As COVID-19 deaths rise in Italy, oncologists hope to see the curve flatten

24 Mar 2020
As COVID-19 deaths rise in Italy, oncologists hope to see the curve flatten

When The Cancer Letter spoke with Giuseppe Curigliano last week, he described the atmosphere in Italy as “spectral”.

At the time, there were 10,000 confirmed cases and 631 deaths from coronavirus in Italy.

At this writing, just a week later, there are 41,035 confirmed cases, and 3,405 deaths and the numbers are rising.

“I don’t want to see more people dying. I would like to flatten the curve and to see this infection go down,” Curigliano, clinical director of the Division of Early Drug Development for Innovative Therapy, co-chair of the Cancer Experimental Therapeutics Program in the Department of Oncology and Hemato-Oncology, University of Milan, at the European Institute of Oncology, said when we checked in with him again.

Cities and states in the United States have just started enforcing the closure of restaurants, movie theatres, and bars to slow the spread of the coronavirus - and to prevent numbers of cases and deaths from climbing as rapidly as Italy’s.

All of Italy began enforcing a mandatory lockdown two weeks ago.

“We can’t see the effect of this locking down and social isolation yet. We will see the effect next week,” Curigliano said, hopefully.

Curigliano has one piece of advice for the United States government:

“The most important thing is to apply, as soon as possible: Procedures of social isolation and of containment in specific areas. I know this will be very expensive in terms of the economy, but I believe that one life is much more important than money.”

Curigliano spoke with Alex Carolan, a reporter with The Cancer Letter.

Alex Carolan: I know you’re very busy and have patients who have COVID-19 who also have cancer, so, again, your time is very valuable and I appreciate you taking the time to speak with me.

I’d like to begin by following up on where we left off last week. What’s changed since then? Have things changed drastically?

Giuseppe Curigliano: Yes. I can show to you the data, because I can share the screen if you want.

AC: Yes, that’d be great.

GC: And I have in front of me the data, and it’s very interesting.

What’s changed in respect to our last interview? We have, actually, something like 41,000 positive patients. And if you look at the curve, there is clearly an increase of the numbers of positive cases.

You have, in yellow, the number of new cases that are defined as patients that have been hospitalised or with symptoms at home, and then you have the number of people who died. This is in grey.

As of March 19, 3,405 people died. We have much more cases and much more death, and if you look at the data in Regione Lombardia, we have close to 8,400 people hospitalised due to symptoms, and 1,006  in intensive care. And in Regione Lombardia, 2,168  died, so it means that the majority of patients who died are concentrated in Regione Lombardia.

Look, this is the epicentre here: 19,884 people are positive. And in all of Italy, 3,405 patients died. The graph shows the number of new positive cases by day.

We had a decrease during the weekend, then we had a rapid increase - and yesterday these were the new cases, most of them in the Milan area.

Because, you know, up to now in Milano we were very few there, the positive cases. Now, they are increasing day by day. We expect that after the lockdown established one week ago, we expect to see the decrease of this curve in one week, finally. Let us see. We hope so.

AC: Do you expect the curve to go down or flatten out in one week?

GC: First flat, like The Washington Post presented, and then to go down. Yes.

AC: So, that will indicate that these policies of being on lockdown and social distancing actually do work in this situation?

GC: We hope so, because we can’t see the effect of this locking down and social isolation yet. We will see the effect next week.

AC: That makes sense. Some have said that the U.S. seems to be only a week or two behind Italy in this regard, and you can even see since last week we have over 10,000 cases now. I think this time last week we had less than 1,000. Do you think that the U.S. seems similar to Italy in how things are progressing here?

GC: Looking at the data in Spain and in France, actually, the increase in the number of cases was very similar to the one in Italy.

We started with very few cases and very few deaths. We started our experience on Feb. 24, and the number of people who died then were seven. Feb. 24 was just three weeks ago.

Now, we have 41,000 cases positive, and 3,400 deaths. So, I don’t believe that in the United States, the logarithmic curve will be different, unless you will start with specific lockdown recommendation or social isolation before you have all of the positive cases that we have.

AC: Right. That’s what some cities and states are trying to do now, but the question is whether it’s enough. We don’t know yet.

GC: There is nothing more to do, because in order to prevent the epidemic spread of a virus, the only thing that you can do is social isolation, reduce contact, and containment of areas where you have patients who are much more concentrated.

If you don’t do this, you will have many patients who arrive in the hospital, and you will spend a lot of money to treat the infection with antiretroviral treatment.
For those that will have access to intensive care, the cost in terms of lives, and in terms of the health care system will be higher.

So, it’s better to do a low-cost approach, low-cost in terms of health approach, because I know it is a high cost in terms of economics. But in Italy, we decided to give priority to health and not to economy.

