GOG 258 results in NEJM (Another indication for radiation gone)!

[fiji128]

https://www.nejm.org/doi/full/10.1056/NEJMoa1813181?af=R&rss=currentIssue

Background
Stage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence.

Methods
In this randomized phase 3 trial, we tested whether 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) is associated with longer relapse-free survival (primary end point) than six cycles of combination chemotherapy alone in patients with stage III or IVA endometrial carcinoma. Secondary end points included overall survival, acute and chronic toxic effects, and quality of life.

Results
Of the 813 patients enrolled, 736 were eligible and were included in the analysis of relapse-free survival; of those patients, 707 received the randomly assigned intervention (346 received chemoradiotherapy and 361 received chemotherapy only). The median follow-up period was 47 months. At 60 months, the Kaplan–Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group.

Conclusions
Chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone in patients with stage III or IVA endometrial carcinoma.

While one may argue that there is somewhat of a local control benefit to adjuvant radiation I can't really see the Gyn/Oncs sending these patients to us anymore for that reason.

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[deleted947887]

https://www.nejm.org/doi/full/10.1056/NEJMoa1813181?af=R&rss=currentIssue

Background
Stage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence.

Methods
In this randomized phase 3 trial, we tested whether 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) is associated with longer relapse-free survival (primary end point) than six cycles of combination chemotherapy alone in patients with stage III or IVA endometrial carcinoma. Secondary end points included overall survival, acute and chronic toxic effects, and quality of life.

Results
Of the 813 patients enrolled, 736 were eligible and were included in the analysis of relapse-free survival; of those patients, 707 received the randomly assigned intervention (346 received chemoradiotherapy and 361 received chemotherapy only). The median follow-up period was 47 months. At 60 months, the Kaplan–Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group.

Conclusions
Chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone in patients with stage III or IVA endometrial carcinoma.

While one may argue that there is somewhat of a local control benefit to adjuvant radiation I can't really see the Gyn/Oncs sending these patients to us anymore for that reason.

Why would they observe more distant mets in the CRT group? Does RT diminish chemotherapy's effect? To me, it looks like RT did exactly what it was supposed to do. This really needs more follow up. That said, the rad onc on the paper was probably thrilled to get his name out there so he doesn't care what it says. I do agree with your underlying point. Like I said, latency of incompetence.

 

[Ray D. Ayshun]

https://www.nejm.org/doi/full/10.1056/NEJMoa1813181?af=R&rss=currentIssue

Background
Stage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence.

Methods
In this randomized phase 3 trial, we tested whether 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) is associated with longer relapse-free survival (primary end point) than six cycles of combination chemotherapy alone in patients with stage III or IVA endometrial carcinoma. Secondary end points included overall survival, acute and chronic toxic effects, and quality of life.

Results
Of the 813 patients enrolled, 736 were eligible and were included in the analysis of relapse-free survival; of those patients, 707 received the randomly assigned intervention (346 received chemoradiotherapy and 361 received chemotherapy only). The median follow-up period was 47 months. At 60 months, the Kaplan–Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group.

Conclusions
Chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone in patients with stage III or IVA endometrial carcinoma.

While one may argue that there is somewhat of a local control benefit to adjuvant radiation I can't really see the Gyn/Oncs sending these patients to us anymore for that reason.

It definitely proved that waiting an extra 6-8 weeks before starting less systemic therapy (with worse compliance) is worse for distant control.

 

[CptCrunch]

Why would they observe more distant mets in the CRT group? Does RT diminish chemotherapy's effect? To me, it looks like RT did exactly what it was supposed to do. This really needs more follow up. That said, the rad onc on the paper was probably thrilled to get his name out there so he doesn't care what it says. I do agree with your underlying point. Like I said, latency of incompetence.

Fewer planned cycles of carbo/taxol in the CRT group (4 vs 6) and less compliance (75% vs 85%).

This provides the rationale at our institution to complete 6 cycles of carbo/taxol before pelvic RT in order to maximize distant and pelvic control.

 

[scarbrtj]

Surprised by finding, scientists say this may change locally advanced endometrial cancer care

Chemo itself is poised to go "gen two" as its linked to antibodies to be delivered directly into cells. You can read about that here; cool article if for no other reason it mentions Paul Ehrlich. If you get a chance see the movie 'Dr. Ehrlich's Magic Bullet' ("[t]he concept behind ADCs was envisioned in 1900 by German Nobel laureate Paul Ehrlich, who formed the idea of a magic bullet in which a single toxic molecule would be delivered to attack a diseased cell without damaging surrounding healthy cells). It's the best medical movie ever made.

