Changes to Endometrial Cancer Treatment with Daniela Matei, MD  

Erin Spain: This is Breakthroughs a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, executive editor of the Breakthroughs newsletter. Results from a randomized phase three clinical trial just published in the New England Journal of Medicine could change the way women are treated for later stage endometrial cancer. Northwestern's Dr. Daniela Matei led the trial and is here with details. She's a gynecologic oncologist and physician scientist here at Northwestern and is the co-leader of the translational research in solid tumors program at the Robert H. Lurie comprehensive cancer center of Northwestern University. Thank you so much for joining me.

Daniela Matei: Thank you for having me here. It's such a pleasure.

Erin Spain: Endometrial carcinoma is the most common type of gynecological cancer in the US and in general endometrial cancer, which is also called uterine cancer is on the rise. Can you share with me some background about the disease?

Daniela Matei: Yes, that's right, Erin. Endometrial cancer is the most common gynecologic cancer with approximately 62,000 new cases being diagnosed every year in the United States. Which leads to the fact that the lifetime risk for developing endometrial cancer for any given one is about 2.9%. In parallel, mortality from endometrial cancer has also been going up by about 1.6% a year in the United States.

Erin Spain: And we're going to get into a little bit of the results of your trial, but right now what is the standard of care for people with early stage and then late stage and endometrial cancer.

Daniela Matei: For patients diagnosed with early stage endometrial cancer, the standard treatment is surgery and then they learn the risk for local recurrence. Radiation is being used as well for those patients at higher risk for recurrence. In respect to patients with stage III and IVA endometrial cancer, which represents the patient population for my trial on the GOG-258 trial - typically these patients undergo surgery. Historically radiation was part of the treatment. However, over the past 10 years, several US based as well as international studies have shown that a use of systemic chemotherapy prevents are our distant metastasis and distant recurrence in these patients and this led to the incorporation of systemic chemotherapy in the treatment for this patient population. The big question though remains whether these patients after surgery need both chemotherapy and radiotherapy or whether chemotherapy alone could do the job. This is the question that we are asking in GOG-258.

Erin Spain: This latest clinical trial published in the New England Journal of Medicine may help end some of this debate. Tell me about the trial and what are the results?

Daniela Matei: So this is a large international randomized study performed predominantly in the US and Iran through the gynecologic oncology group. This is protocol 258 as it's known in the field. Basically this a trial randomized over 800 patients to either a combined regimen, which was the experimental arm consisting of two cycles of chemotherapy given together with radio therapy followed by four cycles of chemotherapy against the control arm, which was chemotherapy alone given for six cycles. The primary endpoint of this study was to measure recurrence free survival, hoping that the combined regimen would lead to an improved recurrence free survival. And we also had some secondary end points such as measuring acute and chronic toxicities, patient reported quality of life, as well as overall survival.

Erin Spain: The gold standard has been using radiation with these patients and you sort of expected that that was going to continue to be the gold standard. That wasn't the case when you got the results.

Daniela Matei: That is right. The trial was supposed to be a positive trial demonstrating that the combined regimen was superior to chemotherapy given alone. However, the results with a median follow up of six months show that the recurrence free survival for the two arms of the trial were very similar, 59% for the chemo radiation arm and 58% for chemotherapy alone. In terms of toxicity, the regimens both relatively well tolerated with slightly more toxicity for gastrointestinal constitutional and muscular skeletal events higher in the combination arm, but also importantly with measured patient reported outcomes and noted that the quality of life indices were slightly decreased at the end of therapy and this decreased persisted for about a year after treatment for the combination arm compared to the chemotherapy alone arm.

Erin Spain: Because there are some side effects that come with radiation.

Daniela Matei: That is right. This is why the results of this study are important. Here we show that the combined modality regimen did not result in an improvement the recurrence free survival and the results of these studies support that chemotherapy alone should remain the standard of care for stage III uterine cancer and our data are indeed compatible with findings from prior studies are showing that completion of chemotherapy is key to preventing that these don't relapse.

Erin Spain: So how do you think the oncology community is going to react to this? This trial does carry some weight. It's the gold standard here.

Daniela Matei: This trial will be debated in the short and long term. This will be a difficult change because radiation has been used historically in this group of patients and clearly has a role reducing the rates of local pelvic recurrence. Even here in this study we show that patients who were randomized to the combined modality treatment had lower five year incidents of a vaginal pelvic and paraaortic lymph node reoccurrence compared to those patients who receive chemotherapy alone. However, these patients eventually will succumb disease because of their high risk for systemic outside of pelvis failure. And for this risk chemotherapy, alone is clearly beneficial and should remain the mainstay of treatment.

