The Shifting Landscape of Genitourinary Oncology During the Covid-19 Pandemic and How Italian Oncologist Reacted

1. European Urology
The Shifting Landscape of Genitourinary Oncology During the COVID-19 Pandemic
and how Italian Oncologists Reacted: Results from a National Survey
--Manuscript Draft--
Manuscript Number: EURUROL-D-20-00508
Article Type: Research Letter
Keywords: COVID-19; genitourinary cancers; immunotherapy; Medical Oncology; patient
management
Corresponding Author: Laura Marandino
Fondazione IRCCS Istituto Nazionale dei Tumori
ITALY
First Author: Laura Marandino, M.D.
Order of Authors: Laura Marandino, M.D.
Massimo Di Maio, Prof.
Giuseppe Procopio
Saverio Cinieri
Giordano Domenico Beretta
Andrea Necchi, M.D.
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3. The authors listed below have made substantial contributions to the intellectual content of
the paper in the various sections described below.
(list appropriate author next to each section – each author must be listed in at least 1 field.
More than 1 author can be listed in each field.)
_ conception and design Laura Marandino, Massimo Di Maio, Andrea Necchi
_ acquisition of data All authors
_ analysis and interpretation of data Laura Marandino, Massimo Di Maio, Andrea Necchi
_ drafting of the manuscript Laura Marandino, Massimo Di Maio, Andrea Necchi
_ critical revision of the manuscript for
important intellectual content All authors
_ statistical analysis Laura Marandino, Massimo Di Maio, Andrea Necchi
_ obtaining funding Not applicable
_ administrative, technical, or
material support Not applicable
_ supervision Andrea Necchi, Massimo Di Maio
_ other (specify) Not applicable
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4. Massimo Di Maio received advisory board or consultant fees from Merck Sharp & Dohme,
Bristol Myers Squibb, Eisai, Janssen, Astellas, AstraZeneca, Pfizer, Takeda and institutional
research grant from Tesaro.
Giuseppe Procopio received advisory board or consultant fees from AstraZeneca, Bayer,
Bristol Myers Squibb, Janssen, Ipsen, Merck Sharp & Dohme, Novartis, Pfizer.
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6. The Shifting Landscape of Genitourinary Oncology During the COVID-19 Pandemic
and how Italian Oncologists Reacted: Results from a National Survey
Laura Marandino a,
*, Massimo Di Maio b
, Giuseppe Procopio a
, Saverio Cinieri c
, Giordano
Domenico Beretta d
, Andrea Necchi a
The outbreak of the novel coronavirus disease-19 (COVID-19) caused by severe acute
respiratory syndrome corona virus 2 (SARS-CoV-2) suddenly revolutionized the way we take
care of patients with cancer. This situation was dramatically felt in geographic regions where
the spread of the infection, qualified as a pandemic by the World Health Organization on
March 11, 2020, was causing an emergency health care situation. After the original outbreak
in Wuhan City, Hubei Province, China, the infection rapidly spread throughout the world in
more than 199 countries (www.worldometers.info/coronavirus). At the time of writing, Italy,
and the Lombardy region in particular, was ranked first in terms of COVID-19-associated
deaths, making this region one of the most critical hotspots of the COVID-19 outbreak [1]. In
Italy, a total of 10 779 deaths had been reported by the health care authorities and 3906
patients required intensive care unit (ICU) admittance at the time of writing.
Patients diagnosed with cancer have a higher risk of developing serious complications and
dying from COVID-19 [2,3]. Besides this consideration, a number of critical dilemmas have
emerged regarding indications for cancer therapies and management of associated side
effects. General clinical recommendations for patients with genitourinary cancers have
already been published, obviously biased by the lack of actual data for most of the guidelines
[4].
It is important to anticipate the shifting landscape that will probably occur in the management
of patients with cancer to better prepare health care providers and systems for future needs. In
March 2020 we therefore carried out a nationwide survey among Italian medical oncologists
that focused on the management of patients with genitourinary malignancies.
The survey was endorsed by and conducted through the Associazione Italiana di Oncologia
Medica (AIOM) network, and took the form of an online questionnaire sent to all AIOM
members.
A total of 72 physicians provided feedback; their general characteristics are shown in
Supplementary Table 1. The questions and corresponding results are shown in Figure 1. In
general, there was consensus among oncologists to pursue treatment, possibly without delays
or interruptions, for patients with locally advanced or metastatic disease for which an
induction or first-line therapy option is indicated in guidelines, particularly for patients
suffering from prognostically aggressive disease requiring timely treatment (Fig. 1A–H). A
higher proportion of physicians were willing to consider delays or interruption for clinical
settings characterized by more indolent disease or treatments associated, on average, with
clinical benefit of lower magnitude. Of note, despite the public health care emergency, Italian
oncologists were still in favor of close adherence to guidelines regarding administration of
perioperative therapies, such as neoadjuvant chemotherapy in patients with clinical T3–
4N0M0 urothelial bladder cancer (Fig. 1C,D) and adjuvant therapy in high-risk, clinical stage
I germ-cell tumors (Fig. 1F,G). Overall, although the main factor taken into account for
treatment decisions was its proven survival benefit, the number of hospital visits ranked
second, ahead of other factors usually considered important in clinical decisions.
Lastly, two important notions emerged from this survey. First, Italian oncologists are still in
favor of considering delivery of the best treatment option for genitourinary cancer patients
through inclusion in clinical trials (61%), although most of them (54%) underlined the
unavoidable more stringent selection and the need to face severe logistic difficulties, as
Manuscript