 

[deleted947887]

Fewer planned cycles of carbo/taxol in the CRT group (4 vs 6) and less compliance (75% vs 85%).

This provides the rationale at our institution to complete 6 cycles of carbo/taxol before pelvic RT in order to maximize distant and pelvic control.

"There may be rationale at to complete 6 cycles of carbo/taxol before pelvic RT in order to maximize distant and pelvic control."

If the radiation oncologist had any value in "the house of medicine," that right there would've been the conclusion.

 

[fiji128]

From the end of the discussion section,

The results of our trial could lead to speculation that external-beam radiotherapy should be delivered after completion of chemotherapy. Single-institution retrospective studies using a “sandwich” radiotherapy–chemotherapy approach have suggested a reasonable side-effect profile and estimated 5-year overall and distant metastasis-free survival of 77% and 85%, respectively.36,37 Because these results have not been validated prospectively, they should not be adopted without further study. Likewise, substituting vaginal brachytherapy for external-beam radiotherapy may be tempting, but because the risk of vaginal recurrence is low, intracavitary radiotherapy should be reserved for women who are at high risk for vaginal relapse. Finally, the short-term and long-term effects of treatment on quality of life should be considered. Although acute toxic effects were more common in the chemoradiotherapy group than in the chemotherapy-only group in our trial, most were low-grade and reversible on treatment discontinuation. Chronic toxic effects included diarrhea, lymphedema, and musculoskeletal events and were more common with chemoradiotherapy, which affected patient-reported outcomes. Late second cancers are also a risk.

In summary, in this randomized trial, the combined regimen of chemotherapy plus radiation did not provide a benefit over chemotherapy alone with respect to relapse-free survival in patients with stage III or IVA endometrial carcinoma. Our data are compatible with the hypothesis from previous studies that completion of chemotherapy is important for the prevention of distant relapse.

 

[scarbrtj]

From the end of the discussion section,

The results of our trial could lead to speculation that external-beam radiotherapy should be delivered after completion of chemotherapy. Single-institution retrospective studies using a “sandwich” radiotherapy–chemotherapy approach have suggested a reasonable side-effect profile and estimated 5-year overall and distant metastasis-free survival of 77% and 85%, respectively.36,37 Because these results have not been validated prospectively, they should not be adopted without further study. Likewise, substituting vaginal brachytherapy for external-beam radiotherapy may be tempting, but because the risk of vaginal recurrence is low, intracavitary radiotherapy should be reserved for women who are at high risk for vaginal relapse. Finally, the short-term and long-term effects of treatment on quality of life should be considered. Although acute toxic effects were more common in the chemoradiotherapy group than in the chemotherapy-only group in our trial, most were low-grade and reversible on treatment discontinuation. Chronic toxic effects included diarrhea, lymphedema, and musculoskeletal events and were more common with chemoradiotherapy, which affected patient-reported outcomes. Late second cancers are also a risk.

In summary, in this randomized trial, the combined regimen of chemotherapy plus radiation did not provide a benefit over chemotherapy alone with respect to relapse-free survival in patients with stage III or IVA endometrial carcinoma. Our data are compatible with the hypothesis from previous studies that completion of chemotherapy is important for the prevention of distant relapse.

The radiation oncologist will think what he or she wants.
The referring gyn onc will think what he or she wants: "[C]hemotherapy alone remains the standard of care for stage III uterine cancer."
But yes the radiation oncologist can still think whatever he or she wants. The radiation oncologist can also bark at the moon.

 

[Palex80]

GOG 258 had a serious flaw in its design. What was the standard of care when the trial was conceived?
It was mainly extensive volume radiotherapy or intensive chemotherapy.

When you are thinking about testing a new regime in a phase III setting against SOC you should not alter too may factors from the SOC when you design the new regime.
Combining RT and CT in this setting is a no-brainer. What "killed" the trial was that the experimental arm was "too experimental".
They changed the chemotherapy regime, they changed the intensity of chemotherapy, they changed the sequence, they changed the volume of radiotherapy.
That's appears innovative, but it's also risky.

The bottom line is that concurrent radiochemotherapy is toxic and unnecessary, I think we can all agree to that.

PORTEC-3 looked into these patients too and randomized them between standard RT +/- chemotherapy. The chemotherapy benefit was small, but it was there.

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30079-2/fulltext

The trial that we are missing to fill the gap is probably standard CT versus standard RT versus standard CT followed by standard RT.

