Localized Prostate Cancer Management in the Time of COVID-19

The rapid spread of Coronavirus Disease 2019 (COVID-19) throughout the world, caused by the betacoronavirus SARS-CoV-2, has had dramatic effects on health care systems with impacts far beyond the patients actually infected with COVID-19. Patients who manifest severe forms of COVID-19 requiring respiratory support typically require this for prolonged durations, with a mean of 13 days of respiratory support reported by the China Medical Treatment Expert Group for COVID-19.1 This lengthy requirement for ventilator support and ICU resources, exacerbated by relatively little excess health system capacity to accommodate epidemics, means that health care systems can (and have in the case of many hospitals in Italy) become overwhelmed relatively quickly.

In an effort to conserve hospital resources, on March 13th the American College of Surgeons recommended that health systems, hospitals, and surgeons should attempt to minimize, postpone, or outright cancel electively scheduled operations.2 This was done with the primary goal to immediately decrease the use of items essential for the care of patients with COVID-19 including ICU beds, ventilators, personal protective equipment, and terminal cleaning supplies. On March 17th, the American College of Surgeon then provided further guidance on the triage of non-emergent surgeries, including an aggregate assessment of the risk incurred from surgical delays of six to eight weeks or more as compared to the risk (both to the patient and the health care system) of proceeding with the operation.3 In the UK, all non-urgent elective surgical procedures have been put on hold for three months to use all of those clinical resources to care for patients with COVID-19.

Most bodies, including the American College of Surgeons, have recommended proceeding with most cancer surgeries. Thus, clinicians and patients must carefully weigh the benefit of proceeding with cancer treatment as scheduled, the risks of COVID-19 to the individual patient, to health care workers caring for patients potentially infected with COVID-19, and the need to conserve health care resources. Work from China demonstrated that patients with cancer had a higher incidence of COVID-19 infection than expected in the general population and had a more severe manifestation of the disease with a significantly higher proportion requiring invasive ventilation in the ICU or death.4 Thus, considering the differences in the natural history of different cancers may meaningfully change this balance of risks and benefits.

For urologists, this is most notable for prostate cancer. From the collective experience with active surveillance, urologists know that delays in the definitive management of patients with low-risk prostate cancer are very rarely associated with adverse clinical outcomes.5 In 2015 at the Sunnybrook Hospital in Ontario, Canada, Klotz et al. reported a cohort of 993 men undergoing active surveillance which included men with both low-risk and some intermediate-risk disease. A total of 149 (15%) patients died with a median follow-up of 6.4 years (range 0.2 years to 19.8 years).6 As a result, overall survival was 80% at 10 years and 62% at 15 years. Of the 149 patients who died, only 15 (1.5%) deaths were due to prostate cancer. Thus, actuarial cause-specific survival is 98.1% at 10 years and 94.3% at 15 years. In addition to the 15 men who died of prostate cancer, an additional 13 (1.3%) men developed metastatic disease. Of these, nine men were alive with metastasis at the time of publication and four died of other causes.

However, in an updated analysis, Musunuru et al. found that the risk of metastasis-free survival (hazard ratio [HR] 3.14, 95% confidence interval [CI] 1.51 to 6.53) and prostate cancer-specific survival were worse for patients with intermediate-risk disease undergoing active surveillance compared to those with low-risk disease.7This appeared to be driven by tumor grade rather than PSA: 15-year metastasis-free survival was 94% in men with Gleason score 6 + PSA less than 10 ng/mL, 94% in men with Gleason score 6 + PSA 10 to 20 ng/mL, 84% in men with Gleason score 7 (3+4) + PSA less than 20 ng/mL, and 63% in men with Gleason score 7 (4+3) + PSA less than 20 ng/mL. Thus, it appears that for men with intermediate-risk disease (and presumably also for those with high-risk disease) there is a risk to the strategy of indefinitely deferring therapy.

Thus, in the setting of widespread community penetrance of COVID-19 and the need to conserve valuable health care resources, it is worthwhile to examine the role of curative-intent treatment in patients with prostate cancer. For context, it is worth noting that it took 22 years of follow-up in the Prostate Cancer Intervention Versus Observation Trial to demonstrate a statistically significant survival benefit to radical prostatectomy over observation.8 Thus, the survival benefit to any intervention should neither be over-estimated nor over-stated.

The National Comprehensive Cancer Network very recently published recommendations to guide the “Care of Prostate Cancer Patients During the COVID-19 Pandemic”. A discussion of these recommendations, as well as an assessment of the literature examining the effect of treatment delays in patients with prostate cancer, will comprise the remainder of this article.

In 2014, Bourgade and colleagues published a systematic review examining the “Impact of the length of time between diagnosis and surgical removal of urologic neoplasms on survival”.9Based on the literature available at that time, the authors concluded that the heterogeneous nature of prostate cancer meant that generalizable conclusions could not be drawn in routine care. They drew predominantly on three studies.

