Paxlovid and COVID; Breast Cancer and Lymph Node Removal

TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine in Baltimore, and Rick Lange, MD, president of the Texas Tech University Health Sciences Center in El Paso, look at the top medical stories of the week.

This week’s topics include a new drug for early Parkinson’s, Paxlovid and COVID, pragmatic model for chronic kidney disease, and lymph node removal and breast cancer.

Program notes:

0:45 Breast cancer and lymph node removal

1:47 Usual care survival 90%

2:45 One percent over five years

3:00 Rate of hospitalization in chronic kidney disease

4:00 Outcomes the same

5:01 Usual care pretty good

6:01 Engage physicians and patients early

6:20 Paxlovid indications

7:20 Twelve or thirteen days to resolution

8:23 Early Parkinson’s medicine

9:23 12 months of treatment

10:23 Should enroll more?

11:57 End

Transcript:

Elizabeth: A new medicine for early Parkinson’s disease.

Rick: Is Paxlovid good for all patients with COVID?

Elizabeth: A pragmatic trial of hospitalization rate in chronic kidney disease.

Rick: And deciding if breast cancer patients need to have all of their lymph nodes removed.

Elizabeth: That’s what we’re talking about this week on TTHealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I’m Elizabeth Tracey, a Baltimore-based medical journalist.

Rick: And I’m Rick Lange, president of Texas Tech University Health Sciences Center in El Paso, where I’m also dean of the Paul L. Foster School of Medicine.

Elizabeth: Rick, this week it’s all NEJM all the time and I’m going to toss the ball to you. Which of them would you like to start with?

Rick: Great. Let’s start with the one that I have teed up about breast cancer and removing all lymph nodes. I should have said all lymph nodes that drain the breast cancer. The original therapy for breast cancer was to do a complete mastectomy. Then we realized that causes a lot of complications and not all women need that, and metastasis can be detected clinically and sometimes you can’t see it clinically; it’s only revealed when you do a lymph node biopsy.

This particular study addresses the issue of, “Do all of the lymph nodes need to be removed if there is evidence of metastasis determined by a lymph node biopsy, or can you just continue with routine therapy?” They looked at over 2,760 patients and they all had breast cancer. But at the time they actually removed the breast cancer and did a biopsy of the lymph node, they were able to determine that there was in fact some cancer there.

Now, some of those women were randomized to remove all the lymph nodes in the armpit and others just usual care. Then they followed these women over a 5-year period. Those that had extensive lymph node dissection the 5-year survival was 89%. The 5-year survival just usual care was about 90%. Elizabeth, as you know, those that had extensive lymph node dissection were more common to have lymphedema and other complications.

Elizabeth: This is the sentinel node that’s positive that then causes them to be randomized into further dissection or not?

Rick: Right, and again if there is evidence of metastasis there, either they removed all the lymph nodes or they just continue with adjuvant therapy. Again, the 5-year outcome is the same regardless.

Elizabeth: This is irrespective of what type of breast cancer it is?

Rick: Most of these were a particular kind of breast cancer called luminal breast cancer, but they didn’t distinguish among different types of breast cancers.

Elizabeth: This notion that lymphedema, which many women identify as one of the most problematic sequelae of being treated for breast cancer, I guess I’m not surprised that it might result in a slightly shorter lifespan.

Rick: It’s 1% over 5 years.

Elizabeth: This sounds like this is going to be a change in practice kind of thing.

Rick: It is. They have tried to do other studies to look at it and they were either underpowered or they had women with low-risk breast cancers, low risk of recurring. The results of this study are quite valuable.

Elizabeth: Let’s turn then to our pragmatic trial on this rate of hospitalization in chronic kidney disease. Interestingly, they are calling this thing — which is the concurrence of chronic kidney disease, type 2 diabetes, and hypertension — the kidney dysfunction triad. I have heard it described in a number of ways and so now this is my first time, at least, I’m hearing it described this way.

In this study, they had 11,182 patients with this triad being treated at 141 primary care clinics — wow, lots of folks — and they were looking at, “If we have an intervention that uses a personalized algorithm and also employs practice facilitators to assist providers in delivering guideline-based interventions, or usual care, what happens to our primary outcome of hospitalization for any cause at 1 year?” And then there are secondary outcomes including ED visits, readmissions, cardiovascular events, dialysis, and death.

They had 71 practices in the intervention group and 70 in the usual care group. Here is the data: the hospitalization rate at 1 year was 20.7% in the intervention group and 21.1% in the usual care group. The risks of emergency department visits, readmissions, cardiovascular events, dialysis, or death were similar in these two groups. So very unfortunately, this model did not translate into any improved outcomes for these folks.

Rick: Elizabeth, a shout-out. This was done at my old stomping grounds at Parkland Hospital, the VA system, two other health systems in Dallas. A shout-out to Miguel Vasquez, Brett Moran, Robert Toto, and Ruben Amarasingham. They did this really large study with a hypothesis in these high-risk patients [that] if you combine ticklers from the electronic health record and people that were there to help navigate individuals, that it would improve the outcome, but the outcomes were the same.

I’d say a couple of things. One is the usual care in that system is usually put good. When you look at the two groups, those in the usual care and those with all these interventions, the same percentage of people seem to receive the same type of care. But it does say that we still have room for improvement.

