Prostate cancer management challenges due to COVID-19 in countries with low-to-middle-income economies: A radiation oncology perspective Desafíos de los países con economías de bajo-a-mediano ingreso para el manejo del cáncer de próstata por la pandemia por COVID-19: La perspectiva del Oncólogo Radioterápico

Description: The COVID-19 pandemic poses an unprecedented challenge for urologic oncology and radiotherapy. Radiation oncology departments and international collaboration groups are sharing their management adaptations made in response to the pandemic. The present narrative review summarizes the current recommendations. Relevance: There is a need to define which patients are candidates for safe treatment delay until the pandemic is over or controlled, to reduce exposure to the virus in the healthcare personnel and patients. Conclusions: Telemedicine is recommended for follow-up visits. Active surveillance is the preferred treatment for patients with favorable intermediate risk. In greater risk disease, hormone therapy safely postpones radiotherapy up to 7 months. Radiosurgery is suggested in centers that have the necessary technology and previous experience. A moderately hypofractionated regimen is recommended if radiosurgery/ultra-hypofractionation is not available. Hypofractionation should be implemented if image-guided radiation therapy is already in place. Countries with low and middle-income economies face challenges in adopting the recommendations for prostate cancer management during the pandemic. Postponing treatment may result in the overwhelming of radiation oncology center capacity, after the pandemic.


Introduction
From the time the first patient was diagnosed with SARS-CoV-2 in Wuhan, China, incidence rates have risen rapidly in countries all over the world. (1) The current SARS-CoV-2 pandemic poses an unprecedented challenge for cancer management. Cancer patients have become a highly vulnerable population during the pandemic. (2) Oncologists need to ensure a safer approach and direct strategies to prevent the exposure of patients to the virus, while continuing to manage oncologic disease. (3) Of the cancer treatment services, radiotherapy faces a unique challenge in managing cancer patients during the pandemic, given that a majority of treatments need to be delivered daily.
There are unique radiotherapeutic considerations in the management of prostate cancer. Overall prognosis is generally favorable, enabling the delay of radiation in a selected population, in times of crisis. (4,5) Prostate cancer is the most common cancer in men. Although countries with high-income economies (HIEs) report higher incidence rates than countries with low and middle-income economies (LMIEs), the latter have higher mortality-to-incidence ratios. (6,7) Because more cases are diagnosed in the late stage of disease, radiation treatment is fundamental in the management of those patients. (8) There is a pressing demand to define which patients require urgent or nonurgent treatment (including a 2 to 4-month delay), until the pandemic is over, or at least controlled. (9,10) The development of novel public health protocols and the consequent modification of cancer centers are both a challenge and an opportunity. Global initiatives to ensure adequate prostate cancer treatment are arising in response to the COVID-19 pandemic. (11,12) Nevertheless, health systems and cancer care facilities in the countries with LMIEs have particularities that need to be considered when providing a recommendation for oncology care, in response to SARS-CoV-2.
We summarize herein the available radiation therapy recommendations for prostate cancer during the pandemic and provide recommendations for their implementation in radiation oncology centers in countries with (LMIEs).

Methods
We conducted a search in the PubMed electronic database (via Medline) on April 11, 2020

Results
Of the 2231 screened titles and abstracts, seven articles were selected. The analyses reviewed included 2 studies from international collaborations (multi-continent), (10,11) 1 national oncology guideline from Spain, (12) 2 national collaborations from Europe (Germany n=1, Italy n=1). (13,14) The remaining articles were institutional recommendations from two European countries (Switzerland and Italy). (15,16) No LMIE-based study met our inclusion criteria.
Of the studies included, only two exclusively addressed prostate cancer. (11,12) General recommendations for facing the pandemic were also provided by all studies and are summarized in Table 1.     NCCN. (30) Fx: Fraction, N+, regional lymph node involvement, PSA: Prostate-Specific Antigen.
* Post-prostatectomy, fossa only Finally, we presented a summary of treatment recommendations focusing on LMIE populations (Figure 1). It includes general recommendations, stage group-specific recommendations, and follow-up consultation guidance (Telemedicine). Overall, telemedicine for follow-up and in-treatment visits is being implemented. (11,15) Telemedicine has previously been described as an effective alternative in prostate cancer for follow-up visits (31)  practice. (9,11,15,35) Prostate cancer is unique, as its usual progression permits safe treatment delay. Disease staging (risk groups) is critical for defining the suitability of the patient for treatment delay or postponement that will not compromise the oncologic outcome. In early-stage disease, current practice promotes active surveillance as the preferred treatment in very low and low-risk disease ( Table 2). (18) Although current guidelines do not have a preferred treatment during the pandemic in relation to favorable intermediate-risk disease, active surveillance is being adopted as the recommended modality, given that it has previously been shown to be a safe approach. (11)(12)(13)19) Because active surveillance requires periodic prostate-specific antigen (PSA) testing, patients should be referred to laboratories and centers that are less busy, to minimize their risks for exposure and infection.
Recommendations for advanced disease are particularly relevant in countries with LMIEs, where most patients are diagnosed in later disease stages and radical treatment is almost always imperative. (7,36) For unfavorable and high-risk disease, radical treatment with radical prostatectomy or radiotherapy is usually required. Androgen deprivation therapy can be used to delay the start of said treatment.
Recommendations for the duration of neoadjuvant ADT vary, with a maximum acceptable delay of 6 to 7 months, based on the previously published RTOG 9910 trial. (37) Because a delay of 7 months is safe, schedules that reduce the number of hospital visits, such as 6-month subcutaneous delivery systems, are preferred. (38,39) The availability of ADT could be more challenging in low-resource settings. We recommend that professionals keep a record of postponed treatments and ensure that all patients are safely getting the proper ADT doses.
Even before the current pandemic, radiotherapy for prostate cancer was developing towards hypofractionated schedules. (40,41) During the SARS-CoV2 pandemic, that has become more relevant, so that the exposure of patients and medical staff to the virus can be reduced. (11)(12)(13)(14)16) Ultra-hypofractionated radiotherapy is preferred for localized disease in the new recommendations (Table 3). (11)(12)(13)(14) Only two of the authors included in the review assessed the possible lack of technology and considered a 20-fraction regimen that could be used in centers with no image-guided radiation therapy (IGRT) or previous experience in ultra-hypofractionation. (12,13) Very few radiotherapy centers in countries with LMIEs have the technologic capacity and the necessary devices to administer ultra-hypofractionation in prostate cancer. (42) Furthermore, the use of non-modulated three-dimensional conformal radiation therapy (3D-CRT) is not supported for the delivery of moderate hypofractionation. We believe hypofractionated schedules should be started if IGRT capacities are already in place, (43) but even though hypofractionation is beneficial in reducing the number of hospital visits, it should not be implemented in centers that do not have previous experience or when high treatment conformation cannot be guaranteed. (12,13) If IGRT is available, moderate hypofractionation is now more feasible in radiation oncology centers in countries with LMIEs.
Hypofractionation should be a priority in those countries, not only during the present situation but afterwards, as well, because it enables broader machine availability and increases the capacity of the radiation oncology services. (44) The adoption of the recommendations presented herein involves treatment postponement for most prostate cancer patients. Thus, after the crisis, the capacity of radiation therapy facilities may be overwhelmed. (11,45) That situation becomes even more challenging in LMIE settings that have lower machine capacity and human workforce per capita, with one linear accelerator for 5 million inhabitants, compared with one for every 120,000 inhabitants in countries with HIEs. (44,46) We suggest the following key points for implementing the newly formulated recommendations for prostate cancer during the pandemic in countries with LMIEs: