While so much of the medical community has focused its attention on treating and caring for patients with the coronavirus disease 2019 (COVID-19), the unfortunate truth is that the need for quality and compassionate cancer care continues.

, we spoke with David R. Gandara, MD, director of the thoracic oncology program and senior adviser to the director of the University of California Davis Comprehensive Cancer Center, about the impact of the pandemic on the current management and treatment of patients with lung cancer, as well as the future of patient care in a post–COVID-19 world.

“What has happened has dramatically changed how we practice, how we interact with lung cancer patients,” says Gandara. “But it hasn’t altered the basic premise that lung cancer is now a highly treatable disease.”

Gandara also looks ahead at how the current state of virtual interactions in medical education might persist once the pandemic has passed. “I actually hope some long-term changes will occur in both cancer care and education,” says Gandara. “Attendees, virtual attendees, will be able to select what sessions they tune into and which they don’t. I think this will change the face of [continuing medical education].” 

Also in this issue, you will read about how Judd W. Moul, MD, and his colleagues at the Duke Cancer Institute are managing their care of surgical patients with prostate cancer in the face of the COVID-19 pandemic. Moul’s report, along with expert commentary from Eric A. Klein, MD, regarding his experience at the Cleveland Clinic, attests to the ability of oncologists, and the medical community at large, to adapt and continue to provide expert care in the face of unprecedented challenges.

For this month’s clinical quandary, you will read about the case of a 56-year-old man with immune-mediated adverse events involving multiple organ sites. How do we resolve this? Read on to find out.

Within these pages, you will also find a review of novel neoadjuvant treatment strategies for triple-negative breast cancer, a roundup of some of the recently released abstracts from the Society of Gynecologic Oncology 2020 Annual Meeting on Women’s Cancer, and an Image IQ to test your knowledge of hematological malignancies.

I hope you find our journal helpful in caring for your patients through what is likely one of the most challenging times in their lives. As always, thank you for reading.

Articles

Navigating Uncharted Waters

The coronavirus disease 2019 (COVID-19) pandemic is affecting every aspect of medical care worldwide. Our patients with an oncologic diagnosis are among the most vulnerable populations. In addition, oncology patients often have other known risk factors, such as advanced age and other comorbidities, that put them at the greatest risk for COVID-19 complications should they become infected.  Although few data are published yet, results from the experience in Wuhan, China, demonstrated that patients with cancer who were infected with COVID-19 had increased complications and mortality.

 In this study population, 28 patients with COVID-19 infection had a median age of 65 years (range, 56-70 years) and lung cancer was the most frequent diagnosis (25%). A total of 15 (53.6%) patients had severe events and the death rate was 28.6%. The risk of developing severe events was even greater if the last antitumor treatment was given within 14 days of hospitalization.  

Given this information, most cancer centers have taken drastic steps to modify the risk of COVID-19 infection in our oncology patients and medical staff. As a result, many nonurgent visits in medical, surgical, and radiation oncology subspecialties are being conducted by telehealth. It is estimated that up to 60% to 70% of physician visits are not being performed in person during this time of the pandemic. In addition, chemotherapy sessions or oncologic surgery that require inpatient hospital care are also being evaluated carefully to decrease volume and create hospital capacity for symptomatic patients with COVID-19 infection. We have now become very familiar with online meetings, which work surprisingly well, and in some ways allow increased participation from healthcare workers who may be at several different sites or at home. At many centers, basic research laboratories are closed and clinical research is reduced to include only critical protocols open for our patients with cancer.  

Some areas of the country, such as New York City, have gone through a peak time of infection and the incidence of cases and hospitalizations are decreasing. However, other areas of the country, such as the less-populated areas and rural areas, are still experiencing a slow increase in the number of cases and hospitalizations. Each area should be considered separately with respect to oncology preparations and needs. Another concern for all oncology providers is that we may experience secondary peaks of COVID-19 activity over the upcoming weeks to months following the first peak of infection. It will be very difficult for patients who need oncologic care to wait much longer, and oncology practices need to keep financially solvent.  

Are there any positive outcomes from this pandemic? We can hope that the use of telehealth will continue for appropriate patients even after this crisis passes. Telehealth visits can be a viable option for some patients as long as the amount of revenue for these visits continues to be the same for in-person visits. Another positive aspect of this pandemic is that health care providers are able to cross state lines to help bolster health care workers in another state. We are certainly learning a great deal about working efficiently and trying to maximize the tests and treatments we have available. This pandemic has also brought out the importance of sharing  information worldwide to assist each other against a common enemy.

As oncology health care providers, we must all work together to help our patients get the treatment and active follow-up they need. Perhaps we can use this time to improve and focus oncology care and research for the benefit of our patients.

1. 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. 2020 (in press);S0923-7534(20)36383-3. doi:10.1016/j.annonc.2020.03.296.

Editor in chief Julie M. Vose, MD, MBA discusses the difficulties of treating and caring for patients with cancer during the COVID-19 pandemic.

Fighting 2 Enemies: Cancer and COVID-19

The  coronavirus disease 2019 (COVID-19) pandemic has rapidly placed tremendous stress on health systems around the world. In response, multiple health systems have postponed elective surgeries in order to conserve hospital beds and personal protective equipment, minimize patient traffic, and prevent unnecessary utilization and exposure of health care workers. The American College of Surgeons released the following statement on March 13, 2020: “Each hospital, health system and surgeon should thoughtfully review all scheduled elective procedures with a plan to minimize, postpone, or cancel electively scheduled operations, endoscopies or other invasive procedures until we have passed the predicted inflection point in the exposure graph and can be confident that our health care infrastructure can support a potentially rapid and overwhelming uptick in critical patient care needs."Within this current COVID-19 environment, we outline our approach to stratifyingsurgical management of prostate cancer here at Duke University Hospital.