7. indicated in Fig. 1I. Second, although the risks associated with immune checkpoint inhibitors
in the present pandemic context are not well defined, most of the respondents would justify
interruption of therapy only after case-by-case discussions with patients with a sustained
response during treatment, or would consider skipping some doses to reduce the number of
hospital visits (Fig. 1M).
Implementation of telemedicine will be critical in managing follow-up visits and oral drug
delivery, as is currently done in several institutions nationwide.
This survey provides a snapshot of the opinion of Italian oncologists regarding the
management of patients with genitourinary malignancies. Similar considerations would
probably apply to other solid tumors. In our opinion, the main message is that in spite of huge
sudden changes in a geographic area representing an epicenter of the COVID-19 pandemic,
oncologists are still determined to achieving treatment delivery as close as possible to clinical
guidelines or routine clinical practice, at least for treatments supported by evidence of a
clinically relevant gain in life expectancy. In the setting of advanced disease without curative
intent, a non-negligible number of oncologists would delay treatment initiation (or consider
interruption) in the second or further lines of treatment associated with a lower clinical
benefit. For patients who deserve a systemic treatment with curative intent, we should still
rely on the multidisciplinary approach among several other specialists. This continuing
collaboration will require profound organizational changes, primarily related to the obvious
delays in biopsies or radical surgical interventions that were promptly outlined by Italian
urologists [5].
Conflicts of interest: Massimo Di Maio has received advisory board or consultant fees from
Merck Sharp & Dohme, Bristol Myers Squibb, Eisai, Janssen, Astellas, AstraZeneca, Pfizer,
and Takeda and an institutional research grant from Tesaro. Giuseppe Procopio has received
advisory board or consultant fees from AstraZeneca, Bayer, Bristol Myers Squibb, Janssen,
Ipsen, Merck Sharp & Dohme, Novartis, and Pfizer. The remaining authors have nothing to
disclose.
References
1. Grasselli G, Pesenti A, Cecconi M. Critical care utilization for the COVID-19 outbreak in
Lombardy, Italy: early experience and forecast during an emergency response. JAMA. In
press. https://doi.org/10.1001/jama.2020.4031
2. Liang W, Guan W, Chen R, et al. Cancer patients in SARS-CoV-2 infection: a nationwide
analysis in China. Lancet Oncol 2020;21:335–7.
3. Zhang L, Zhu F, Xie L, et al. Clinical characteristics of COVID-19-infected cancer
patients: a retrospective case study in three hospitals within Wuhan, China. Ann Oncol. In
press. https://doi.org/10.1016/j.annonc.2020.03.296
4. Gillessen Sommer S, Powles T. Advice regarding systemic therapy in patients with
urological cancers during the COVID-19 pandemic. Eur Urol. In press.
5. Naspro R, Da Pozzo LF. Urology in the time of corona. Nat Rev Urol. In press.
https://doi.org/10.1038/s41585-020-0312-1
Fig. 1 – Questions and corresponding answers collected during the survey.