Elizabeth: Of course, a strength of this study is that they include academic, private, and veterans’ clinics as part of their whole cohort, so they really covered quite a lot of the bases. They do note that improvements in their opinion will likely require additional technology such as clinical decision support. They also say that there are additional and expanding evidence for using these additional agents to treat chronic kidney disease and that the employment of those also might be able to move these numbers a little bit.

They also see something that in criticizing their own study I thought was really important. They said that by increasing the engagement of both providers and patients early in the design and conduct of trials, they may be able to once again budge some of these numbers a little bit better than they demonstrate here.

Rick: What it says is engagement alone isn’t enough. As they said, we need to do more. What that more is, well, we should talk to the physicians and patients early on to figure out how we can up the game a little bit.

Elizabeth: Now, let’s turn to COVID, which we didn’t start with this time in a break with our normal tradition.

Rick: No. In fact, we haven’t talked about COVID in a while. There’s Paxlovid — and remember Paxlovid is a combination of two antiviral agents, one called nirmatrelvir and the other is ritonavir. It’s been effective in individuals that are unvaccinated and they have at least one risk factor for severe COVID disease. If they receive Paxlovid in the first 3 to 5 days of their infection, it can reduce COVID-related hospitalizations or death by as much as 85% to 90%.

What about vaccinated individuals that have a risk factor? Or what about individuals that have no risk factors and have not been recently vaccinated? They had almost 1,300 patients and they randomized them to placebo or Paxlovid and the major outcome was the time to sustained alleviation of the signs and symptoms. Unfortunately, what I can report is that the Paxlovid in these two particular groups didn’t change that at all. Regardless of whether you took Paxlovid or placebo, it took about 12 to 13 days for the symptoms and signs to be alleviated.

Elizabeth: That’s rather curious. Is there any speculation on why that is in this particular group versus the ones who have benefited?

Rick: We know that vaccination already reduces the risk that you have either a severe COVID infection or hospitalization, and Paxlovid doesn’t offer any benefit to those.

Now, what about those that don’t have any risk factors? Well, they are at low risk for having either severe infection or hospitalization and so trying to lower that even further with Paxlovid — you really can’t see much of a difference. This doesn’t really address hospitalizations or death, and in this particular group it happened in less than 2% of all patients. If there was any hint at all that Paxlovid could reduce deaths or hospitalization, we need to do a study that’s 10 times larger.

Elizabeth: I’m going to grant you that. Then I’m also going to point out the confusion about when a medicine is indicated, and when we slice and dice the subgroups in whom it looks like it’s going to be effective to this degree, results in people just saying, “You know what, I’m not going to go and get on this medicine. Why should I?”

Rick: Yep.

Elizabeth: Finally, let’s talk about this medicine for early Parkinson’s disease. It’s called lixisenatide. It is a glucagon-like peptide-1 (GLP-1) receptor agonist and it’s used for the treatment of diabetes. We know that, boy, these agents have turned out to have a lot of efficacy in lots of other conditions. In this case, a previous animal model showed that it might help in Parkinson’s disease.

This study conducted in France is a phase II, double-blind, randomized, placebo-controlled trial and they looked at lixisenatide on the progression of motor disability in people with early Parkinson’s disease. That’s those who were diagnosed less than 3 years earlier and who were receiving a stable dose of medications to treat their symptoms and who did not have motor complications.

They were given this daily subcutaneous injection of the medication or a placebo for 12 months and then they were followed by a 2-month washout period. Their primary endpoint was the change in baseline and scores for movement disorders, with higher scores indicating greater motor disability. 156 people were enrolled, 78 assigned to each group.

Interestingly, the folks who took the injectable medication actually had alleviation or improvement of some of their symptoms, while those in the placebo group had worsening disability. After their 2-month washout period, they still demonstrated that the folks who were on the lixisenatide were better off than those with a placebo.

They did have some side effects — nausea in 46% of the folks with lixisenatide and vomiting in 13%. Some of that was bad enough that they withdrew from the trial. But in toto, this looks like it could be promising.

Rick: It does appear to be promising. This is a phase II trial and it’s a relatively short period of time; it’s a 1-year time period. But you have pilot trials to see whether we should enroll a larger number of patients and follow them for a longer period of time, and to see whether it’s a benefit.

The reason why I’m glad you picked this study is we really don’t have a lot of good therapy that’s considered to be neuroprotective — that protects the neurons — in early-onset Parkinson’s, so hopefully this will pan out.

Interestingly enough, they have tried other GLP-1 inhibitors that weren’t helpful. Now, this one has four times more affinity for the receptor than human GLP-1, so it’s really potent. We know that it improves the motor manifestations of Parkinson’s. It really didn’t do anything at all with the non-motor manifestations and it’s a really fairly modest improvement.

But, again, it’s a short period of time. Either a longer time period will either say maybe that widens and there is even more significant improvement, or perhaps it’s relatively short-lived and we need additional trials to figure that out.

Elizabeth: The authors also note that they only employed one dose of lixisenatide in this particular trial, and who knows? I mean, we may end up having to titrate it up or down.

Rick: Right. Well, as you mentioned, about 46% of people had nausea and 13% had vomiting. In those individuals, they had to cut the dose in half. It’s an important trial. I hope it leads to either new medications or new pathways to help early treatment of Parkinson’s.

Elizabeth: On that note then, that’s a look at this week’s medical headlines from Texas Tech. I’m Elizabeth Tracey.

Rick: And I’m Rick Lange. Y’all listen up and make healthy choices.

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