The  coronavirus disease 2019 (COVID-19) pandemic has rapidly placed tremendous stress on health systems around the world. In response, multiple health systems have postponed elective surgeries in order to conserve hospital beds and personal protective equipment, minimize patient traffic, and prevent unnecessary utilization and exposure of health care workers.

 The American College of Surgeons released the following statement on March 13, 2020: “Each hospital, health system and surgeon should thoughtfully review all scheduled elective procedures with a plan to minimize, postpone, or cancel electively scheduled operations, endoscopies or other invasive procedures until we have passed the predicted inflection point in the exposure graph and can be confident that our health care infrastructure can support a potentially rapid and overwhelming uptick in critical patient care needs.”

In our state, North Carolina, Governor Roy Cooper requested that all hospitals postpone elective and nonurgent procedures and surgeries effective March 23, 2020.

Aside from clear-cut examples of immediately life-threatening versus truly elective cases, most procedures exist on a continuum of potential harm that may result from postponing surgical treatment. This is particularly germane to surgeries for cancer, in which long-term outcomes are often dependent on timely intervention. In urology, considerations regarding case stratification have been published to help guide our review processes.

 However, ultimately, this process needs to be customized to the level of COVID-19 severity in each region. The goal is to remain vigilant and prepared for the population-level risk of COVID-19, but to reasonably ration available resources to treat non–COVID-19 diseases that threaten our patients. 

In North Carolina, testing-confirmed COVID-19 case numbers and hospital resources are illustrated in the 

. At this point (as of April 9, 2020), case numbers in North Carolina are rising but lag behind those of the main US epicenters; hospital resources remain relatively well preserved.

Within this current COVID-19 environment, we outline our approach to stratifying surgical management of prostate cancer here at Duke University Hospital. 

The diagnosis and management of adenocarcinoma of the prostate, or prostate cancer (PC), have been and remain controversial during the best of times, but the COVID-19 pandemic certainly adds fuel to the fire. Providing safe and appropriate care requires a nuanced approach. Fortunately, risk stratification of the severity of localized and advanced PC has been in practice for many years and is being used now to its full extent to triage prostate cancer patients for surgical care. 

Traditionally, PC had been placed into 3 risk groups as defined by D’Amico et al: low, intermediate, and high risk. These were later adopted by major professional organizations, including the American Urological Association, National Comprehensive Cancer Network, and American Society of Clinical Oncology.

 These organizations have relied on American Joint Committee for Cancer for the backbone stage groups

 In 2020, most experts use a classification of 5 risk groups for localized prostate cancer (

). The boxed areas are the two highest categories of high and very high risk disease.  Men in these two groups at our center have been considered to move forward with scheduled surgery during the COVID-19 pandemic subject to local hospital considerations regarding the severity of COVID and would be the first patients to be rescheduled for surgery once the COVID pandemic subsides. In our risk schema, we have reverted to the traditional 3 risk group system collapsing very low and low risk and combining high and very high risk.

The staffs of the Duke Cancer Institute Center for Prostate and Urologic Cancers, working with the Duke Cancer Center’s surgeon-in-chief and his office, developed a COVID-19 triage table (

) to help our teams make prudent and consistent decisions about prostate cancer surgeries during the pandemic surge for as long as local conditions dictate. This schema also stratifies patients for clinic visits and procedures. Currently, our timelines for care are:

Importantly, when this is communicated to patients, it must be made clear that these timelines are approximate and likely will change. If COVID-19 worsens, the timelines will shift to incorporate significantly longer delays.

To further illustrate the process for triage of localized prostate cancer at our center, we offer several specific surgery case examples. With these, we hope to help practicing urologic oncologists to make triage and treatment recommendations for their patients. 

Judd Moul, MD, FACS harnesses his prior military experience and uses this knowledge in concert with his colleagues at Duke to provide risk stratification in order to triage the care of men with prostate cancer during this current pandemic. As he points out the treatment of all stages of prostate cancer, particularly early prostate cancer remains controversial. The current challenges and limitations of care posed by the COVID-19 pandemic has further highlighted these controversies.

I applaud Moul and his associates for educating us in this very difficult time.

involves a high-risk 62-year-old African American man with a prostate-specific antigen (PSA) measurement higher than 20. We contemplated moving forward with his case but instead decided to postpone surgery and start androgen deprivation therapy (ADT) with leuprolide at a 45-mg 6-month depot dose. This decision was due to several factors, including his very large prostate gland (measuring more than 100 cc), the possibility of a narrow pelvis due to his ethnicity, and prior pelvic surgery. We surmised that his case, as treated at our center, could be more difficult as compared with an average overnight admission for open or robotic radical prostatectomy (RP), with potentially more bleeding and more use of health care resources. Based on the literature about the use of neoadjuvant ADT, we felt that this course of action would have a low probability of harm and would also decrease his prostate size, making future surgery potentially less morbid. Based on work from Gleave et al in a Canadian randomized controlled trial, we will continue the ADT for at least 3 months and reevaluate him for RP at that time.

Under normal conditions, we generally do not administer neoadjuvant ADT to RP patients because of the lack of a proven survival benefit.

 However, during COVID-19, we are trying to alleviate harm from delaying surgery, and prior trials did show that taking the time to prescribe hormonal therapy did not lessen survival versus proceeding directly to surgery.

 Here, an African American male aged 64 years has high-volume grade group 2 and 3 PC, a PSA of 44, and clinical stage T2a disease. As such, he is classified as high risk. We elected to postpone his surgery in part because he also has uncontrolled diabetes, and we had concern that proceeding to RP during this pandemic could have led to excess hospitalization and use of excess health care resources. We also elected to start neoadjuvant ADT, a more controversial decision in this case because the hormonal therapy could make diabetes control more challenging. In the end, however, we felt that the high-volume cancer should be controlled without delay; we also took into consideration that the patient might ultimately favor radiation over surgery. Some experts could argue that we should postpone this case for only 30 days and hold off on use of ADT. However, the current uncertainty of the COVID-19 peak and the potential need to use excess health care resources in the perioperative period for this patient prompted us to make the case management decisions described above.