Assessing 3,149 patients treated with radical prostatectomy at a single center who all received treatment within one year, Vickers et al. found no clear evidence of an association between delays from prostate biopsy to surgery and biochemical recurrence at three, five, eight, or ten years following surgery, particularly among those treated within six months of diagnosis.10 However, the 95% confidence intervals were wide precluding definitive conclusions.

Similarly, Korets and colleagues examined 2,739 men who underwent radical prostatectomy at Columbia University.11 They stratified these men according to the time between biopsy and surgery: ≤60 days, 61-90 days, and >90 days. Durations longer than 60 days between biopsy and radical prostatectomy were not associated with adverse outcomes, including adverse pathology, biochemical recurrence or survival. Notably, this effect persisted across risk strata of localized prostate cancer (low-, intermediate-, and high-risk).

Examining only low-risk patients, van den Bergh et al. found no difference in histopathologic findings or biochemical recurrence whether patients were treated in the immediate group (mean 0.5 years following diagnosis) or in a delayed fashion (mean 2.6 years following diagnosis).12This should not be surprising given the known safety of active surveillance in patients with low-risk disease but suggests, at least in this cohort, that safe delays may be measured in years rather than days, weeks, or months.

A subsequent meta-analysis by van den Bergh and colleagues included 17 studies of which 13 assessed patients treated with radical prostatectomy, three studies assessed patients treated with radiotherapy, and one study assessed patients treated with either modality. While all were retrospective and non-randomized, the authors concluded that a treatment delay of several months or years is unlikely to affect treatment outcomes of men with low-risk prostate while limited data suggested that there may be an effect in men with intermediate- or high-risk prostate cancer.13

However, given changes in the risk characteristics of patients undergoing radical prostatectomy in 2020,14 much of these data is not applicable as few patients with low-risk disease undergo prostatectomy. Fortunately, newer studies provide some guidance.

In 2019, Gupta and colleagues published their analysis assessing the impact of the length of time from diagnosis to surgery in patients with unfavorable intermediate-risk prostate cancer, high-risk prostate cancer, and very high-risk clinically localized prostate cancer.15 The authors identified 2,303 men treated at The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University who underwent radical prostatectomy within six months following a diagnosis of Gleason Grade Group (GGG) ≥3 prostate cancer on biopsy. They examined differences in pathological outcomes at radical prostatectomy, uses of adjuvant therapy, biochemical recurrence-free survival and metastasis-free survival for patients who underwent surgery within three months of diagnosis compared to those treated three to six months following diagnosis.

Among the 2,303 included patients, 1,244 had GGG3 disease, 608 had GGG4 disease, and 451 had GGG5 disease. Seventy-two percent of included patients had surgery within three months of diagnosis while 28% had surgery between three to six months following diagnosis. Stratified by Gleason Grade Group, the authors found no significant differences in pathologic findings (positive surgical margins, extraprostatic extension, seminal vesicle invasion, of lymph node involvement) or use of adjuvant therapy between patients who received surgery within three months and those who received surgery three to six months following diagnosis. Similarly, there were no differences in two- or five-year biochemical recurrence-free survival or two-, five-, or 10-year metastasis-free survival between patients receiving earlier surgery and those who had delayed treatment when stratified by biopsy Gleason Grade Group.

Patel and colleagues found no increase in adverse pathologic findings (Gleason upgrading, extraprostatic extension, seminal vesicle invasion, positive surgical margins, or lymph node involvement) with delays of up to six months, regardless of preoperative risk stratification.16 Examining time intervals up to 180 days (six months) between diagnosis to radical prostatectomy, Aas et al. found no difference in prostate cancer-specific survival for patients according to the duration between diagnosis and treatment, including patients with intermediate-risk localized disease, high-risk localized disease, and high-risk locally advanced disease).17 Similarly, there was no difference in rates of upstaging, upgrading, or positive surgical margins.

Fossati and colleagues examined even longer durations of delay between diagnosis and surgery.18 Among 2,653 patients treated with radical prostatectomy at San Raffaele Hospital in Milan, the authors used non-parametric curve-fitting models to assess the relationship between the time from diagnosis to surgery and oncologic outcomes including biochemical recurrence and clinical recurrence. This analysis was performed in the whole cohort and then stratified by risk category. The median time from diagnosis to surgery was 2.8 months. Among all patients, the authors identified a significant association between the time to surgery and the risk of biochemical recurrence (HR 1.02, p = 0.0005) and clinical recurrence (HR 1.03, p=0.0002) though this relationship was non-linear. Utilizing non-parametric curve fitting, the authors identified that the risk of biochemical recurrence significantly increased with delays greater than 18 months. In sensitivity analyses, this effect was seen only in patients with high-risk disease. Among patients with high-risk disease, an increased risk of biochemical recurrence with pre-surgical delays exceeding 12 months.