8. a
Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori,
Milan, Italy
b
Department of Oncology, University of Turin, Azienda Ospedaliera Ordine Mauriziano,
Turin, Italy
c
Medical Oncology & Breast Unit, Antonio Perrino Hospital, Brindisi, Italy
d
Medical Oncology Department, Humanitas Gavazzeni Clinic, Bergamo, Italy
* Corresponding author. Department of Medical Oncology; Fondazione IRCCS Istituto
Nazionale dei Tumori, Via G. Venezian 1, 20133 Milan, Italy. Tel. +39 02 23902402; Fax:
+39 02 23903150.
E-mail address: laura.marandino@istitutotumori.mi.it (L. Marandino).

9. RENAL CELL CARCINOMA
• Do you consider it appropriate to evaluate a delay in
treatment initiation in these clinical settings?
56
26
9
35
16
44
62
36
0% 20% 40% 60% 80% 100%
Metastatic renal cell carcinoma –
Third and further lines
Metastatic renal cell carcinoma -
Second Line
Metastatic renal cell carcinoma –
First Line; Intermediate/Poor risk
Metastatic renal cell carcinoma –
First Line; Favorable risk
Yes
No
Figure 1A
figure one

10. RENAL CELL CARCINOMA
• Do you consider it appropriate to evaluate interruption
of treatment in these clinical settings?
44
55
22
33
3
27
16
49
37
68
0% 20% 40% 60% 80% 100%
Metastatic renal cell carcinoma –
Long responders to
Antiangiogenic Drugs
Metastatic renal cell carcinoma –
Long responders to Immunotherapy
Metastatic renal cell carcinoma –
Second and further Lines,
Antiangiogenic Drugs
Metastatic renal cell carcinoma -
Second and further Lines,
Immunotherapy
Metastatic renal cell carcinoma –
First Line
Yes
No
Figure 1B

11. UROTHELIAL CANCER
• Do you consider it appropriate to evaluate NOT starting
a systemic treatment in these clinical settings?
38
15
10
38
33
56
61
33
0% 20% 40% 60% 80% 100%
Muscle-invasive bladder cancer–
Adjuvant therapy
Muscle-invasive bladder cancer–
Neoadjuvant therapy, in case of
long waiting list for radical surgery
Muscle-invasive bladder cancer
cT3-4N0 – Neoadjuvant therapy
Muscle-invasive bladder cancer
cT2N0 – Neoadjuvant therapy
Yes
No
Figure 1C

12. UROTHELIAL CANCER
• Do you consider it appropriate to evaluate a delay
in treatment initiation in these clinical settings?
58
38
8
15
13
33
63
56
0% 20% 40% 60% 80% 100%
Metastatic Urothelial Cancer -
Second and further lines
Metastatic Urothelial Cancer- First
Line, in patients without visceral
disease or rapid progression
Metastatic Urothelial Cancer- First
Line, all cases
Locally advanced disease N+
Yes
No
Figure 1D

13. UROTHELIAL CANCER
• Do you consider it appropriate to evaluate interruption
of treatment in these clinical settings?
58
37
51
61
4
11
35
20
10
66
0% 20% 40% 60% 80% 100%
Metastatic Urothelial Cancer - Second and
further lines, long responders to
immunotherapy
Metastatic Urothelial Cancer - Second and
further lines, immunotherapy regardless of
the number of cycles administered
Metastatic Urothelial Cancer - Second and
further lines, chemotherapy
Metastatic Urothelial Cancer - First Line,
after 4 cycles of platinum-based
chemotherapy
Metastatic Urothelial Cancer - First Line,
regardless of the number of cycles
administered
Yes
No
Figure 1E

14. GERM CELL TUMOURS
• Do you consider it appropriate to evaluate NOT starting
a systemic treatment in these clinical settings?
34
16
25
38
31
53
43
30
0% 20% 40% 60% 80% 100%
In all these cases, I would request an
opinion from a referral center
Stage I non seminoma - adjuvant
therapy; in case of vascular invasion
Stage I non seminoma - adjuvant
therapy; all cases
Stage I seminoma - adjuvant therapy
Yes
No
Figure 1F