 This case involves a very healthy African American man, aged 61 years, with Gleason 4+4=8 in only 2 cores but with a PSA higher than 30. Because he was in excellent health and had high-risk disease, he was deemed appropriate for surgery based on day-to-day conditions at our center. He was negative for COVID-19 based on a test performed 72 hours before surgery at our drive-through testing site. (As of early April 2020, our health system requires preoperative COVID-19 testing for all scheduled surgery patients, performed at our center; we currently do not allow testing outside of our own health system.) 

To not overutilize health care resources, we performed only a unilateral right-side pelvic lymphadenectomy in association with the radical retropubic prostatectomy; we did not perform an extended lymph node dissection. Our reasoning was that we did not want to risk a lymphocele that would possibly increase utilization of health care resources during our upcoming COVID-19 peak. 

Our enhanced recovery after surgery protocol for RP dictates the use of bupivacaine liposome injectable suspension (Exparel 266 mg/20 cc mixed with 20 cc 0.25% standard bupivacaine) in the incision on closure and use of enoxaparin sodium (Lovenox 0.4 ml/40 mg subcutaneous, daily). The upivacaine increases the probability of discharge from the hospital on postoperative day 1, which is always desirable but is even more so during the COVID-19 pandemic. The enoxaparin is for deep venous thrombosis prophylaxis, but this might also increase the risk of a lymphocele. This was our reasoning for the unilateral standard lymphadenectomy.

 This healthy 58-year-old healthy Caucasian man with lower volume Gleason 8 prostate cancer but with a PSA level of over 20.  This gentleman is a commercial pilot and was originally contacted and asked to postpone his surgery and initiate short term ADT (this was very early in our hospital preparedness where any surgery was being subject to postponement).  The patient was, understandably, not keen for preoperative ADT and was concerned that use of ADT may lengthen his return to flight status with the Federal Aviation Administration (FAA).  Ultimately, he was deemed high risk and was approved to move forward with radical retropubic prostatectomy and unilateral pelvic lymphadenectomy after negative COVID-19 testing.

 This Caucasian male business executive, aged 75 years, was recommended by his community urologist to undergo external beam radiotherapy and neoadjuvant hormonal therapy due to his age and morbid obesity (body mass index = 38). However, the patient was keen to have surgery instead and presented to our center for a second opinion soon before COVID-19 arrived in our area. He was scheduled for radical retropubic prostatectomy but was very strongly encouraged to see a radiation oncologist for proper multidisciplinary education and counseling. When the COVID-19 crisis emerged, he and his local urologist were contacted by our team with our recommendation that he start leuprolide neoadjuvant hormonal therapy and then strongly consider external beam radiotherapy and not proceed to RP. The patient refused and is currently on the surgical schedule for fall 2020. This case illustrates that, even in a pandemic, we cannot force therapy decisions on patients. As of now (early April 2020), it remains unclear what management this patient will ultimately elect.

 Prior to the pandemic, this individual with male hypogonadism and obesity, aged 62 years, was diagnosed with low-risk localized prostate cancer. He initially elected RP because he has low testosterone which, arguably, might lessen the long-term success of active surveillance and increase his risk for recurrence and unfavorable pathology. Under normal circumstances, low-risk men are asked to choose between active treatment and active surveillance, and this patient chose surgery. When COVID-19 worsened in our region and our COVID-19 surgical guidelines were announced, we contacted him to say that his surgery could be postponed up to 6 months. At that point, he agreed to active surveillance. He will have a follow-up PSA measurement and prostate examination 6 months after his biopsy date, and he may ultimately have a prostate MRI and/or repeat prostate biopsy before being reconsidered for surgery. Low-risk men, most of whom should probably be placed on active surveillance anyway, are “low-hanging fruit” during COVID-19, those in whom surgery can be postponed or avoided to help prevent overburdening the health care system during the surge. 

 A healthy Caucasian man, aged 70 years, presented to our center with Gleason 8 in 4 of 12 cores, a PSA of 7.5, and clinical stage T1c disease. He had been scheduled for RP, with a surgery date several weeks out. This date proved to coincide with the start of the COVID-19 pandemic in our area. At the time of the COVID-19 surgery postponement process for this patient, we realized that a pathology review had not yet been completed in accordance with our policy of having outside pathology slides reviewed at our center for accuracy. Interestingly, after the pathology review, the patient was downgraded to Gleason 3 + 4 = 7 in the 4 involved cores, reclassifying his risk group from high to intermediate; surgery was postponed for up to 3 months. Before the pathology review, the patient had been offered neoadjuvant ADT but declined. In retrospect, in light of the subsequent pathology downgrading, this was a wise move.

The COVID-19 pandemic scenario continues to change and vary throughout the United States and the world. Our process at Duke will undoubtedly evolve. Nevertheless, we wanted to share our initial experience with COVID-19 surgical triage with some specific examples.

Overall, healthy men with high- and very high-risk localized prostate cancer are currently proceeding to surgery, while low- and intermediate-risk men are being postponed. We have also elected to employ neoadjuvant ADT selectively in less-healthy men who may require more health care resources at a critical time when our health system is at or nearing peak COVID-19 capacity.