Erin Spain: Is that something you're going to start using in your own clinic?

Daniela Matei: Yes, we have adopted this here at Northwestern. We still have a lengthy debates in our tumor board and are trying to individualize treatment for each patient by trying to assess or quantify on this ratio of the risk of systemic versus local recurrence.

Erin Spain: You know, more and more women are now being diagnosed with endometrial cancer and that's partially due to the obesity epidemic. Can you tell me about that?

Daniela Matei: You are right, Erin There is a clear association between obesity and cancer risk. Very interestingly among all malignancies, endometrial cancer association with obesity is the strongest. More than half of cases of endometrial cancer in the United States are in fact thought to be attributable to being overweight and obese. There is actually a kind of a response relationship with the more obese you are, the higher the risk for endometrial cancer. How is that explained? I guess biologically the visceral fat which is composed of adipocytes and preadipocytes is thought to secrete a number adipocytes factors that stimulate both a state of chronic inflammation as well as these are factors that stimulate the proliferation of endometrial cells. So that is one mechanism by which obesity is linked to endometrial cancer. Also we know that obesity is linked to the risk of diabetes and high levels of glucose, high levels of insulin and insulin growth factor have been shown in preclinical models to be stimulators for endometrial cancer proliferation. Again, hyperglycemia, insulin, the IGF factor all contribute to a protumorigenic risk in this disease. Lastly, in postmenopausal women where the risk for endometrial cancer is highest the adipose tissue is the main site for estrogen synthesis. The adipose sites and preadipocytes within the fat tissue are the main source of aromatase. The enzyme that converts androgens to estrogens and the aromatase level as well as the estradiol level increase as a function of adiposity. It is well known that estrogenic also stimulates endometrial cell proliferation. So I think that their adiposity link to endometrial cancer it can be explained through several biological mechanisms.

Erin Spain: So many of the women that you see in the clinic are premenopausal going through menopause, have gone through menopause, but this obesity epidemic does play a part in effecting more women than that population?

Daniela Matei: So it's true. Endometrial cancer is more commonly seen in postmenopausal women. The median age is about 60. However, we are seeing more cases also in younger women that are overweight and aware obesity plays a role in bringing up the sugar levels as well as the estrogen levels. So we are seeing an increase in incidents of uterine cancer in this subgroup of patients.

Erin Spain: Another reason why this study is so important because as maybe more women will be diagnosed with his cancer you do have a treatment that really might work better.

Daniela Matei: That is true. Also, it is important to know that endometrial cancer is curable when diagnosed at early stage with surgery alone. There will be many survivors. I think in fact, more than half a million survivors of endometrial cancer are currently alive in the United States. So their long term functional status is very important and meeting treatments that can have sequella long term is very important.

Erin Spain: One thing to note though, there is not really a good screening tool right now for this cancer?

Daniela Matei: There is not a good screening tool, but fortunately endometrial cancer presents with symptoms at an early stage and the symptom is bleeding. Also, any woman who would experience postmenopausal bleeding should be evaluated immediately. And that is unlike an ovarian cancer where symptoms don't develop early. So because of early symptoms, many of the cases of endometrial cancer can get diagnosed at an early stage.

Erin Spain: You're also a molecular biologist and your laboratory looks at the genetics of cancer. How has the field progressing in terms of understanding the biology of gynecological cancers and tailoring treatments?

Daniela Matei: I think a lot of progress has been made and I'm very happy to state this because five years ago that was not the case. With the completion of the tumor cancer atlas program we have now improved molecular data for both endometrial as well as ovarian cancer and we're starting to understand both genetic risk factors for developing these cancers. But more importantly, we are starting to have new treatment tools that are based on the molecular characteristics of these cancers. For example, for endometrial cancer we are now recognizing the role of mismatched repair defects that put these patients at risk for developing endometrial cancer and other cancers and those patients who would have mismatched repair defects are eligible for our newer forms of therapies such as immunotherapy. In terms of ovarian cancer, we have recognized over the past five years the importance of homologous recombination deficiency which affects more than half of the cases of ovarian cancer. This explains the exquisite sensitivity of ovarian tumors to platinum drugs and also has opened a venue to new treatment options such as the PARP inhibitors.

