The Risks of Delaying Kidney Cancer Treatment During COVID-19

The rapid spread of Coronavirus Disease 2019 (COVID-19), caused by the betacoronavirus SARS-CoV-2, has had dramatic effects throughout the world on healthcare 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 healthcare 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 healthcare 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 healthcare workers caring for patients potentially infected with COVID-19, and the need to conserve health care resources. A severe SARS-CoV-2 phenotype is seen more commonly in men and older, more comorbid patients.4 Baseline characteristics among 1,591 patients admitted to the ICU in the Lombardy Region, Italy, showed that the median age was 63 years (IQR 56-70), 82% were male, 68% had ≥1 comorbidity, 88% required ventilator support, and the mortality rate was 26%, with a large proportion requiring ongoing ICU level care at the time of data cut-off.5 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.6 Patients at increased risk of COVID-19 are comparable to the kidney cancer population, namely more likely male, hypertensive, and with more than one comorbidity.5

Thus, considering the differences in the natural history of different cancers may meaningfully change this balance of risks and benefits. Kidney cancer has a wide range of phenotypic presentations ranging from very indolent, incidentally diagnosed small renal masses to large, symptomatic tumors with vascular or adjacent organ invasion and de novo metastatic disease. Previous articles in the UroToday Kidney Cancer Today Center of Excellence have discussed the Epidemiology and Etiology of Kidney Cancer and particular nuances of staging and management for Malignant Renal Tumors. The vast majority of patients have localized disease at the time of presentation. According to Siegel et al., 65% of all patients diagnosed with kidney and renal pelvis tumors between 2007 and 2013 had localized disease at the time of presentation while 16% had regional spread, and 16% had evidence of distant, metastatic disease.7

While the effect of delays in surgical intervention has been most thoroughly explored in muscle-invasive bladder cancer and prostate cancer in the urologic literature, both data and inference may help guide the management of patients with kidney cancer at this time. A single previous narrative review has assessed this question,8 however, conclusions from this study are limited. In the absence of data, the guidance of care relies on expert opinion, including a collaborative review pre-published in European Urology (Wallis et al.). This article will discuss the impact of potential delays among patients with kidney cancer, providing recommendations as to who can safely defer treatment until after the pandemic is over versus those that should be treated without delay.

While there are no randomized data, numerous institutional studies have demonstrated both the safety and feasibility of active surveillance (AS) with delayed intervention in patients with small renal masses (SRMs).9,10

Among 457 patients treated at Fox Chase Cancer Center, McIntosh et al. found that rates of delayed intervention were 9%, 22%, 29%, 35%, and 42% at one-, two-, three-, four-, and five-years following diagnosis.11 Importantly, delayed intervention was not associated with overall survival (OS) (hazard ratio [HR] 1.34, 95% confidence interval [CI] 0.79-2.29), and of the 99 patients on AS without delayed intervention for more than five years, only one patient metastasized. Interestingly, they found a median initial linear growth rate was 1.9 mm/year (IQR 0-7) which was not associated with OS.

Data from the University of Michigan has also assessed the effect of delayed resection (at least six months from presentation) after initial surveillance for patients with SRMs.12 In this study, there were 401 patients that underwent early resection and 94 patients (19%) that underwent delayed resection. The median time to resection was 84 days (IQR 59-121) in the early intervention group and 386 days (IQR 272-702) in the delayed intervention group. Importantly, there was no difference in adverse final pathology (grade 3-4, papillary type 2, sarcomatoid histology, angiomyolipoma with epithelioid features, or stage ≥ pT3) comparing those that underwent early vs late intervention.

Among 497 patients in the DISSRM registry, 223 (43%) chose AS and 274 (57%) chose primary intervention with 21 (9%) eventually undergoing delayed intervention after a period of AS. There was no difference in cancer-specific survival (CSS) at five-years between the groups (primary intervention: 99%; AS 100%, p=0.3) though patients choosing surveillance had lower five-year OS (75% vs 92%), likely attributable to comorbidity which drove their initial selection of surveillance.

Taken together, there is robust data supporting AS for masses < 4cm, even up to five years after the initial diagnosis, without age restriction.13,14 Thus, delays in the diagnosis and management of these patients during the COVID-19 pandemic is unlikely to meaningfully affect their outcomes.