For additional commentary and perspective from Eric A. Klein, MD of the Glickman Urological & Kidney Institute at the Cleveland Clinic, visit 

http://cancernetwork.com/klein_perspective

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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2. COVID-19: recommendations for management of elective surgical procedures. American College of Surgeons. Published March 13, 2020. Accessed April 9, 2020. https://www.facs.org/covid-19/clinical-guidance/elective-surgery

3. Ficarra V, Novara G, Abrate A, et al; Members of the Research Urology Network (RUN). Urology practice during COVID-19 pandemic. Minerva Urol Nefrol. Published online March 23, 2020. doi:10.23736/S0393-2249.20.03846-1

4. Goldman HB, Haber GP. Recommendations for tiered stratification of urologic surgery urgency in the COVID-19 era. J Urol. Published online April 21, 2020. doi:10.1097/JU.0000000000001067

5. Stensland KD, Morgan TM, Moinzadeh A, et al. Considerations in the triage of urologic surgeries during the COVID-19 pandemic. Eur Urol. Published online April 9, 2020. doi:10.1016/j.eururo.2020.03.027

6. Bekelman JE, Rumble RB, Chen RC, et al. Clinically localized prostate cancer: ASCO clinical practice guideline endorsement of an American Urological Association/American Society for Radiation Oncology/Society of Urologic Oncology guideline. J Clin Oncol. Published online September 5, 2018.  doi:10.1200/JCO.1800606

7. Carter HB. American Urological Association (AUA) guideline on prostate cancer detection: process and rationale. BJU Int. 2013;112(5):543-547. doi:10.1111/bhu.12318

8. D’Amico AV, Moul J, Carroll PR, Sun L, Lubeck D, Chen MH. Cancer-specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era. J Clin Oncol. 2003;21(11):2163-2172. doi:10.1200/JCO.2003.01.075

9. Mohler JL, Antonarakis ES. NCCN Guidelines updates: management of prostate cancer. J Natl Compr Canc Netw. 2019;17(5.5):583-586. doi:10.6004/jnccn.2019.5011

10. Buyyounouski MK, Choyke PL, McKenney JK, et al. Prostate cancer - major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA: Cancer J Clin. 2017;67(3):245-253. doi:10.3322/caac.21391

11. Gleave ME, Goldenberg SL, Chin JL, et al; Canadian Uro-Oncology Group. Randomized comparative study of 3 versus 8-month neoadjuvant hormonal therapy before radical prostatectomy: biochemical and pathological effects. J Urol. 2001;166(2):500-506; discussion 506-507.

12. Fair WR, Cookson MS, Stroumbakis N, et al. The indications, rationale, and results of neoadjuvant androgen deprivation in the treatment of prostatic cancer: Memorial Sloan-Kettering Cancer Center results. Urology. 1997;49(3A suppl):46-55. doi:10.1016/s0090-4295(97)00169-6

13. Klotz LH, Goldenberg SL, Jewett M, et al. CUOG randomized trial of neoadjuvant androgen ablation before radical prostatectomy: 36-month post-treatment PSA results. Canadian Urologic Oncology Group. Urology. 1999;53(4):757-763. doi:10.1016/s0090-4295(98)00616-5

Experts from the Duke Cancer Institute outline their current approach to stratifying surgical management of patients with prostate cancer.

Managing Prostate Cancer Surgical Patients during the COVID-19 Pandemic: A Brief Report of the Duke Cancer Institute’s Initial Experience

Judd W. Moul, MD and colleagues have nicely outlined the challenges that virtually all developed countries are facing during the onslaught of SARS-CoV-2. Most states have enacted temporary bans against all but essential surgeries; they have left local physicians to use their judgment to determine the meaning of “essential,” considering individual threats to life, limb, and vital organ systems and progression in stage or metastasis for cancers, while ensuring the safety of patients and caregivers with respect to maintaining an adequate supply of intensive care unit (ICU) beds, ventilators, and personal protective equipment (PPE). Thus, in large measure, the definition of “essential” depends on local conditions: the incidence of infection, the capacity of the regional hospital system, the number of affected caregivers who may be temporarily out of the workforce, the daily burn rate of PPE use, and so on.

For the management of cancer in general, there are other factors to consider in deciding what is “essential,” including increased potential exposure to coronavirus infection in immunocompromised patients needing to go to a treatment center for chemo- or immunotherapy; patient anxiety related to delaying initiation of or ongoing therapy; and concerns about whether delaying therapy could influence the chance for cure. 

Fortunately for patients with prostate cancer, a substantial amount of evidence from vast experience with active surveillance indicates that those with very low-, low-, and intermediate-risk disease do not compromise their chance for cure by delaying curative treatment.

 Although fewer data are available for those with high-risk (HR) and very high-risk (VHR) disease, in a recently published retrospective pooled analysis from 3 high-volume tertiary centers, we found no difference in rates of biochemical failure, metastasis, prostate-cancer–specific mortality, or all-cause mortality in those with HR or VHR disease treated <8, within 8-12, or >12 weeks after diagnosis.

 In our observation and experience, a delay of up to 90 days for locally advanced or high-grade prostate cancer does not seem to have an adverse effect on short-term outcomes, although 1 prior report found that for HR disease, biochemical failure rates were worse for those with a delay of >90 days.

 An alternative strategy is the use of androgen deprivation therapy as a delaying tactic, which presumably can delay the risk of tumor progression indefinitely. This is also likely safe, at least for a few months, but it’s not clear if the extra cost and toxicity are worth the presumed safety margin, and there is a risk that use for as little as 24 weeks can induce genomic changes characteristic of metastatic castrate-resistant disease, which could compromise cure.

At Cleveland Clinic, we have considered cancer-related and non–cancer-related factors and devised a tiered approach to performing urological surgery and office procedures (Figure).

 At the initial stage of the crisis, when the magnitude of the number and severity of SARS-CoV-2 cases was unknown, we worked with institutional leadership and the decision was made to put all tier 3 and 4 surgeries on hold. As events evolved, and it became clear that early stay-at-home orders and social distancing were effective in flattening the incidence curve in northeast Ohio and that our hospital and caregiver resources would not be overwhelmed with cases, we began (starting the week of April 20) doing tier 3 cases on a limited basis as our system ramps up again, based on availability of operating rooms and nursing and anesthesia personnel, and on patient preference. We have followed a similar process for office-based and nursing procedures. System-wide real-time information with daily monitoring of resources has allowed us to do this safely: The creation of dashboards to monitor system-wide hospitalization and ICU usage for COVID-19-related and non–COVID-19-related care and PPE usage/stock availability, along with our tiered approach to procedures, allows for a rational, measured, and real-time approach that can be dialed back or ramped up as dictated by events related to SARS-CoV-2.

1. Ahmad AE, Richard PO, LeÃ£o R, et al. Does time spent on active surveillance adversely affect the pathologic and oncologic outcomes in patients undergoing delayed radical prostatectomy? 

. Published online April 7, 2020. doi:10.1097/JU.0000000000001070

2. Reichard CA, Nyame YA, Sundi D, et al. Does time from diagnosis to treatment of high- or very-high-risk prostate cancer affect outcome? 

 2019;124(2):282-289. doi:10.1111/bju.14671

3. Zanaty M, Alnazari M, Ajib K, et al. Does surgical delay for radical prostatectomy affect biochemical recurrence? a retrospective analysis from a Canadian cohort. 

 2018;36(1):1-6. doi:10.1007/s00345-017-2105-6

4. Sowalsky AG, Ye H, Bhasin M, et al. Neoadjuvant-intensive androgen deprivation therapy selects for prostate tumor foci with diverse subclonal oncogenic alterations. 

 2018;78(16):4716-4730. doi:10.1158/0008-5472.CAN-18-0610.

5. Goldman HB, Haber GP. Recommendations for tiered stratification of urologic surgery urgency in the COVID-19 era. 

. Published online April 21, 2020. doi:10.1097/JU.0000000000001067

The chairman of the Glickman Urological & Kidney Institute at the Cleveland Clinic provides commentary and an adjacent perspective to the Duke Cancer Institute report.

A Rational Approach to Managing Prostate Cancer in an Irrational Time

The coronavirus disease 2019 (COVID-19) pandemic has greatly impacted all areas of the medical world. While nurses and physicians on the front lines search for answers on how to treat this novel disease, oncologists and cancer care providers around the world search for answers of their own. Should treatments be continued or halted? Should surgeries be postponed? And how can the same standard of care in be delivered in a socially distanced world? 

 recently sat down with David R. Gandara, MD, director of the thoracic oncology program and senior advisor to the director of the University of California (UC) Davis Comprehensive Cancer Center, to discuss the impact of the pandemic on the current management and treatment of patients with lung cancer, as well as the future of education and patient care in a post–COVID-19 world. While the crisis may have “dramatically changed how we practice,” Gandara says, “it hasn’t altered the basic premise that lung cancer is now a highly treatable disease.”

Q: COVID-19, a respiratory pandemic, is obviously the biggest news in the world right now. How has that changed the way you practice as a lung cancer physician and the way you research?

 Well, what has happened has dramatically changed how we practice, how we interact with lung cancer patients. But it hasn’t altered the basic premise that lung cancer is now a highly treatable disease, that it is both genomically and immunologically complex, and that we want to offer our patients their best therapeutic options.

That being said, right now at UC Davis and most other community and academic cancer centers around the United States-including the National Cancer Institute, which has allowed this for patients on clinical trials-we have converted all of our routine follow-up to virtual or video virtual visits. I just had my first series of those in the past 2 weeks. I can visually see the patient and they can see me. I can see their scans and their laboratory results and talk and interact with them. This is now a forum for seeing patients that is accepted by insurers, including CMS for Medicare. Although virtual visits don’t have, of course, the ability to do a physical exam on the patient, for routine care of cancer patients, even those receiving cancer chemotherapy, it’s a way to have those interval or interim visits without exposing them to the risk of coming in to our office and possible exposure to COVID-19.

At UC Davis Cancer Center, everyone entering the door has their temperature taken and [is administered] questions regarding possible symptoms that could be associated with COVID-19. If they have either an elevated temperature or symptoms, they don’t come into the cancer center and are referred instead to a COVID-19 center at UC Davis. There, we would engage them and work them up for COVID-19, depending on what the situation was.

So, this is a huge change. Of course, a lot of our cancer drugs now are oral, so the patient doesn’t have to come into the infusion center. But a lot of them, including the checkpoint immunotherapeutics, are intravenous. In that case, the patient comes into the cancer center after they’ve been checked, and they get their cancer treatment through the infusion center in a very safe manner-as safe as possible. But if they didn’t need to see the physician in a separate visit, then they don’t face-to-face. That’s done virtually. 

Q: Obviously, patients with lung cancer are a uniquely vulnerable patient population. Have you had to change treatment plans at all in light of the virus?

 We’re dealing with a population who has a cancer which either started or is still present in their lung. Many of them, if they were smokers, have chronic obstructive pulmonary disease. They are older patients in general, although, of course, as everyone knows, we do have a cohort of patients who are young, never smokers, women. But most are older and previous smokers, so they are at higher risk. There is a considerable debate, not only in lung cancer, but around the United States for all types of cancers, about whether we should alter our therapy, whether we should withhold chemotherapy or immunotherapy, or whether should we give it on schedule. 

I did a social media poll last week and asked practicing oncologists whether they would arbitrarily hold either chemotherapy or immunotherapy or neither or both in a lung cancer patient. Of 357 people who responded, almost 70% said no, they would treat patients on schedule, assuming that they don’t have active COVID-19 infection. A small percentage, about 10%, said they would hold chemotherapy, 5% said they would hold immunotherapy, and about 5% said they would hold both. But the great majority would treat patients on schedule. In this social media poll, I also had a number of patients who independently responded with their views, and every single one of them said, in effect, “I know that COVID-19 may kill me, but lung cancer untreated will kill me, so please treat us like you are treating us every week.” So, although there is considerable debate about this, and some institutions are holding therapy, my own belief, and that of our institution, is that we should treat patients if we can do it safely.

