Dr Peng: Thanks for having me here. It is a great pleasure to meet Professor Curigliano and Professor Mei Heng. We read the paper published in Lancet Oncology indicating that cancer patients have a higher risk for COVID-19. The definition of cancer though was very heterogeneous including many cancer types (solid tumors like lung cancer， breast cancer and colon cancer， and the hematological malignancies). Stages also ranged from early to advanced， also some locally advanced stages. So the definition and stratification of cancer patients varied. Also， in terms of the prevalence of cancer patients with COVID-19 infection， we needed to consider their comorbidities， age， immune status and the treatments they had received. Professor Mei Heng has published in Lancet Oncology that patients receiving chemotherapy may see a higher incidence of infection， but patients receiving tyrosine kinase inhibitor or immune checkpoint inhibitor might not. So the point is that we can’t really conclude that all cancer patients have a higher risk. I am interested to hear from Professor Curigliano， because you have published a paper in the European Journal of Cancer that I have read， regarding the checkpoint inhibitors in the era of COVID-19 in cancer and non-cancer patients.

 

Dr Curigliano: For sure， I completely agree with you that cancer patients have a higher risk of mortality compared to non-cancer patients， but in the context of multiple comorbidities and older age. I agree with you that not ALL cancer patients have a higher risk of mortality. If we look at the data， the first data published in Lancet Oncology was from Chinese cases， and then with data from the COVID-19 and Cancer Consortium (CCC19) and TERAVOLT， it is quite clear that we have three important risk factors. Older age. Comorbidities. Use of chemotherapy. It is clear that if you have lung cancer， for example， and you are older， you have comorbidities， and receiving chemotherapy， your risk will be higher. So my final message is， yes， you are at higher risk if you have cancer， but not for all types of cancer， and related to comorbidities and old age.

 

Dr Peng: Of course. On the topic of checkpoint inhibitors and the prognosis for cancer patients， I have read two papers from the same center. One is from the Department of Thoracic Oncology， and the other from Department of Infectious Diseases (the latter was a preprint and not yet been published). Their conclusions were different. The first one said that immune checkpoint inhibitors (ICI) do not impact prognosis， while the second one said that ICI have an adverse impact， across a range of cancers patients. Different conclusions from separate departments of the same center. Why is that? Is that due to different baseline characteristics of patients， or different statistical analysis approaches. I am interested to here both of your comments on that?

 

Dr Curigliano: We don’t have a clear demonstration that immune checkpoint inhibitors increase risk over time. In both CCC19 and TERAVOLT， immunotherapy was not a negative prognostic factor. Maybe you are right that the baseline factors of the patients can increase the risk of mortality. In my institution， we have a database of over 400 patients receiving immunotherapy for melanoma， and there were no deaths during the COVID epidemic， even if infected. It is clear that it is patient-by-patient， and according to comorbidities.

 

Dr Mei: I am in Wuhan and witnessed the massive outbreak of the coronavirus in my center. Then， from Wuhan to the world， it became a pandemic. As oncologists， we were involved in the battle to control the spread of the epidemic. From the middle of January to the end of February， 2020， I was working on the frontline. After that， colleagues from Zhejiang and other provinces came in to give us a rest. During those 1 1/2  months， we were looking after >1000 cancer patients， including 150 hematological malignancies. The immune status of these patients is often compromised and they are heavily reliant on the availability of medical resources. At that time， resources were limited， which renders these patients very vulnerable to the impact of the epidemic. Therefore studies were very important and challenging. I agree with you that in these types of patients， the infection rate is higher than non-cancer patients. Our investigations showed the infection rate in cancer patients was 2%， which was five-times higher than in the general Wuhan population. Mortality rates were higher， especially in hematological malignancies. Nearly half of the hematological malignancy patients died， compared to only 2 deaths in the solid tumor patient population. In terms of treatment， I agree that in these tough times， we should utilize low-dose chemotherapy， even better by oral administration. Data from 33 cancer patients with COVID-19 showed eight patients treated with kinase inhibitors (TKIs and PDK inhibitors) and two with multiple myeloma given proteasome inhibitors and two lymphoma patients received immune checkpoint inhibitors. The outcomes for these patients were good compared to those who received high-dose chemotherapy. Our transplantation unit was closed during this time， so no patients received transplantations. The treatment strategy is then even more important for those potential candidates. I agree with Professor Curigliano that age is an important risk factor. We have submitted a paper to Lancet Oncology where we investigated 380 patients with an average age of 64， and compared to moderate patients， the serious and critically ill patients were significantly older. Half of those had comorbidities such as hypertension and diabetes. Diabetes is very dangerous for these patients particularly with coronary disease. So comorbidities are also very important for these patients’ prognoses.