Although the data is less robust, several studies have assessed the impact of a surgical delay for larger localized kidney tumors (≥pT1b). An institutional cohort from Memorial Sloan Kettering Cancer Center examined 1,278 patients who underwent radical or partial nephrectomy with renal masses > 4 cm between 1995 and 2013. The authors tested the association between surgical wait time and disease upstaging at the time of surgery, as well as two- and five-year recurrence rates.15 Among these patients, 267 (21%) had a surgical wait time of more than three months, including 82 patients (6%) with a wait time of more than six months. On multivariable analysis, the surgical wait time was not associated with disease upstaging, recurrence or CSS, but longer wait time was associated with worse OS (HR 1.17, 95% CI 1.08-1.27), potentially reflecting comorbidity which necessitated the initial delays.

Similarly, an institutional cohort from the Fox Chase Cancer Center of patients with cT1b/cT2 renal masses assessed the safety of active surveillance.16 Twenty-three patients (34%) underwent delayed intervention. Over a median follow-up of 32 months (range 6-119), no patients progressed to metastatic disease or died of kidney cancer. The median linear growth rate was 0.34 cm/year (range 0-1.48) suggesting that delays of months to years are unlikely to affect the resectability of these tumors.

Finally, a retrospective review of 722 patients undergoing partial or radical nephrectomy for relatively large kidney tumors (mean tumor size of 6.4 +/- 4.4cm; 64.7% ≥pT1b and 49.0% ≥pT2) from Stec et al. assessed the effect of delays to surgery on survival.17 They found that the mean time from initial visit to surgery was 1.2 months (range 0-30 months) and that 64.1% of patients underwent surgery within 30 days of initial visit and 94.3% within three months. The authors found no difference in OS for patients receiving early vs. late surgery, whether using a threshold of one month (p=0.87), two months (p=0.46), three months (p=0.71), or six months (p=0.75). However, T-stage was a significant predictor of recurrence-free survival (RFS), independent of time to surgery.

There are essentially no available data on the effect of delays in treating patients with locally advanced kidney cancer. However, several large institutional studies have described timing of preoperative imaging for assessing renal vein/inferior vena cava (IVC) thrombus, which may guide the urgency of surgical timing. While Woodruff et al. recommended the longest interval between imaging (CT/MRI) and surgery being no longer than 30 days,18 studies from the Mayo Clinic and Berlin, Germany report a median interval from imaging to resection of 4 and 16 days, respectively.19,20 As a result, the collaborative review pre-published in European Urology suggested that these patients should be prioritized for intervention given the locally advanced nature of their disease, unknown risk of delayed resection, and potential for significant symptomatic complications including bleeding and IVC occlusion.

In contrast, in patients with known metastatic kidney cancer, cytoreductive nephrectomy during the ongoing pandemic was not recommended in this collaborative review on account of the evidence from the CARMENA trial which failed to demonstrate a survival benefit to the addition of cytoreductive to systemic therapy with sunitinib.21 Additionally, the SURTIME trial found that upfront systemic therapy followed by cytoreductive nephrectomy was associated with longer survival than patients who received upfront cytoreduction followed by systemic therapy.22

The question of when to initiate systemic therapy in patients with metastatic kidney cancer is also pertinent during this pandemic and depends on symptoms, patient comorbidities, and tumor risk stratification. In treatment-naïve patients with favorable and intermediate-risk disease who are asymptomatic or minimally symptomatic with limited disease burden, a number of studies, including two narrative reviews23,24 and two prospective trials,25,26 have assessed the safety and feasibility of delaying the initiation of systemic therapy. In the largest prospective study of surveillance in patients with metastatic kidney cancer, Rini et al. enrolled fifty-two asymptomatic patients in a Phase II trial.26 All but one patient had favorable (23%) or intermediate (75%) risk disease according to IMDC criteria with the vast majority (80%) of patients having only one or two organ sites with metastases. The median time on surveillance was 14.9 months and 37 of 43 patients experiencing RECIST-defined disease progression started systemic treatment. The median PFS and OS from the start of surveillance was 9.4 and 44.5 months, respectively. In a smaller study of 15 patients who received CN followed by observation until progression, Wong et al. found a median time to progression of eight weeks and a median OS of 25 months.25 Neither of these studies have compared outcomes with patients who started systemic therapy upfront. However, this has been assessed in two large retrospective studies. Among a European cohort of patients ineligible for active surveillance, Iacovelli and colleagues found that a delay of more than six weeks in the initiation of systemic therapy did not significantly affect the cancer-specific outcomes.27 Further, delayed treatment initiation was not independently associated with worse OS in an analysis based on the National Cancer Database utilizing multivariable logistic regression analyses.28

There is no evidence to guide the choice of systemic therapy during the COVID-19 pandemic and thus, standard guideline recommendations should prevail. However, at least theoretically, the risk of severe adverse reactions associated with immunotherapy using checkpoint inhibitors, as well as the requirement for infusion, may preferentially support the use of VEGF-targeted therapy with the convenience of oral administration.