A good argument against a chemotherapy-only approach is GOG249. Although carried out for patients with earlier stages of the disease, it randomized between CT and RT. Both showed the same PFS, but RT was better tolerated. I quote GOG249 every time my gynecologist push for Carboplatin/Paclitaxel in early stage disease with unfavorable histology.

https://ascopubs.org/doi/full/10.1200/JCO.18.01575

 

[seper]

Comments are right on. My surgeons refer patients for RT either after 6 cycles or as a "sandwich".
I would not advise brachy alone for N+ endometrial cancer.

 

[TDDro]

They changed the chemotherapy regime, they changed the intensity of chemotherapy, they changed the sequence, they changed the volume of radiotherapy.
That's appears innovative, but it's also risky.

Yeah I'm a little confused by the idea behind tweaking the concurrent chemo dosing. Went from 30 weekly to...50 every 4 weeks? Hell, in head and neck we do 100 q3w. Was the idea to give as little chemo benefit as possible during concurrent? Then just leave out the chemo and make it RT alone vs. CT alone.

 

[deleted941485]

Yeah I'm a little confused by the idea behind tweaking the concurrent chemo dosing. Went from 30 weekly to...50 every 4 weeks? Hell, in head and neck we do 100 q3w. Was the idea to give as little chemo benefit as possible during concurrent? Then just leave out the chemo and make it RT alone vs. CT alone.

Not like our interpretation really matters but I’ll need to take the temperature on this with our referring MOs and GOs.

 

[evilbooyaa]

All this proves is that upfront concurrent chemoRT in endometrial cancer is a loser to systemic chemotherapy first.

CarboTaxol x 6 cycles, re-stage, if no metastases, treat with pelvic RT. Sandwich is fine if you're so inclined.

This is appropriate management of Stage III/IVA endometrial cancer IMO.

 

[xrthopeful]

All this proves is that upfront concurrent chemoRT in endometrial cancer is a loser to systemic chemotherapy first.

CarboTaxol x 6 cycles, re-stage, if no metastases, treat with pelvic RT. Sandwich is fine if you're so inclined.

This is appropriate management of Stage III/IVA endometrial cancer IMO.

Loser? The OS was the same. It just wasn’t better.

 

[Palex80]

Loser? The OS was the same. It just wasn’t better.

But toxicity was worse. The trial was negative.

 

[xrthopeful]

Oh was it? Didn’t see a p value on that toxicity comparison
It was indeed a negative trial, but that does not make RT the loser, because it was a superiority trial. Just the terminology thing.

Also - if 4 cycles plus RT is more toxic (by 5 percent), then 6 plus RT is surrly also more toxic

 

[xrthopeful]

Also the winning arm of PORTEC3 was chemoradiation in terms of PFS

Ultimately like everything in endometrial cancer, it comes down to your own institution’s approach/tumor board.

 

[seper]

Ultimately, I think EBRT will continue to be used for some subsets of stage III disease but not all.

 

[thecarbonionangle]

Gyn oncs will decide as they wish and we will simply bend the knee, anyways.

 

[seper]

I don't see US RadOncs designing the next generation of NRG trials for stage III endometrial, true.

Gyn oncs will decide as they wish and we will simply bend the knee, anyways.

 

[deleted947887]

I don't see US RadOncs designing the next generation of NRG trials for stage III endometrial, true.

I don't see why not-you can do anything you set your mind to!

 

[ramsesthenice]

Gyn oncs will decide as they wish and we will simply bend the knee, anyways.

Gyn Onc is such a weird discipline. Lets do a huge surgery without any comprehensive preop imaging or tissue! Oh ****, that ovarian thing we saw on US was actually metastatic rectal cancer sitting mere inches from a massive primary tumor and a pelvis full of disease. Oh well.

I wouldn't worry too much about GOG 258 affecting referrals or practice patterns for most people. There are a decent number of thoughtful gyn oncs out there that agree collectively we still don't know what to do with these people. Recurrences after surgery and chemo are bad. You can try to downplay the fact that PA nodal failures are technically regional but what is the salvage rate for PA nodal failures after surgery and chemo? Hint, not good. Does it suggest that sequencing of therapy might be important? Sure. But collectively the chemo literature is not a slam dunk for stage 3 or high risk endometrial patients. Where I practice the Gyn Oncs just kinda shrugged at 258. Still recommending sandwich. I suspect most of the people who would use 258 to stop giving RT all together for stage 3 disease probably didn't send many in the first place.

 

[evilbooyaa]

Loser? The OS was the same. It just wasn’t better.

But toxicity was worse. The trial was negative.