Q: It seems like this is where medicine was headed in the first place, but the COVID-19 experience has super-charged the move toward more virtual medicine and doing more things online rather than face-to-face.

 Yes, I think we were moving in this direction already, and this accelerated the pace. Obviously, we have regularly scheduled WebEx CME, grand rounds, and a variety of other [presentations] that we do, and there is good uptake by attendees. It has very often been difficult for physicians, except on an occasional basis, to take off from a practice or from their academic research to attend a meeting face-to-face. But attending virtually is easier, and also, if there is enduring material from it, then that physician could, for example, view it at night, after they have dinner and have some free time. So, yes, we’re moving more quickly in that direction.

Q: At the upcoming International Lung Cancer Congress

 (ILCC), what events and discussions are you most excited to attend?

I think I should start with saying that our ILCC is a unique CME experience, because it’s purposely placed about 6 weeks after the annual ASCO meeting. Faculty and attendees will have heard the news and the advances that are presented there, and then at ILCC, they’ll be able to listen to expert faculty and interact with them about the new information. I’ve always referred to our meeting as a think tank, because it’s much more like that than like a regular meeting. It has not only classic lectures, but it has a number of panel discussions with experts, multidisciplinary, including all the disciplines that are involved in lung cancer or thoracic malignancy care. The new and important things this year-we’re still early in the year-or I would maybe say for 2019-2020 so far, are new drug approvals. We have quite a variety of those. We [also] have new guidelines about how to use liquid biopsy. [Plus,] we have increasing information about lung cancer screening; we believe lives have been saved because we’re finding patients with earlier-stage disease. So, a whole variety of things are new, that are educational opportunities, that will be presented at ILCC 2020.

Q: Are you especially looking forward to certain sessions?

At ILCC each year, we have a session on new drugs that are coming out and new classes of drugs that are available. That will be a highlight of this meeting. In particular, although new findings have occurred in several drug classes, one that is brand new is the development of drugs for 

 G12C mutation. KRAS has been an undruggable target-I’ve always said this myself-because of the difficulty in developing a drug that could inhibit that mutation. But now we [do] have drugs, and 5 of them are in development and we’ll be hearing about them at ILCC. That will clearly be a highlight.

Q: How does the virtual nature of the meeting change things?

 It’s not the same as a face-to-face meeting, obviously, but an advantage is that you can incorporate attendees who are not able to physically travel to Huntington Beach for ILCC. You’re also able to broaden the scope of the faculty, because some faculty, for instance, will be coming from Europe or Asia, and as COVID-19 evolves, they and we may still have travel restrictions. So even if there’s a face-to-face component, having a virtual component will be important. We also will be able to have enduring material, which is developed in a more comprehensive way because the entire meeting, of course, will be audio- and videotaped. So not only attendees, but sponsors as well, will be able to have this information available for educational purposes of their own.

Q: Jumping to a broader clinical question, we’ve seen so many advances in lung cancer over the past 10 years. What major trends or developments do you anticipate seeing in the near future?

So many rapid advances have occurred in the therapeutic options for lung cancer, and also in diagnostics, that it’s hard to believe that they could continue to come at such a fast rate over the next year or two. But already we have a number of challenges and opportunities which have [evolved from] these advances. I’ll just give you 1 example: We now have 8 oncogene-driven lung cancers, non–small cell lung cancers (NSCLCs), that are recognized in guidelines. You should test a patient’s tumor for these oncogenes before offering therapy, and we soon will have number 9 because I’m sure the 

 G12C will soon be FDA approved. With that, it’s even more important for practicing oncologists to realize that even a patient who is a previous smoker might have 1 of these 8 or 9 oncogenes. [In fact,] 

 G12C is associated with smoking, and the best treatment for [patients with a 

 G12C mutation] is a targeted therapy rather than chemotherapy or immunotherapy or even a combination of the 2.

Another example, related to diagnostics and molecular testing: We already know that patients with 

-translocated lung cancer, don’t fare well with checkpoint immunotherapy. They do much better when treated with targeted drugs. So how does a practicing oncologist then test for all of these oncogenes in a time-efficient manner, with good sensitivity, good specificity, and have a turnaround time of 1 to 2 weeks, so that they can treat the patient with a personalized or precision medicine approach rather than empiric? We now have that ability, and liquid biopsy is bringing us that faster, next-generation sequencing and tissue is bringing us that, so that it can all be done simultaneously, rather than testing for one gene right after the other, sequentially, which takes a long time, and if it’s a tissue, would use up all the tissue. That’s another example of where we have opportunities to move the field forward. 

Q: Have you noticed any sort of overarching theme or clinical development, especially one that will be reflected at ILCC?

 The theme of personalized medicine, of course, has been present for several years, and it continues to grow. I’ll give you a perspective on this. With the recognition that in advanced-stage NSCLC, checkpoint immunotherapy plus platinum-based chemotherapy is very effective, there has been some divergence of opinion about what that means. Some people say, “This makes things simpler, because I can just treat everybody who comes in the door with advanced NSCLC with this regimen.” But many other people, including myself, say, “No, this actually makes things more complex, because even with the efficacy of the combination of checkpoint immunotherapy and platinum-based chemotherapy, we need to make sure the patient who comes in doesn’t have one of the oncogenes and would [in fact] be better served by a targeted therapy.”

 So, at ILCC this year, we will continue to define that personalized medicine approach. One component of this is a special part of the meeting, a molecular tumor board, with case presentations, and the audience is asked, with audience-response devices, “What would you do in this case? Would you empirically treat the patient? Would you wait until the testing comes back?” [Another component] of the meeting is the Addario Lectureship, named after Bonnie Addario from the Addario Lung Cancer Foundation, which has a precision medicine team. Each year, a world-recognized lung cancer oncologist is chosen for that award. Last year, the awardee was Solange Peters from Switzerland, and she is the president-elect for the European Society for Medical Oncology. We have already made our selection for this year, which would be July 2020 when ILCC occurs, but of course I cannot tell you who the awardee is yet because it is secret until close to the meeting. But I will tell you that as part of this award, the awardee is featured on a big billboard at Times Square in New York City. Their picture is there for an entire day, the same day as the presentation. So, assuming we’re through COVID-19 by the end of July, all of this will happen in real time.