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

Written by: Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
References: 1. Guan, Wei-jie, Zheng-yi Ni, Yu Hu, Wen-hua Liang, Chun-quan Ou, Jian-xing He, Lei Liu et al. "Clinical characteristics of coronavirus disease 2019 in China." New England Journal of Medicine (2020).
2. March 13, Online, and 2020. “COVID-19: Recommendations for Management of Elective Surgical Procedures.” American College of Surgeons. Accessed April 20, 2020.
3. March 17, Online, and 2020. “COVID-19: Guidance for Triage of Non-Emergent Surgical Procedures.” American College of Surgeons. Accessed April 20, 2020.
4.COVID, CDC, and Response Team. "Severe outcomes among patients with coronavirus disease 2019 (COVID-19)—United States, February 12–March 16, 2020." MMWR Morb Mortal Wkly Rep 69, no. 12 (2020): 343-346.
5. Grasselli, Giacomo, Alberto Zangrillo, Alberto Zanella, Massimo Antonelli, Luca Cabrini, Antonio Castelli, Danilo Cereda et al. "Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy." JAMA (2020).
6. Liang, Wenhua, Weijie Guan, Ruchong Chen, Wei Wang, Jianfu Li, Ke Xu, Caichen Li et al. "Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China." The Lancet Oncology 21, no. 3 (2020): 335-337.
7. Siegel, Rebecca L., and Kimberly D. Miller. "Jemal A (2018) cancer statistics." Ca Cancer J Clin 68, no. 1 (2018): 7-30.
8. Bourgade, Vincent, Sarah J. Drouin, David R. Yates, Jerôme Parra, Marc-Olivier Bitker, Olivier Cussenot, and Morgan Rouprêt. "Impact of the length of time between diagnosis and surgical removal of urologic neoplasms on survival." World journal of urology 32, no. 2 (2014): 475-479.
9. Mir, Maria Carmen, Umberto Capitanio, Riccardo Bertolo, Idir Ouzaid, Maciej Salagierski, Maximilian Kriegmair, Alessandro Volpe, Michael AS Jewett, Alexander Kutikov, and Phillip M. Pierorazio. "Role of active surveillance for localized small renal masses." European urology oncology 1, no. 3 (2018): 177-187.
10. Sanchez, Alejandro, Adam S. Feldman, and A. Ari Hakimi. "Current management of small renal masses, including patient selection, renal tumor biopsy, active surveillance, and thermal ablation." Journal of Clinical Oncology 36, no. 36 (2018): 3591.
11. McIntosh, Andrew G., Benjamin T. Ristau, Karen Ruth, Rachel Jennings, Eric Ross, Marc C. Smaldone, David YT Chen et al. "Active surveillance for localized renal masses: tumor growth, delayed intervention rates, and> 5-yr clinical outcomes." European urology 74, no. 2 (2018): 157-164.
12. Hawken, Scott R., Naveen K. Krishnan, Sapan N. Ambani, Jeffrey S. Montgomery, Elaine M. Caoili, James H. Ellis, Lakshmi P. Kunju et al. "Effect of delayed resection after initial surveillance and tumor growth rate on final surgical pathology in patients with small renal masses (SRMs)." In Urologic Oncology: Seminars and Original Investigations, vol. 34, no. 11, pp. 486-e9. Elsevier, 2016.
13. Kutikov, Alexander. "Surveillance of Small Renal Masses in Young Patients: A Viable Option in the Appropriate Candidate." European urology focus 2, no. 6 (2016): 567-568.
14. Pierorazio, Phillip M., Michael H. Johnson, Mark W. Ball, Michael A. Gorin, Bruce J. Trock, Peter Chang, Andrew A. Wagner, James M. McKiernan, and Mohamad E. Allaf. "Five-year analysis of a multi-institutional prospective clinical trial of delayed intervention and surveillance for small renal masses: the DISSRM registry." European urology 68, no. 3 (2015): 408-415.
15. Mano, Roy, Emily A. Vertosick, Abraham Ari Hakimi, Itay A. Sternberg, Daniel D. Sjoberg, Melanie Bernstein, Guido Dalbagni, Jonathan A. Coleman, and Paul Russo. "The effect of delaying nephrectomy on oncologic outcomes in patients with renal tumors greater than 4 cm." In Urologic Oncology: Seminars and Original Investigations, vol. 34, no. 5, pp. 239-e1. Elsevier, 2016.