Erin Spain: Speaking of ovarian cancer and the other area you are studying is the role of cancer stem cells in ovarian cancer. What are cancer stem cells and what role do they play in ovarian cancer reoccurrence?

Daniela Matei: My laboratory has studied for the past few years the ovarian cancer stem cells. These are cells that are characterized by presence of a certain surface markers and have properties of being more motogenic than the other known cancer stem cells, they can self-renew and also differentiating two daughter cells. We know that these cancer stem cells are resistant to traditional chemotherapy and radiotherapy and therefore we think that finding new characteristics or vulnerabilities will open the option of finding new treatments that can get rid of these resistance cells and hopefully lead to a cure.

Erin Spain: So you're in your laboratory right now working on some of those things. You're in the clinic as well. You split your time between these two places. And I want to shift gears a little to talk about your life and the clinic. You see patients at some of the most vulnerable times of their life and you've developed bonds with a lot of them. One of your patients is the author and literary critic, Susan Gubar who you treated for advanced ovarian cancer. She's talked a little bit about your relationship. Let's take a listen to what she said about you for an interview with the National Coalition for cancer survivorship. Susan Gubar: I have a wonderful oncologist who is able to communicate with me and make decisions collaboratively with me. I very much appreciate that. I just recently read I Atul Gawande's new book and he talks about his shift from doctor informative to doctor interpretive. Doctor informative says, well, there are four things you can do. It's up to you. And that's the kind of doctor Dr. Gawande said he used to be. And now he says he's moved from doctor informative to doctor interpretive where he says, what are your values? What are your tradeoffs? What are your goals? What shall we do? What's best for you? And my doctor has always been doctor interpretive. I'm very happy that she has been, I think it's partly because she's a poet, but I do think that talking is one way of creating a relationship between two whole people, not just doctor, patient, active, passive, but two people who are participating together in some kind of a collaborative decision.

Erin Spain: So that's some high praise from one of your patients there.

Daniela Matei: Yes, it's true. I have a long and very friendly relationship with Susan Gubar and I'm very thankful for her appreciation of my style. She's also said in her book that I'm a very direct and a truth teller. I don't really sugar coat the findings and the facts. And I think that's true and maybe linked to my background as an Eastern European person. This is indeed a difficult balance that I try to refine every day and sometimes I'm better at it and some days I'm not that good at it, but always, you know, having the correct facts I feel it's very important to be informative so that the patient can work with a physician to make the right treatment choice when different choices are available. I find this balance between my academic laboratory life and my clinic life as being rewarding, although sometimes it is exhausting and the interaction with patients is a privilege, a gift, but also an overwhelming burden. Sometimes at the end of a long hard clinic day it's hard for the doctor as well.

Erin Spain: Susan mentioned in that clip we just heard that she called you a doctor poet. Is poetry a way for you to sort of escape from the lab and the clinic and sort of that the heavy lifting that you're doing as a physician scientist. Is poetry a way for you to kind of flex a different part of your mind?

Daniela Matei: That's right. I hope that in a different life I would have been a writer or a poet and writing poetry, although it doesn't come that easy to me, I kind of work for months on a single piece. It helps alleviate carrying the burden I spoke about earlier. My gift for writing has been very helpful though in my life as a scientist, writing papers and writing grants. I value poetry. I wish I had more time for it.

Erin Spain: Well, you did write one poem that does sort of address your life as a physician and scientist and then leaving when you walk out the door after a long day, it's called "Bloom". Would you mind reading that for me?

Daniela Matei: Oh, I would love to read this poem. It was published in the Annals of Internal Medicine and sometimes I joke that this was my easiest publication. It took me ten minutes to write, about an hour to go through the submission process, and it was accepted without revisions. Bloom. I dressed up in my new tight perfectly tailored brooks brothers skirt I put on mademoiselle perfume blue shadow around my eyes tan peep-toe heels before heading out I kept my smile the misty pleasant scent throughout the day I did not flinch sharing my compassion endlessly I shook hands patted shoulders I did not feel pain until five o’clock when I walked out spring was finally here the balmy wind blossoms on every tree cancer is pink

Erin Spain: Lovely. Thank you so much for sharing that. A note for physicians who listen to this show. You can now claim continuing medical education credit just by listening. Go to our website, feinberg.northwestern.edu and search CME for more details. If you're a regular listener and enjoy the podcast, go to iTunes and rate us.