However, others have found that safe delays may be considerably shorter. Berg et al. found that among their cohort (which was much less contemporary), the risk of adverse pathological findings increased beyond 150 days for patients with low-risk disease, 60 days for patients with intermediate-risk disease, and 30 days for patients with high-risk disease.19 Meunier and colleagues found that there was no identifiable threshold beyond which there was an increased risk of biochemical recurrence for patients with Gleason 6 disease while patients with Gleason 3+4 disease had an increased risk with delays greater than 90 days and those with Gleason ≥8 had an increased risk with delays greater than 60 days.20 In a single-center analysis from Montreal, Canada, Zanaty et al. found no significant association between the time to surgery and pathological outcomes, regardless of preoperative risk stratification.21 In the same cohort, the authors found no association between time to surgery and biochemical recurrence in men with low- and intermediate-risk disease.22 In patients with high-risk disease, they found a significant association with a threshold of around 90 days. However, a recent analysis from the Mayo Clinic suggested that patients with high-risk disease who waited more than six months without neoadjuvant androgen deprivation therapy had an increased risk of biochemical recurrence, though they did not assess shorter time intervals.23

Notably, early surgery (less than four or six weeks from diagnosis) has been associated with significantly higher rates of peri-operative complications22, 23 without differences in post-operative erectile function25 or urinary continence.26 Patients treated early following diagnosis were significantly less likely than those waiting at least 12 weeks to receiving nerve-sparing in a recent analysis from the Mayo Clinic.23

The analyses presented thus far have for the most part examined patients who underwent delays between diagnosis and definitive local therapy without any further treatment. However, neoadjuvant androgen deprivation therapy (ADT) may offer an option to temporize patients at high-risk of progression during forecast delays to definitive treatment. In a Cochrane systematic review and meta-analysis published in 2006, Kumar and colleagues examined outcomes of neoadjuvant ADT in patients with localized and locally advanced prostate cancer in randomized or quasi-randomized clinical trials.27 Neoadjuvant ADT prior to radical prostatectomy was associated with reduced rates of positive surgical margins (odds ratio 0.34, 95% CI 0.27 to 0.42) along with other pathologic characteristics. While there was a marginal benefit in terms of disease recurrence (odds ratio 0.74, 95% CI 0.55 to 1.00), there was no benefit in terms of prostate cancer-specific survival (odds ratio 0.99, 95% CI 0.75 to 1.32) or overall survival (odds ratio 1.11, 95% CI 0.67 to 1.85). While neoadjuvant ADT has not been routinely adopted on the basis of a failure to improve survival outcomes compared with early definitive treatment, in the current environment, these data may be viewed in another manner: neoadjuvant ADT may offer the ability to safely defer definitive intervention without compromising long term outcomes.

Synthesizing the available data, it is clear that patients with low-risk prostate cancer may defer definitive treatment nearly indefinitely. For patients with intermediate and high-risk disease, delays of three months and likely up to six months appear not to be associated with adverse pathologic outcomes, biochemical recurrence, or survival outcomes. Some data suggest that these intervals may be longer (up to 12 months in patients with high-risk disease).18 For patients at particularly high risk of progression or recurrence, the use of neoadjuvant ADT appears to allow for equivalent outcomes as an immediate intervention.

The recently published recommendations from the NCCN are consistent with these data. The NCCN panel recommended ceasing staging, investigation, and treatment of patients with very low-, low-, and favorable intermediate-risk disease until resolution of the COVID-19 pandemic. For patients with unfavorable intermediate-, high-, and very high-risk disease, the panel recommended deferring further staging and treatment with the specific note that delays of up to six months are unlikely to negative effect outcomes. The panel added a few considerations for patients considering radiotherapy: first, to forgo prophylactic whole pelvic radiotherapy due to increased risks of lymphopenia; second, to consider a period of four to six months of neoadjuvant ADT for patients with unfavorable intermediate- and high-risk disease to postpone the initiation of radiotherapy; and third, to use the shortest external beam radiotherapy regime possible, consisting of five to seven fractions. For patients with symptomatic prostate cancer, the panel recommended prioritizing conservative measures including ADT and clean intermittent catheterization over surgical or radiotherapy interventions. Finally, for patients who have previously undergone definitive treatment, post-treatment monitoring should be deferred or arranged through a telehealth approach.

In summary, the vast majority of patients with localized (and even locally advanced) prostate cancer can safely defer therapy for a period of time which should be sufficient to determine the extent and duration of the COVID-19 pandemic. Oncologic risks are rarely if ever are expected to supersede the risks to the individual patient, health care providers, and health care system of proceeding with prostate cancer treatment at this time.

Written by: Christopher J.D. Wallis, MD, PhD, Instructor in Urology, Vanderbilt University Medical Center, Nashville, Tennessee; Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Atlanta, Georgia

Related Content:
Download: Care of Prostate Cancer Patients During the COVID-19 Pandemic: Recommendations of the NCCN

Published Date: April 17th, 2020
Written by: Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
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