16. Mehrazin, Reza, Marc C. Smaldone, Alexander Kutikov, Tianyu Li, Jeffrey J. Tomaszewski, Daniel J. Canter, Rosalia Viterbo, Richard E. Greenberg, David YT Chen, and Robert G. Uzzo. "Growth kinetics and short-term outcomes of cT1b and cT2 renal masses under active surveillance." The Journal of urology 192, no. 3 (2014): 659-664.
17. Stec, Andrew A., Benjamin J. Coons, Sam S. Chang, Michael S. Cookson, S. Duke Herrell, Joseph A. Smith Jr, and Peter E. Clark. "Waiting time from initial urological consultation to nephrectomy for renal cell carcinoma—does it affect survival?." The Journal of urology 179, no. 6 (2008): 2152-2157.
18. Woodruff, Daniel Y., Peter Van Veldhuizen, Gregory Muehlebach, Phillip Johnson, Timothy Williamson, and Jeffrey M. Holzbeierlein. "The perioperative management of an inferior vena caval tumor thrombus in patients with renal cell carcinoma." In Urologic Oncology: Seminars and Original Investigations, vol. 31, no. 5, pp. 517-521. Elsevier, 2013.
19. Psutka, Sarah P., Stephen A. Boorjian, Robert H. Thompson, Grant D. Schmit, John J. Schmitz, Thomas C. Bower, Suzanne B. Stewart, Christine M. Lohse, John C. Cheville, and Bradley C. Leibovich. "Clinical and radiographic predictors of the need for inferior vena cava resection during nephrectomy for patients with renal cell carcinoma and caval tumour thrombus." BJU international 116, no. 3 (2015): 388-396.
20. Adams, Lisa C., Bernhard Ralla, Yi-Na Y. Bender, Keno Bressem, Bernd Hamm, Jonas Busch, Florian Fuller, and Marcus R. Makowski. "Renal cell carcinoma with venous extension: prediction of inferior vena cava wall invasion by MRI." Cancer Imaging 18, no. 1 (2018): 17.
19. Méjean, Arnaud, Alain Ravaud, Simon Thezenas, Sandra Colas, Jean-Baptiste Beauval, Karim Bensalah, Lionnel Geoffrois et al. "Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma." New England Journal of Medicine 379, no. 5 (2018): 417-427.
21. Bex, Axel, Peter Mulders, Michael Jewett, John Wagstaff, Johannes V. Van Thienen, Christian U. Blank, Roland Van Velthoven et al. "Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial." JAMA oncology 5, no. 2 (2019): 164-170.
23. Pickering, Lisa M., Mohammed O. Mahgoub, and Deborah Mukherji. "Is observation a valid strategy in metastatic renal cell carcinoma?." Current opinion in urology 25, no. 5 (2015): 390-394.
24. Nizam, Amanda, Jonah A. Schindelheim, and Moshe C. Ornstein. "The role of active surveillance and cytoreductive nephrectomy in metastatic renal cell carcinoma." Cancer Treatment and Research Communications (2020): 100169.
25. Wong, Alvin S., Kian-Tai Chong, Chin-Tiong Heng, David T. Consigliere, Kesavan Esuvaranathan, Khai-Lee Toh, Benjamin Chuah, Robert Lim, and James Tan. "Debulking nephrectomy followed by a “watch and wait” approach in metastatic renal cell carcinoma." In Urologic Oncology: Seminars and Original Investigations, vol. 27, no. 2, pp. 149-154. Elsevier, 2009.
26. Rini, Brian I., Tanya B. Dorff, Paul Elson, Cristina Suarez Rodriguez, Dale Shepard, Laura Wood, Jordi Humbert et al. "Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial." The Lancet Oncology 17, no. 9 (2016): 1317-1324.
27. Iacovelli, Roberto, Luca Galli, Ugo De Giorgi, Camillo Porta, Franco Nolè, Paolo Zucali, Roberto Sabbatini et al. "The effect of a treatment delay on outcome in metastatic renal cell carcinoma." In Urologic Oncology: Seminars and Original Investigations, vol. 37, no. 8, pp. 529-e1. Elsevier, 2019.
28. Woldu, Solomon L., Justin T. Matulay, Timothy N. Clinton, Nirmish Singla, Yuval Freifeld, Oner Sanli, Laura-Maria Krabbe et al. "Incidence and outcomes of delayed targeted therapy after cytoreductive nephrectomy for metastatic renal-cell carcinoma: a nationwide cancer registry study." Clinical genitourinary cancer 16, no. 6 (2018): e1221-e1235.