Adjuvant Chemoradiotherapy Superior to Radiotherapy Alone in Women With High-Risk Endometrial Cancer

LisaPizza

Link to a detailed PDF:

 https://www.thelancet.com/action/showPdf?pii=S1470-2045(19)30395-X

 

TAKE-HOME MESSAGE

• This post hoc survival analysis of a phase III trial was designed to compare outcomes following treatment with adjuvant chemoradiotherapy and radiotherapy versus radiotherapy alone among women with high-risk endometrial cancer. The 5-year rate of overall survival was 81.4% in the chemoradiotherapy group and 76.1% in the radiotherapy-alone group. Similarly, the 5-year failure-free survival rate was significantly better in the chemoradiotherapy group compared with the radiotherapy-alone group. The rates of serious adverse events were similar between groups.

• The use of chemoradiotherapy should be recommended for women with high-risk endometrial cancer given the improved overall survival and failure-free survival associated with it.

– Neil Majithia, MD

 

 

BACKGROUND

The PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We updated the analysis to investigate patterns of recurrence and did a post-hoc survival analysis.

METHODS

In the multicentre randomised phase 3 PORTEC-3 trial, women with high-risk endometrial cancer were eligible if they had International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III disease; or stage I-III disease with serous or clear cell histology; were aged 18 years and older; and had a WHO performance status of 0-2. Participants were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or chemoradiotherapy (two cycles of cisplatin 50 mg/m2 given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2 given intravenously), by use of a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival and failure-free survival. Secondary endpoints of vaginal, pelvic, and distant recurrence were analysed according to the first site of recurrence. Survival endpoints were analysed by intention-to-treat, and adjusted for stratification factors. Competing risk methods were used for failure-free survival and recurrence. We did a post-hoc analysis to analyse patterns of recurrence with 1 additional year of follow-up. The study was closed on Dec 20, 2013; follow-up is ongoing.

FINDINGS

Between Nov 23, 2006, and Dec 20, 2013, 686 women were enrolled, of whom 660 were eligible and evaluable (330 in the chemoradiotherapy group, and 330 in the radiotherapy-alone group). At a median follow-up of 72·6 months (IQR 59·9-85·6), 5-year overall survival was 81·4% (95% CI 77·2-85·8) with chemoradiotherapy versus 76·1% (71·6-80·9) with radiotherapy alone (adjusted hazard ratio [HR] 0·70 [95% CI 0·51-0·97], p=0·034), and 5-year failure-free survival was 76·5% (95% CI 71·5-80·7) versus 69·1% (63·8-73·8; HR 0·70 [0·52-0·94], p=0·016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21·4%; 95% CI 17·3-26·3) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29·1%; 24·4-34·3) in the radiotherapy-alone group (HR 0·74 [95% CI 0·55-0·99]; p=0·047). Isolated vaginal recurrence was the first site of recurrence in one patient (0·3%; 95% CI 0·0-2·1) in both groups (HR 0·99 [95% CI 0·06-15·90]; p=0·99), and isolated pelvic recurrence was the first site of recurrence in three women (0·9% [95% CI 0·3-2·8]) in the chemoradiotherapy group versus four (0·9% [95% CI 0·3-2·8]) in the radiotherapy-alone group (HR 0·75 [95% CI 0·17-3·33]; p=0·71). At 5 years, only one grade 4 adverse event (ileus or obstruction) was reported (in the chemoradiotherapy group). At 5 years, reported grade 3 adverse events did not differ significantly between the two groups, occurring in 16 (8%) of 201 women in the chemoradiotherapy group versus ten (5%) of 187 in the radiotherapy-alone group (p=0·24). The most common grade 3 adverse event was hypertension (in four [2%] women in both groups). At 5 years, grade 2 or worse adverse events were reported in 76 (38%) of 201 women in the chemoradiotherapy group versus 43 (23%) of 187 in the radiotherapy-alone group (p=0·002). Sensory neuropathy persisted more often after chemoradiotherapy than after radiotherapy alone, with 5-year rates of grade 2 or worse neuropathy of 6% (13 of 201 women) versus 0% (0 of 187). No treatment-related deaths were reported.

INTERPRETATION

This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. This treatment schedule should be discussed and recommended, especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival

 

TeddyandBears_Mom

Thanks for sharing Lisa. I

Thanks for sharing Lisa. I was stage 1A / Grade 3 Serous and had Carbo/Taxol and Brachy. I'm so glad I did! It will be 4 years post treatment in January. So far, so good. Also, I believe doing what my doctors recommended has given me peace of mind. ( Which I think is important to get back to any kind of normalcy. )

Love and Hugs,

Cindi

zsazsa1

The PORTEC 3 should be

The PORTEC 3 should be weighed against the GOG 258 (which showed no improvement in survival when radiation was added to chemotherapy for stage III/IV endometrial cancer).  I was swayed by the PORTEC 3 to add external beam pelvic IMRT.  I don't know whether it improved my chances or not, but the GI toxicity was significant, and I fear long term side effects.

LisaPizza

zsazsa1 said:

The PORTEC 3 should be

The PORTEC 3 should be weighed against the GOG 258 (which showed no improvement in survival when radiation was added to chemotherapy for stage III/IV endometrial cancer).  I was swayed by the PORTEC 3 to add external beam pelvic IMRT.  I don't know whether it improved my chances or not, but the GI toxicity was significant, and I fear long term side effects.

They weren't really comparing

They weren't really comparing the same thing. 

 

GOG 258 was only stage 3/4.