People will point to the increased risk of metastatic disease with upfront chemoRT is hand-wavingly 'worse' than a locoregional failure. I personally disagree, but any trial that is not overwhelmingly positive for radiation will not lead to an increase in RT. Toxicity didn't have p-values but was actually WORSE for chemo - Grade 4 rates of 30% in CT only and 18% in CRT.

Give chemo upfront to minimize metastatic risk (most concerning risk), then once you've 'controlled' that as best as possible, give RT to prevent regional recurrence. IMO this avoids the spike in metastatic disease seen with upfront CRT, and may partially address the locoregional recurrence numbers seen in chemo only.

I guess I don't really get the rationale behind sandwich compared to sequential. Are patients routinely doing CarboTaxol x 3, then RT (is it RT alone or chemoRT) and then somehow tolerating an additional 3 cycles of CarboTaxol? What percentage of patients are actually completing the final 3 cycles of CarboTaxol?

I know there's no good data comparing sandwich to sequential (if there is something recent, please link) and it's all just institutional practice (not really sure where sandwich came from), but are people still going to be doing upfront chemoRT followed by chemo for this patient population?

 

[thecarbonionangle]

Gyn Onc is such a weird discipline. Lets do a huge surgery without any comprehensive preop imaging or tissue! Oh ****, that ovarian thing we saw on US was actually metastatic rectal cancer sitting mere inches from a massive primary tumor and a pelvis full of disease. Oh well.

I wouldn't worry too much about GOG 258 affecting referrals or practice patterns for most people. There are a decent number of thoughtful gyn oncs out there that agree collectively we still don't know what to do with these people. Recurrences after surgery and chemo are bad. You can try to downplay the fact that PA nodal failures are technically regional but what is the salvage rate for PA nodal failures after surgery and chemo? Hint, not good. Does it suggest that sequencing of therapy might be important? Sure. But collectively the chemo literature is not a slam dunk for stage 3 or high risk endometrial patients. Where I practice the Gyn Oncs just kinda shrugged at 258. Still recommending sandwich. I suspect most of the people who would use 258 to stop giving RT all together for stage 3 disease probably didn't send many in the first place.

In my experience, the worst “oncologists” of them all. Within the realms of surgery, not that skilled. Entire field held back by its ludite culture in a discipline that operates and gives chemo on the side. Trials that do not make any sense or address wrong questions. So sad that systemic therapy for gyn malignancies is so limited, really held back by the grip the field has (rare med onc involvement).

 

[ramsesthenice]

I know there's no good data comparing sandwich to sequential (if there is something recent, please link) and it's all just institutional practice (not really sure where sandwich came from), but are people still going to be doing upfront chemoRT followed by chemo for this patient population?

I don't know about everyone else but I have literally never seen anyone do upfront chemoRT as was done in PORTEC-3 or 258. Never. Its always been sandwich or sequential everywhere I have ever been. Hence the collective shrug.

 

[evilbooyaa]

I mean CRT as a choice for PORTEC-3 and 258 was based on the phase II RTOG 9708 trial, but I agree that I have only seen sequential.

 

[Mandelin Rain]

Sandwich works well. After 3 cycles, many ladies are ready for a break from the carbo/taxol. The XRT is a convenient excuse to do so.

 

[medgator]

I don't know about everyone else but I have literally never seen anyone do upfront chemoRT as was done in PORTEC-3 or 258. Never. Its always been sandwich or sequential everywhere I have ever been. Hence the collective shrug.

I've only seen it for unresectable gross disease recurrences and that's it

 

[seper]

They do upfront at MDA and as of a 1 year ago P. Eifel was still pushing for upfront CRT before chemo (ASTRO, oral boards).

I don't know about everyone else but I have literally never seen anyone do upfront chemoRT as was done in PORTEC-3 or 258. Never. Its always been sandwich or sequential everywhere I have ever been. Hence the collective shrug.

 

[Palex80]

Toxicity didn't have p-values but was actually WORSE for chemo - Grade 4 rates of 30% in CT only and 18% in CRT.

Indeed, you are correct. However the general preception is that the concomitant part is excessive treatment with potential more side effects and not worth it.

Constitutional symptoms, fatigue, gastrointestinal events, renal or genitourinary events, and musculoskeletal events were significantly more frequent per grade in the chemoradiotherapy group.

That's quite a few more AEs. Although indeed, the quoted rates, as you said, were higher in the chemotherapy group. There is also the impression that the radiochemotherapy group patients were able to receive less of the planned chemotherapy, probably due to issues with tolerating it not so well; 75% vs. 85% of planned chemotherapy received.