 

Dr Peng: Professor Curigliano， angiotensin-converting enzyme 2 (ACE2) expression seems to have some relation to COVID-19 infection. Do you think that has much to do with age and/or gender preference for ACE2， and other factors such as smoking history? I have also read a paper indicating that location with respect to altitude also decreases the expression of ACE2. This might mean that people living at a higher altitude are less prone to COVID-19 infection. So， do gender and age result in different ACE2 expression that may lead to differences in susceptibility to COVID-19?

 

Dr Curigliano: I read with interest your paper published in the European Journal of Cancer. Your analysis from the CGA clearly showed that ACE2 is more greatly expressed in normal versus cancer tissues， both in breast cancer and hepatocellular carcinoma. We also did a study in Italy that suggested that higher altitude might decrease the risk of infection. We have more male patients affected in our country. Out of 35000 patients， 70% were male， and their mortality was higher than for females. But all of these are statistics of observation. I am not so sure that ACE2 is not important. Maybe it is very important as you stated in your paper. What we need to understand is the polymorphism. Maybe we will discover that some patients who have a specific polymorphism will have worse outcomes compared to patients with another polymorphism. This would explain gender differences between male and female mortality. But an important observation in your paper is the one related to prostate cancer. It seems that in your analysis， there is no difference in prostate cancer. Other people are claiming that since there is another target in prostate cancer that the COVID virus is attracted to， maybe anti-androgen therapy will have a protective effect for prostate cancer patients. Overall， I believe gender may be a factor with ACE polymorphism. Regarding altitude， that would be possible， but we need to demonstrate that. In any case， latitude seems irrelevant. Milan and New York are the same.

 

Dr Peng: I have another question regarding the differences between this virus and other SARS-CoV viruses. We have read the paper published in New England Journal of Medicine from Mount Sinai Hospital looking at young and middle age patients with COVID-19 who quickly developed severe illness with clots in their blood vessels. The paper indicated the virus attacking the vessels was the second phase of COVID-19 infection. Why is there a second phase? Why do some patients advance quickly to being critically ill?

 

Dr Curigliano: ACE2 is expressed in endothelial tissues， so there is binding of the virus to this specific receptor. The New England Journal paper is quite clear that there is endothelial dysfunction with the formation of microthrombi， which are also seen in the lungs of many patients at autopsy. So there are different mechanisms. One is inflammatory. The other is thrombotic. Did our colleague in Wuhan do autopsies and what were the findings in the lungs of patients with COVID-19? Did you find microclots and endothelialitis?

 

Dr Mei: I have a question regarding treatment. We know now that for the mechanism of COVID-19， the cytokine storm is very important. Do you use medications to interfere with cytokines in your Italian practice， such as IL6 inhibitors or GM-CSF inhibitors?

 

Dr Curigliano: When we started working with the pandemic taskforce from Wuhan in Milan， we started the exact same trial with tocilizumab you had been doing with your patients. I must confess， in many cases， there is a limited activity with tocilizumab in later stage of disease. We observed some activity in the beginning of the infection where there was reduction of the cytokine storm. We also started looking at IL1 blockade， but the most effective treatment was plasma of patients who had recovered. You did the exact same thing in Wuhan. Plasma therapy seems to be the most promising as it was in the case of Ebola. My conclusion is that we don’t have an effective therapy against this coronavirus， not with tocilizumab， not with chloroquine， not with any type of antiviral therapy. The only promising activity is being seen with the plasma of recovered patients. That could be an effective therapy.

 

Dr Mei: So you are doing trials at the moment?

 

Dr Curigliano: Yes， we have. Now the number of cases is very low. We are no longer in the peak of the pandemic， and are seeing <1000 cases per day. No one is currently in intensive care. We started this trial one-month ago， and the analysis is showing that in advanced cases， there is no activity.

 

Dr Mei: We are the same. We have no patients here， so it is difficult to carry on with clinical trials. Maybe in the winter of next year， the opportunity will arise again.

 

Dr Peng: I have another question， Professor Curigliano， regarding the role of artificial intelligence in drug selection. Our collaborator， Justin Stebbing， has selected baricitinib from the AI draft. Baracitinib focuses on intracellular targets of JAK， but we are also looking at the IL6 inhibition of tocilizumab. They are active on different parts of the cell. What are your thoughts on the drugs targeting IL6 and JAK， as well as interferon?