Can you discuss some study results that have been published in the past year or so that might be considered transformative or practice-changing?

I think one [transformation] would be in regard to RET fusions. We have had some nonspecific drugs-and when I say nonspecific, they’re multitargeted-which had activity against RET before. But now we have multiple drugs which are either just approved or have breakthrough designation for RET; these are much more targeted against the gene and much more active. One of those drugs is called LOXO 292, and the response rate in patients with these fusions is 75% or above. That sort of thing is happening in many areas of lung cancer oncology.

Another example would be in extensive-stage small cell lung cancer (SCLC), where we literally have had no major advance in more than 20 years. Platinum chemotherapy, at least in the United States, remains the standard of care. Now, that being said, in this past year we have seen 2 new regimens based on adding a checkpoint inhibitor to that same platinum–etoposide chemotherapy base, and in two phase 3 studies, that combination regimen showed superior response and progression-free survival, and also overall survival was better with the combination compared with the platinum chemotherapy alone. So now 2 drugs-2 checkpoint inhibitors, atezolizumab and durvalumab-are approved for extensive-stage SCLC.

These advances are not just in one area or the other: They’re in multiple areas. Again, what that means is that a practicing oncologist has to stay on top of the field, [which can be] increasingly difficult, and the best way to do that is by CME such as we’re providing in our meeting.

Q: Looking forward, what other studies do you anticipate coming out in the next year or so?

One opportunity that comes up is that if a checkpoint inhibitor plus platinum chemotherapy is more effective than chemotherapy alone in extensive SCLC, [can we see what happens] if we move it to the one-third of patients who have limited-stage SCLC? Here, we know already we can cure a percentage, but it’s probably no better than 25%. Could the addition of checkpoint immunotherapy actually increase the cure rate in limited-stage disease?

Moving back to the oncogene sphere, another opportunity would be in an EGFR tyrosine kinase inhibitor (TKI)-resistant lung cancer, or even in initial therapy where we have 5 drugs-all very good drugs, TKIs-to treat 

-mutated lung cancer. But, invariably, even with what could be considered the best of these drugs, osimertinib (Tagrisso), acquired resistance occurs. So, a multitude of trials are ongoing, to try to see if we can enhance the activity of these already very good TKIs in the management of 

-mutated lung cancer. Some are combinations of TKIs, and some are combinations of a drug like osimertinib with an EGFR monoclonal antibody such as necitumumab (Portrazza). Some of these are adding chemotherapy, platinum chemotherapy, to the TKI, and others are adding antiangiogenic agents. Not all of these will be superior, and some will also be associated with more toxicity. So, we’ll have to look at the risk and benefit that come out of these trials. But these trials are clearly important to do, and we’re looking forward to the results.

Q: Let’s discuss your research a bit: You’ve been very involved with the Lung-MAP protocol, correct?

 Lung-MAP is a huge, one-of-a-kind undertaking. It is the only master protocol which has regulatory intent in all the substudies. It is also the only master protocol which is a public–private partnership among the National Cancer Institute with its cooperative groups, the Foundation of the National Institutes of Health (NIH), the Friends of Cancer Research, and now more than 15 pharmaceutical companies who have partnered to develop their drugs within this paradigm.

The other thing that’s unique about it is that we have next-generation sequencing as the foundation for determining whether oncogenes are present or not. That partnership is with Foundation Medicine. We have enrolled more than 2000 patients to date, and we have completed about 10 or 12 substudies so far. So, this is meant to be self-sustaining. We continually have new studies opening and other studies closing. It’s a new way of developing drugs for lung cancer, hopefully ruling out drugs or drug combinations that are not active and doing it very promptly. On the other hand, we are able to screen large numbers of patients- we’re screening 1500 patients per year with lung cancer-so we can test drugs even in rare genotypes. That means [a lot] if, say, a gene [is present in] only 4% of all lung cancers, and there’s a good new drug that we think will work in it. Unless you have a broad-based screening trial like this, and you have multiple studies, you can’t achieve that goal, because no one wants to screen 100 patients to find only 4 who are eligible for a trial. And, a patient doesn’t want to be told, “Oh, you have a rare genotype; you have only a 1-in-a-100 or 4-in-a-100 chance of having it.” So, Lung-MAP is proving to be very successful, and I think it will continue for the longer-term future.

Q: When you say ‘very successful,’ what do you think are the most noteworthy results to come out of this project?

When Lung-MAP was developed 5 years ago, it was really forward-thinking, I would say. Our goal was [to determine if] we could screen lung cancer patients for a variety of genomic mutations and alterations, in a fast, efficient manner, and then place them on to substudies where they would get a drug against that target-and the answer was yes, we could. Our average turnaround time for the FoundationOne test is 10 days. Clearly, that’s within the window of someone in the community using a test like this to screen their patient, unless, of course, it’s an emergency. We’ve shown that it’s feasible; we can screen, and we can do it in a timely fashion. The other thing is, we’ve already completed a dozen trials. Now, some of these were negative, but these are all drugs and mutations that are FDA approved in other cancers. What we showed in a very timely fashion was that the same mutation in a lung cancer patient wasn’t sensitive to the drug, even if it was, let’s say, in breast cancer or chronic lymphocytic leukemia or another malignancy, where these same drugs and targets led to FDA approvals. So, for all of these reasons, we can say that Lung-MAP has been successful.