15. GERM CELL TUMOURS
• Do you consider it appropriate to evaluate a delay in
treatment initiation in these clinical settings?
35
22
5
9
25
28
49
66
60
46
0% 20% 40% 60% 80% 100%
In all these cases I would request an
opinion from a referral center
Advanced disease - Second Line
Advanced disease - Poor prognosis
risk group
Advanced disease - Intermediate
prognosis risk group
Advanced disease - Good prognosis
risk group
Yes
No
Figure 1G

16. PROSTATE CANCER
• Do you consider it appropriate to evaluate a delay in
treatment initiation in these clinical settings?
50
56
15
25
21
15
56
47
0% 20% 40% 60% 80% 100%
Metastatic castration-resistant prostate
cancer – Second and further lines
Metastatic castration-resistant prostate
cancer – First Line, absence of visceral
disease and asymptomatic patient
Metastatic castration-resistant prostate
cancer – First Line, regardless of
disease characteristics
Newly diagnosed hormone-sensitive
metastatic prostate cancer – high
volume
Yes
No
Figure 1H

17. CLINICAL TRIALS
• Do you consider it appropriate to enrol patients in clinical
trials during the emergency period?
28, 39%
5, 7%
39, 54%
No, due to concerns
about logistics and
human resources
Yes, in all cases where
clinical trials are
available
Yes, for selected
patients and in case of
favourable logistics
Figure 1I

18. ORAL ANTICANCER THERAPY
• How are you managing patients receiving oral anticancer
drugs during this emergency period?
20
27
30
52
14
Drug interruption for patients who report toxicity at
telephone interview/mail conversation and update
through telephone interview/mail
Physical examination for patients who report toxicity at
telephone interview/mail conversation
Drug dispensation for more than one cycle of treatment
Telephone interview/Mail conversation + blood tests in
a lab near patient’s residence and drug dispensation
directly in the hospital pharmacy/home delivery
My clinical practice has not changed
0 10 20 30 40 50 60
Figure 1L
(20%)
(73%)
(42%)
(38%)
(28%)
Respondents

19. IMMUNOTHERAPY
• Do you consider it appropriate to evaluate treatment
interruption for patients receiving immunotherapy
during the emergency period?
7, 10%
2, 3%
6, 8%
33, 46%
20, 28%
4, 5% Yes, in case of prolonged complete
response
Yes, in case of prolonged partial
response
Yes, in case of prolonged complete
or partial response
Yes, but only evaluating case by
case in case of prolonged complete
or partial response
No, but I consider to «skip» some
cycle to reduce hospital visits
No, due to the lack of solid
evidence
Figure 1M

20. CHOICE OF TREATMENT
• What are the main factors that you consider in the choice
of treatment during this emergency period? (max 2
choices)
22
16
13
18
11
53
Number of required visits in the hospital
Route of administration (ev/os)
Toxicity
Quality of life benefit
Progression free survival benefit
Proven overall survival benefit
0 20 40 60
(31%)
(22%)
(18%)
(25%)
(15%)
(74%)
Figure 1N Respondents

21. FOLLOW-UP
• How are you managing follow-up of off-treatment
patients during this emergency period?
2, 3%
6, 8%
62, 86%
2, 3%
Follow-up visits are
continuing
Follow-up visits have been
reduced
Follow-up visits have been
cancelled and they are
carried out through
telephone/mail
Follow-up visits have been
cancelled and we are still
unable to carry follow-up in
an alternative way
Figure 1O

22. CHANGE IN CLINICAL PRACTICE
• To what extent has the public health emergency changed
your clinical practice? (0 = minimum; 10 = maximum)
0 0 0
1
4
7
12
17
21
10
1 2 3 4 5 6 7 8 9 10
0
5
10
15
20
25
Figure 1P

23. For TS.
Figures.
Please use sentence case throughout (no change to acronyms).
Ensure all data are legible/visible.
Change ‘max 2 choices’ to ‘max. two choices’.
Ensure one space between digits and opening bracket.
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24. Supplementary Table 1
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Supplementary file
RLE-D-20-00508_Suppl Table
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