 

Dr Curigliano: Those drugs are interfering with inflammation at different stages. If you target IL6， you are targeting the later stage of inflammation. Tocilizumab is actually approved for toxic shock， so when there is late stage shock， tocilizumab is employed to stop the inflammation cascade， like in CAR-T cell therapy. If you interfere with other targets like TNF or other precursors of inflammation， you have much greater opportunity to shut down the inflammation process and give much more benefit to the patient in the early stage of infection. The earlier you intervene， the better the results can be.

 

Dr Mei: Can you tell us about any advances in vaccine research for COVID-19 in Italy?

 

Dr Curigliano: This is being tested in Italy but we don’t have any final results. For therapeutics， some drug results have been published. The FDA has to consider approval in Italy. But if you are asking me， have I seen any important improvements for my patients， my answer is definitively no. I don’t see any breakthrough effect of therapeutic agents in my patients.

 

Dr Mei: My last question is what is your comment on facing COVID-19 in the future? How will it affect our routine work in the hospital? Do we need to be screening every patient on entering the hospital? We have seen that our healthcare workers have been impacted heavily here in China and in Italy. How do you think we can manage this in the future?

 

Dr Curigliano: What I suggest is to proceed to test all patients who admitted to hospital. That is what we are doing now at our cancer center. Perform a CT scan to exclude the presence of active infection. Also provide personal protective equipment for all staff. The best ways to limit access from infected people in cancer centers is to discover infected patients and isolate them and take care of all your other patients. This is the best strategy to guarantee the best care for all of our cancer patients.

 

Dr Mei: Do you use teleconferencing for your patient care?

 

Dr Curigliano: Yes. For patients who need follow-up visits， we use telemedicine. Also， all patients who are receiving oral medication are taking their drugs at home， and we do safety monitoring with telemedicine. We are trying to do telemedicine everywhere we can from follow-up to safety monitoring of oral medication. Of course， there are some patients that should be admitted to hospital. Those are patients are in need of surgery and/or using intravenous treatment.

 

Dr Mei: That is the good way. There has been very rapid development of these strategies. For cancer patients， is the threat of COVID-19 more important than their primary disease? Malignancies like leukemia， for example， can’t wait， but with the threat of COVID-19， when do we make the choice of a treatment strategy?

 

Dr Curigliano: I believe we should prioritize the patient’s leukemia treatment. A leukemia patient can’t wait， so you test them for COVID-19. If it is negative on a swab， you start treatment and try to protect that patient. Leukemia is more dangerous than COVID-19 in terms of mortality if not well treated.

 

Dr Mei: We have seen many patients die of diseases that are not COVID-19， so we need to consider the prioritizing of therapy.

 

Dr Curigliano: Yes. I believe we need to concentrate more on our consultations. In China and Italy， the COVID-19 pandemic is now under control， so now it is time to take care of our cancer patients. We need to protect them， but we also need to care of them.

 

Dr Mei: Recently， in Wuhan， we finished testing 10 million people， the entire city， and there was not one COVID-19-positive patient. I think you have few cases in Italy also?

 

Dr Curigliano: We still have some cases in the country， mainly in the north of the country， but case numbers are decreasing day-by-day.

 

Dr Mei: Do you think it is because summer is coming and temperatures are warming up?

 

Dr Curigliano: I believe it is primarily related to our lockdown. The summer may have a small impact， but primarily and scientifically due to the lockdown.

 

Dr Mei: Maybe. I hope so.

 

Dr Curigliano: I would like to mention the CCC19 and TERAVOLT data presented during ASCO clearly show that older age， comorbidities and chemotherapy are risk factors for cancer mortality. Another important thing for the next pandemic， is that we must not be short of medical resources， as we were and our colleagues from Wuhan and other centers. Some treatments can be delayed， while some others cannot (as for leukemia or other high-risk cancers). We have to be prepared for any other future pandemics. We should reorganize our health systems so that there is personal protection equipment for all health professionals， and so there are hospitals only for COVID patients separate from cancer patients， cardiovascular patients and other types of patients. These are the best lessons from this experience.

 

Dr Mei: Thank you for your comments. I agree with that. We should pay more attention to our cancer patients， particularly our COVID cancer patients. We will all benefit next time. That is very important.