AC: I remember last week, when we spoke, you mentioned that your wife is an intensive care doctor. How is she continuing to handle COVID-19? How are you both feeling about the situation?

GC: As I said to you before, my wife is an intensive care doctor, and burnout is quite stressing, because the job of a doctor working in the intensive care is to save lives.

Usually, you have patients with trauma, or patients after car accidents, or patients in the post-cardiac surgery setting, or patients with myocardial infarction—so you need to save as many lives as you can.

If you see the data, we have many patients dying, so for intensive care doctors, I believe and I see that burnout is really a problem. It’s very stressful to see so many people dying.

AC: Of course. Have you both received tests for COVID-19 since we last spoke?

GC: I did. It was negative, and my wife also did, and it was negative.

AC: That’s good to hear. Last week, you said you had symptoms of coronavirus, but you tested negative.

GC: Yes, yes.

AC: But those symptoms have gone away now?

GC: Yes, absolutely. It’s better now. Yes.

AC: That’s great. And I know, yesterday [over email] you had mentioned to me that you were actually treating one of your cancer patients who has COVID-19. Could you talk about how you care for your cancer patients who have tested positive for COVID-19?

GC: Yes. This was a cancer patient with non-small-cell lung cancer, with a specific alteration that was RET-amplified on the primary tumour.

He’s a patient with metastatic lung cancer, and six months ago he started the treatment with an experimental therapy that is an anti-RET tyrosine kinase inhibitor. Ten days ago, he developed a cough and fever. He was living in a high-incidence area for COVID-19 - the city of Bergamo.

So, we really understood that these were symptoms from the infection.

We stopped treatment, and we invited him to contact the national emergency number. He said no, but we did it for him.

We contacted the national emergency number, and the doctors went to his home, picked him up, and they brought him to the hospital. He was COVID-19-positive. After two days of fever, he developed a very serious interstitial pneumonitis, and now he’s in intensive care.

We have daily contact with the intensive care unit taking care of him, because he’s in a clinical trial. He’s alive. He’s stable. There is no improvement until now. We hope, we really hope, he can recover.

AC: How many patients with COVID-19 also have cancer?

GC: In China, they have very limited statistics. Out of 1,000 cases, they identified 18 patients with cancer, so it’s very limited cases.

The data in Italy, we have the data, they have released today. A first analysis on 355 out of 2003 who died (17.7%) has been performed. Of 355, they identified 72 patients (20.3%) with history of active cancer concurrent to COVID-19 infection.

According to the data of the Chinese population, the case fatality rates, access to intensive care units, and acute respiratory distress syndrome, was very high for cancer patients.

In a retrospective analysis including 1,572 COVID-19 patients cases, authors identified 18 patients with cancer. Patients with cancer were observed to have a higher risk of severe events (a composite endpoint defined as the percentage of patients being admitted to the intensive care unit requiring invasive ventilation, or death) compared with patients without cancer (seven [39%] of 18 patients vs 124 [8%] of 1,572 patients).

Moreover, patients who underwent chemotherapy or surgery in the past month had a numerically higher risk (three [75%] of four patients) of clinically severe events than did those not receiving chemotherapy or surgery (six [43%] of 14 patients).

AC: Are you only treating cancer patients right now, or, because of the amount of people who have COVID-19, have you switched to the general patient population?

GC: Actually, my centre is a comprehensive cancer centre that has been selected as a hub centre for cancer patients in the area of Milan.
We are two centres, my centre and the National Cancer Institute. It means that in my hospital, we treat only patients with cancer. In order to reduce the number of COVID-positive patients, we do a checkpoint outside the hospital. We do a holistic briefing in order to understand if they have fever, cough, respiratory symptoms, or contacts with other people who are positive.

If we suspect a COVID-19 infection, we test them before admission to the hospital. There is a special area of the hospital where they can stay isolated with a special team of nurses. If they are positive, of course we take care of them if they have mild symptoms.

They will not start treatment. We wait for resolution of symptoms or infection in a specific area of the hospital. If they are negative, they have access to the hospital and we do surgery or we start the treatment.

AC: The centre that you’re talking about, it’s the European Institute of Oncology?

GC: Yes, the European Institute of Oncology.

AC: Did the European Institute of Oncology have to make any changes to how it admits patients, or the number of patients it can take in because of COVID?

GC: We made a lot of changes. First, we make a lot of phone calls. Every day, we contact up to 500 patients. We ask them if they are fine, if they have fever, if they have a cough - in order to limit the access to the hospital of patients who are potentially sick.

For patients taking oral medication, let’s say, oral chemotherapy, or oral tyrosine kinase inhibitors, or any other type of oral treatment, we use telemedicine in order to assess toxicity, and we provide the oral treatments at home.

We have a delivery service, so we provide them with two months or three months treatment. We invite them to do blood tests close to home. Every three weeks, we have a televisit, in which we assess toxicity.

