery; EORTC ~50% surgery). Studies looking at SRS alone plus or minus WBRT show no improvement in Neuro CSS (Aoyama and Chang). The reason for this is probably because SRS provides substantially better LC, making the modest benefit in the prevention of "distant" brain metastases insufficient to improve neuro CSS.

There is a good study from the University of Maryland addressing this question (Flannery et al. Red J) showing that, in patients with NSCLC with solitary brain mets, treatment with SRS and aggressive local therapy to the primary tumor (with chemoRT or surgery) that 5yr survival was 35%. The question that Palex is getting at is an oligometastases question. If the patient already has widespread seeding of the brain, they don't actually meet the Hellman criteria for oligometastases and, while WBRT might improve intracranial PFS, it will not likely improve OS. NSCLC has a specific tropism for neural tissues, and brain metastases precede other distant metastases in some patients (particularly adenocarcinoma). For these patients, aggresive treatment of solitary brain metastases and the primary site may improve survival.

I would vote for no WBRT. If the patient had been treated with surgery, I would vote for WBRT to improve local control at the tumor bed. If your patient fails distantly in the brain, the question of whether they have oligometastatic disease is answered. Your patient with a superior sulcus tumor has a favorable prognosis, even if he is not eligible for neoadjuvant chemoRT per the INT 0160 regimen. As such, I think that he is more likely to benefit from aggressive oligometastatic treatment than are other patients with stage II-III primary lesions. WBRT, however, is unlikely to affect his outcome....

 

[TarHeelRadOnc]

You could see the smirk on Chang's face when he presented that outrageous data. An overall survival benefit! Waiting for the paper ...

I think now there is level one evidence, though flawed, to say SRS alone is legitimate. If good KPS, only extrapulmonary site of dz, I think that I'd say on boards to add Patchell style WBRT, going slowish (2.0 - 2.5 Gy Fx to 37 to 40ish), b/c that's what I'd actually recommend (though I have feeling my NSG colleagues would veto me).

-S

Paper published in Lancet Oncology 2009. Just as outrageous as the plenary. Independent of the survival difference (which reflects poor randomization and the influence of non-stratified variables), the HVLT endpoint at 4 months is a sham. Med S was only 5 months (!!) in the SRS+WBRT arm... meaning that the HVLT was performed within 1 month of median survival!! Maybe they should re-title the paper "Randomized trial demonstrating that neurocognitive testing outcomes are worse in patients about to die of metastatic cancer." Certainly not plenary worthy, IMO....

 

[deleted4401]

Would treat with SRS to met, and follow with scans. W/o WBRT, high likelihood of failing outside of tumor area, but can chase lesions, so MRI every 3 months-ish. Since the path has been chosen to treat this way, may as well "spot weld," and treat lesions as they appear. No benefit to survival, but makes everyone feel better and grows the economy with all the money spent, re: multiplier effect.

Metastatic NSCLC is an incurable disease. Data showing otherwise is just selecting out good prognosis patients (age, limited volume disease, KPS, histology, SES, etc.) It's not your intervention... it's biology.

Project for med student: at your institution, find all comers with metastatic NSCLC treated definitively and report their outcome. Wait a second? The lung attendings don't want you to do that without selecting patients out? What a surprise...

-S

 

[TarHeelRadOnc]

Would treat with SRS to met, and follow with scans. W/o WBRT, high likelihood of failing outside of tumor area, but can chase lesions, so MRI every 3 months-ish. Since the path has been chosen to treat this way, may as well "spot weld," and treat lesions as they appear. No benefit to survival, but makes everyone feel better and grows the economy with all the money spent, re: multiplier effect.

Metastatic NSCLC is an incurable disease. Data showing otherwise is just selecting out good prognosis patients (age, limited volume disease, KPS, histology, SES, etc.) It's not your intervention... it's biology.

Project for med student: at your institution, find all comers with metastatic NSCLC treated definitively and report their outcome. Wait a second? The lung attendings don't want you to do that without selecting patients out? What a surprise...

-S

You might be right. To be honest, we just don't know. There is selection bias in any retrospective study, of course. That said, the University of Colorado data (Rusthoven et al. Acta Oncol 2009) and Univerisity of Chicago data (Mehta et al. Int J Ca 2004) report the POF in metastatic NSCLC. These data demonstrate that 2/3 of patients progress in known sites of disease when treated with chemo alone. If SBRT/surgery is used to treat patients with limited disease (ie 1-5 discrete lesions), the UofCo data suggests that PFS might be improved. Perhaps we are just talking about a shift in the PFS curve and not long term survival, but the possibility is there and should be formally tested in oligometastatic patients.

You are very quick to dismiss the possibility of solitary brain metastases from NSCLC as potentially curable... laboratory data suggests that NSCLC home to neural tissues much earlier in the metastatic progression than they home to other visceral or bony sites.... this is similar to liver mets in CRC and bone mets in luminal Breast cancer. Surgery for liver mets in CRC is recognized (at least in the surgical community) as a potentially curable condition. I think that it is narrow minded for a young radiation oncologist to dismiss the role of local therapy in oligometastatic disease. If radiation oncologists don't test the theory of oligometastates, then nobody will...

 

[Palex80]

First I'd like to thank everyone for their input.

Then I would like to give a comment to what has been said so far.
IMHO one major drawback of studies comparing SRS+WBRT vs. SRS has been that patients with more than one brain metastasis were included. IMHO the tumour biology of a patient with a solitary lesion can be different than the one of a patient with more than one lesions.
We know this from the experience in liver metastases of colorectal cancer.

Furthermore one major point that should have been addressed in the studies is the extracranial disease control. A patient with an uncontrolled primary has a great potential of metastatic seeding metachronically after SRS+WBRT, the same cannot be said about a patient with a completely controlled extracranial tumor.

 

[deleted4401]

Yeah you right. I shouldn't be so pessimistic or narrow-minded, and oligometastatic disease is a subset of potentially curable disease.

I just think bone mets for breast cancer or liver mets from CRC just seem different than lung cancer. Especially liver mets - I think its a very ordered, sequential metastatic progression and hacking them out may change the course of disease in patients.

It's hard for me to really believe that about lung cancer, though, but I should be a bit more open to the data. I also think if someone is treated definitively for a localized NSCLC and then mets out in the brain with no other evidence of disease is different than one that presents with a brain met.

Maybe it's true that some of these stage IV lung cancer patients are curable. I think we should test it.

-S

 

[medgator]

It's hard for me to really believe that about lung cancer, though, but I should be a bit more open to the data. I also think if someone is treated definitively for a localized NSCLC and then mets out in the brain with no other evidence of disease is different than one that presents with a brain met.

Maybe it's true that some of these stage IV lung cancer patients are curable. I think we should test it.

-S

Seeing yet another excellent PS patient on my current rotation coming back years later for their 2nd-3rd GK SRS made me suggest to my attending that one of our more junior residents publish our experience with it.

Most patients I've seen throughout training with NSCLC with 1-3 mets and nothing else systemically end up living much longer than the 9-12 mos that people quote for Stage IV NSCLC with brain mets.

 

[Gfunk6]

John Suh from Cleveland Clinic just published a great article in NEJM (clinical therapeutics section) re: RS for management of brain mets.