***external rads with 2 concurrent cycles of cisplatin, followed by 4 cycles of taxol/carbo

VS

***6 cycles of taxol/carbo (no radiation)

 

PORTEC 3 included stage 3/4, but also high risk stage 1/2

**external rads with 2 concurrent cycles of cisplatin, followed by 4 cycles of taxol/carbo

VS

***external rads (no chemo)

 

I hope I copied that correctly, no guarantees! I will correct if needed.

zsazsa1

Yes, you are correct.  PORTEC

Yes, you are correct.  PORTEC 3 added in high risk pathology FIGO stage 1 and 2. I was high risk (UPSC/clear cell), supposedly stage 1a, but isolated tumor cells in one of the two sentinel nodes they took made me seek an interpretation as 3c1, so that I would be eligible for Herceptin.  After consulting a number of specialists, I decided to go with the recommendation by two different academic radiation oncology centers, to add external beam pelvic, after I'd already had 6 rounds of carbo/taxol, because of the high risk pathology, and the fact that cells were out in the node.  The medical oncologists recommended only vaginal brachytherapy.  It does seem, when looking at the GOG-258, that the issue was that the cat was already out of the bag - because the problem was recurrence as distal metastases.  Local recurrence in the irradiated field was reduced in the GOG-258, but relapses occurred distally and survival was not improved.  So maybe I was right to do the whole pelvic IMRT.  In any event, it's done.  I honestly don't know what I would recommend to someone newly diagnosed with the exact same staging/pathology as mine.

Soup52

I’ve posted about my

I’ve posted about my agressive treatment before, but it was radiation internal and external with  6 rounds of carbo/taxol. Treatments ended July 2016. So far allclear. Side effects neuropathy, fear of lymphedema , so,e gastro problems. So far I, glad I did it. I really didn’t have many choices. I was grade 3 clear cell, stage 3 C. I know many of you live in larger cities where you could choose different oncologists etc, but that isn’t true here. At one time we only had one gynechological oncologist. Now we are lucky to have 2. I so,etc,we feel out of it that others could pick and choose treatments. I just couldn’t do that considering insurance travel expenses etc. I am happy and alive.

zsazsa1

Soup, it's so encouraging to

Soup, it's so encouraging to hear that you're doing well three years out from end of treatment!

barnyardgal

Thank you for posting. I was

Thank you for posting. I was stage3a, grade 2, and had 7 rounds of adriamyacin/carboplatin and Imrt radiation (25). Fortunately, no issues so far except for a hemorrhoid from radiation. I have no regrets so far. I had surgery 10/17 and finished treatment 6/18. I have a yearly PET scan, scheduled in October but so far so good as far as I know.

MoeKay

Comment from the Lancet on PORTEC-3 and other recent studies

In case you haven't seen it, I came across this Comment, published in The Lancet, discussing PORTEC-3, GOG-258, and GOG-249.  I thought some of you who are following these studies might be interested:

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30416-4/fulltext

 

 

zsazsa1

Thank you.  In addition to

Thank you.  In addition to the editorial's main point, which, after a review of recent studies,  was, "We're not there yet", meaning, we haven't yet found a definitively better treatment protocol, there is a valuable list of references after the editorial, listing a lot of recent studies.

Armywife

MoeKay said:

Comment from the Lancet on PORTEC-3 and other recent studies

In case you haven't seen it, I came across this Comment, published in The Lancet, discussing PORTEC-3, GOG-258, and GOG-249.  I thought some of you who are following these studies might be interested:

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30416-4/fulltext

 

 

Thank You!

MoeKay, thank you - I've been reading all the articles noted in this one as well.  Thought I'd throw out a question before I googled - does anyone know what constitutes the Grade 3 and Grade 4 non-hematologic and hematologic toxicities noted as a result of the treatments?

MoeKay

Armywife said:

Thank You!

MoeKay, thank you - I've been reading all the articles noted in this one as well.  Thought I'd throw out a question before I googled - does anyone know what constitutes the Grade 3 and Grade 4 non-hematologic and hematologic toxicities noted as a result of the treatments?

NCI Common Toxicity Criteria Manual

Hi Armywife, here's a link to the National Cancer Institute's Common Toxicity Criteria Manual, which spells out all the hematalogic and non-hematologic toxicities by grade and explains the various grades:

https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcmanual_v4_10-4-99.pdf

This manual is from 1999, so someone may come across a later version.  

 

LisaPizza

Armywife said:

Thank You!

MoeKay, thank you - I've been reading all the articles noted in this one as well.  Thought I'd throw out a question before I googled - does anyone know what constitutes the Grade 3 and Grade 4 non-hematologic and hematologic toxicities noted as a result of the treatments?

In general terms,  cancer

In general terms,  cancer treatment side effects are graded:

1 - Mild (no treatment required)

2 - Moderate

3 - Severe

4 - Life-threatening

5 - Death

 

Research and doctors tend to write off grade 1 and grade 2 side effects, which sucks, because they still have major impact on iur lives, especially when permanent. 

Armywife

LisaPizza said:

In general terms,  cancer

In general terms,  cancer treatment side effects are graded:

1 - Mild (no treatment required)

2 - Moderate

3 - Severe

4 - Life-threatening

5 - Death

 

Research and doctors tend to write off grade 1 and grade 2 side effects, which sucks, because they still have major impact on iur lives, especially when permanent. 

Thank you!

Thanks for distilling it down, Lisa!  

Armywife

MoeKay said:

NCI Common Toxicity Criteria Manual

Hi Armywife, here's a link to the National Cancer Institute's Common Toxicity Criteria Manual, which spells out all the hematalogic and non-hematologic toxicities by grade and explains the various grades:

https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcmanual_v4_10-4-99.pdf

This manual is from 1999, so someone may come across a later version.  

 

Thanks!

Thank you, MoeKay!  I learn so much from all of you.  Very grateful.