In case patients have any other symptoms before the interval time of three weeks, they can contact us by email, and we do the teleconsultation on the same day.
Then, for any patients who have access to the hospital, we have a checkpoint external to the hospital, where nurses usually take body temperature and do an analysis for cough and contact with other people.

We give a special pin to the patients - a green pin - to enter the hospital, and then there is another checkpoint that is delivered by doctors. We do a second internal checkpoint in order to be sure that the patient is safe and not infected.

For the cases that are suspected, we do the tests for COVID-19, or a nasopharyngeal test. Now, we have several tests that can do assessment of IgG and IgM in the blood, also with a single drop of blood. If they are IgG positive, of course they are not infected. If IgM positive, we also do the nasopharyngeal test.
And then we have a specific area of our hospital with very few patients, less than three, for COVID-infected patients. For patients that are mildly symptomatic, there is a special area, and there is a trained team of nurses and doctors taking care of them.

We expanded the intensive care unit with four sub-intensive care and four intensive care beds, and we already trained the nurses and doctors from other areas to take care of those patients in case we have patients developing ARDS. So, we are doing a lot of training, training for patients, for nurses, and for doctors. It’s another hospital, finally, that is also instructed for COVID infection.

AC: You mentioned that part of this is that you can deliver treatment to your patients. I was wondering about the drug supply. Does it seem like there are disruptions to the drug supply?

GC: The drug supply and the logistics, everything is maintained. There is absolutely nothing disrupted in terms of logistics.

The problem is for some patients, since there is a containment area, and many patients have to travel a lot - not for drugs - but other things are restricted. Many patients have difficulties getting access to the hospital.

For surgery, we have to plan, again, the day of surgery for some patients—but we are trying to take care of any patients. We are trying to minimise the logistical problems for our patients. If you have a patient that is a priority, we adapt our schedule to the logistics of the patient, in order to give the patients the best service available.

AC: And have you seen any disruptions to clinical trials in Italy?

GC: A lot.

AC: I’m sure.

GC: This is a very good question. We are writing specifically, actually, a manuscript on this. We have an increase of protocol violation that is exactly the same of the increase of the COVID-positive patients. Of course, you have to deliver the experimental treatment at home.

Many pharmacies have been very flexible. They said, Yes, you can do delivery, absolutely, because we don’t want to have study treatment interruption. They are submitting, of course, an amendment for these problems, but until the amendment is approved, all are in protocol violation.

We have an exponential increase of protocol violations due specifically to missed visits, missed blood tests, or CT scans performed close to home - on time, but close to home, not in the centre. And then we review internally in the centre.

What I discovered during this crisis, is that many of our patients are very well digitalised. They have access to the internet. They can send you anything with internet, blood tests, images, clinical CT scans or MRIs - so telemedicine is very useful.

The other things that we discovered is that outside the doctors, many administrative people are working at home - so it means that you can do a better job at home without being in the hospital.

I believe many things will change after this crisis, and that we will have a boost for telemedicine and for patient-reported outcomes from home.
We created an app in our hospital. It’s very interesting. The app is on the iPhone for the patients, in which they can inform us every day about body temperature, respiratory symptoms, contact with suspect COVID-19 cases - but they can also report toxicity day-by-day. So. paradoxically, we have much more data now that the patients are not in the hospital than before.

AC: Wow. So, you developed this app because of COVID?

GC: Yes, a top bioinformatician working in my hospital developed it. Now, we are going to validate the app in a larger population. In my division, we started with a very limited number of patients. It works, and we can collect the data directly from the patients.

AC: Are you able to monitor your specific patients through this app?

GC: Yes, if you collect it, every day you receive data. For all the patients in which there is a suspect of infection, you can call him or her. And also, since you have many other parameters related to toxicity, maybe you can discover that the patient has nausea, vomiting or fatigue—and so you contact them. It’s very easy to have a real-life monitoring of patients receiving treatment at home.

AC: Stepping back a little bit, I know that Italy is overwhelmed with cases of COVID right now, and you’re hoping to flatten that curve, make the curve go down. Have you or anyone you know had to prioritise certain patients with COVID to receive care?

GC: You mean for the general population of patients?

AC: Yes.

GC: Actually, the attitude of people working in intensive care is to do a baseline assessment of the patient beyond age and comorbidities.

If you have two patients, one that is 35 years old, and another who is 75 years old, in order to decide, if you have one bed in the intensive care unit, it should be the patient that has a higher probability of survival.

There is no selection of patients based on age or comorbidities, but just based on a triage that is based on the probability of survival.

AC: And bringing this back to cancer patients, is there a suspected mortality rate among cancer patients?

GC: As I said before, today we had the first release of some data. A first analysis on 355 out of 2003 who died (17,7%) has been performed. Of 355 they identified 72 patients (20.3%) with history of active cancer concurrent to COVID-19 infection.

AC: How many of your patients that you’ve treated personally have had COVID?

GC: One confirmed and two suspected.

AC: And that’s because, also, you work in the hub that is COVID-free, right?

GC: Yes, we try to maintain a  COVID-free hub. In our hospital, there were not so many admissions of many patients who were positive from outside.

AC: In the U.S., researchers here have said that they expect five to 10 undiagnosed cases for each confirmed case. Do you know if something similar might be happening in Italy?

GC: My perception in Italy, actually, is that we have many positive cases at home, and so, these patients will never be tested, even though they have symptoms of COVID-19. Many of them may die, especially if they are elderly patients who live alone. We will never register them as a COVID-associated death.

In my opinion, in Italy we have many more cases at home with mild symptoms, which means that we will not really have a clear scenario of the epidemiology of this infection. We believe that we have 41,035 positive cases, because they had access to hospital, but in my opinion we have much more.

AC: Really?

GC: Yes. We have some doctors who are actually positive in my hospital. The last update in Italy is that 3,000 health care personnel have been or are infected. We know also that 14 doctors died. Many doctors are at home, they have symptoms, and some of them have not been tested, but they decided to be in quarantine, because they suspect that they have COVID.

Those are cases that we know, probably, are positive, but they are not registered as positive. And they are doctors; think about all the general population of many patients that have fever, cough, with mild symptoms, and nobody to do the test.

AC: If you’re quarantining at home, how do you receive a test? Can you only go to the hospitals?

GC: Usually, the recommendation of the National Health Service, if you have fever or cough, you should call an emergency number. An assessment will be done by phone. If a patient has mild symptoms, we have the local practitioner.

The National Health Service in Italy is organised with thousands of doctors close to the patients, and usually those patients are visited by the local doctor, and if they have mild symptoms, they have to stay at home. But they are not tested.

AC: Given the patients who are potentially unaccounted for in Italy, is there a realistic number of deaths that your modelers expect to see at the end of this?

GC: My hope, actually, is that social isolation and containment will reduce the number of deaths. If we reduce the number of positive cases, we will reduce the number of deaths.

I believe the number of deaths in China is underestimated. This is a personal opinion, I believe, because out of 80,000 positive cases, 3,000 have died. That’s really a limited number.

Maybe we have many more elderly patients, this can be a reason. Or maybe we have many more patients with comorbidities. The median age of the population in China with COVID-19 was 47 years old, if you look at the paper in The New England Journal of Medicine.

The median age of our population is who have died is 79 years old, so it’s a little bit different. I don’t want to see more people dying. I would like to flatten the curve and to see this infection go down.

AC: I think the U.S. has a lot to learn from Italy, in terms of flattening the curve. It seems like we’re just getting on board, but cases are rising exponentially still, so this is very informative. Do you happen to know of an online source about COVID in cancer patients specifically, or do you know of any preliminary papers about COVID and the disease that we can access right now?

GC: We are collecting information with the the Associazione Italiana di Oncologia Medica (AIOM). There is actually a survey in which we are collecting all the positive cases. It’s ongoing work, and we hope to have the data in a few weeks.

AC: Last week, you described the atmosphere in Milan as spectral. You said only pharmacies, supermarkets and hospitals were open. Has anything changed?

GC: What changed, actually, is that the national atmosphere is more positive now. We have awareness of what is going on, and everybody in the country is trying to stay home and to avoid going around.

Everybody knows, now, that we are doing this to protect ourselves first, and to protect the others. There is much more awareness about being Italians, so it’s a positive atmosphere, actually.

It’s like being in war, but there’s also the awareness that we can win this war altogether, positively, for patients who are hospitalised, but also patients with no disease. It is much more important for people with no disease to stay home, because this will help the patients actually hospitalised.

AC: You’ve probably seen it, but there was a video going around online of people in Italy, on their balconies, singing together.

GC: Yes. These are Italians. Yes, I know. I saw these people on YouTube. In Naples, in Rome, everybody is singing on the balcony, in order to work together and to win this war against COVID-19. Yes.

But Italy is also the country where we increase ICU beds by 50% in 2 weeks. For mild and moderate cases, in Milan, we are going to create a mobile cabin hospital in Fiera Milano Exhibition Center (converted from convention centre into temporary large-space treatment centre for 600 beds).

AC: That’s great. Is there anything else you’d like to add, anything else you think would be really important for our readers to know?

GC: The most important thing is to apply, as soon as possible, procedures of social isolation and of containment in specific areas. I know this will be very expensive in terms of the economy, but I believe that one life is much more important than money.

AC: Of course. I’d love to keep in touch going forward to see how things progress.

GC: Yes, of course.

AC: We do have a lot to learn from your own experiences with the virus, so thank you again for your time.

Reproduced with kind permission from The Cancer Letter.