It was also successful because we wanted to see if we could we engage all of the cooperative groups under the National Cancer Institute in Lung-MAP. And the answer was yes, with people from all the various groups leading various trials, leading various committees. We also said, Can we engage the community? And the answer again is yes. We have 650 sites throughout the United States. The majority are in the community, and the majority of accrual of patients to the trial has come from the community. So, another success story.

But we’ve had many challenges along the way. We’re writing a book. I’m just kidding. But we’re writing a book called 

. When you try to put something together like this, it seems, of course, simpler on the surface than it actually is. Over the period of time we’ve been running Lung-MAP, we found that we had to make multiple adjustments, so we had to be flexible, nimble. For instance, after 1 year of the Lung-MAP, we had the approval of checkpoint immunotherapy in second-line treatment, and that changed everything. But it then gave us more opportunities to develop components of Lung-MAP, to say, “Well, what if a patient doesn’t respond to checkpoint immunotherapy, or what if they respond and then they fail?” So, we have an entire arm of Lung-MAP composed of trials for patients with immunotherapy-refractory disease.

Q: Let’s switch gears and talk a little bit about you and your career. Which of your investigative accomplishments are you most proud of?

 Well, I can start by saying that my particular interest has been in drug development, where I’ve had grants from the National Cancer Institute for 25 years for early therapeutics. One accomplishment I’m proud of is being a founding co-chair of the National Cancer Institute Investigational Drug Steering Committee, of which I am still a member. In addition, my interest in particular tumor types is lung cancer. I’m very proud to have led the lung cancer committee for the Southwest Oncology Group for 15 years, and in that regard, [to have had] many accomplishments associated with more than 100 clinical trials being accomplished through that group and through our association with the National Cancer Institute during that time.

I’ve also always considered myself to be an educator. So, I’m very proud that our ILCC is now in its 21st year. It is always among the highest-rated cancer conferences in terms of attendee ratings for the meeting, and that is quite an accomplishment. Additionally, we have a one-of-a-kind association in lung cancer, the International Association for the Study of Lung Cancer, and I am very proud to have not only led its world conference in San Francisco, but also to have served as the president of the organization. 

I think, lastly, I’ve always valued mentorship. When I had mentorship early in my career, that it was incredibly important to me, so I have tried to be a good mentor as well. At this point, I’ve mentored more than 50 young oncologists as well as PhD students and medical students, and I’m a mentor now to 5 different people on their grant submissions. A very important thing to me is being able to provide my expertise and my experience to help others.

Q: Are you particularly proud of working on specific drugs that have been brought to market?

 Well, I think probably the accomplishment I’m most proud of in terms of what I have developed is not a specific drug, but rather a test. A year and a half ago, I published for the first time an assay which could assess tumor mutational burden (TMB) from blood. This was in collaboration with Foundation Medicine and Roche Genentech, where we used a study on which I’m the senior author. The OAK trial, a positive trial for survival of atezolizumab versus docetaxel, is among my major accomplishments.

We went back to that trial and used blood specimens that had been collected to see if we could duplicate the predictive value that had been seen with tissue analysis of TMB, and, in fact, we could. That diagnostic test has now completed its phase 3 evaluation in a trial called BFAST. We don’t know the results yet, but it is a trial where atezolizumab or platinum chemotherapy were the 2 arms, and the patients were selected by blood TMB. So, I would say that is one of my greatest accomplishments, but I don’t know if we will have a companion diagnostic yet. It depends on the results of the trial.

Q: You’re pretty active on Twitter. How did that come about, and why?

 My interest in Twitter comes from 2 areas, I think. One is being an educator: If you’ve seen my tweets on Twitter, you know most of them are talking about breakthroughs or controversies, where I’m either providing information like the link to a publication, or I’m saying I thought this was quite impressive, what do you think, and engaging not only oncologists who are on Twitter, but patients and patient advocates. There is [also] so much bad information on the internet, I feel like it is part of my moral obligation to do what I can to speak on a factual basis, and to point it out misinformation. Communication with patients and patient advocates has been another aspect of my career that I have concentrated on. Some physicians have the skill to be able to break down complex information regarding genomics of cancer or treatment and describe it to patients in a way that they can understand. I’ve always worked on that skill, to the point where now I think I do a good job of it.

I’ve taken this into many venues. For example, the Addario Lung Cancer Foundation, now known as GO2 after their recent merger, has a monthly session called the Living Room. In their headquarters in the San Francisco Bay area, they have a big room with couches set up like a living room, and once a month they serve dinner and it is filled with patients, patient advocates, their families, and their friends-but it is also webcast live to 140 countries around the world. I have spoken there probably yearly, and among the things I’ve tried to do is to communicate to patients in ways that they can understand. I use a lot of analogies. For example, when you talk about genetic testing of cancer, and how many mutations there could be and why every lung cancer patient is different, I will hold up my finger and I will say, “You know that your fingerprint is different from essentially everyone else’s,” and everybody says yes. Then I tell them that when we’re talking about this molecular testing, this next-generation sequencing for hundreds of genes, that is the molecular fingerprint of your cancer. Then they say, oh, yeah, that makes total sense now, I understand this. Or I will talk about why a TKI against EGFR mutation works initially, and then it stops and there’s drug resistance. I will talk about the driver. I’ll say, “Pretend you’re on a bus, and you’re driving, and you stop at an intermediate stop and the driver gets off, and the person in the row behind him becomes the new driver. That’s what’s happening in your cancer. That’s acquired resistance. You have a new driver for your cancer, so we have to test and find out what it is and treat it appropriately.” So that is another communication skill that I feel is very important, and I try to share it when I can.

Q: I’ve read that you’ve always had an interest in writing. It’s somewhat unusual to see someone who combines a passion for science with the ability to write. How have you found that you can marry those 2 interests?

 I’ll give you a little background story here. When I graduated from high school, I said that I wanted to be a writer. I was going to be the next Hemingway. Once I got into college, I said, oh, Journalism 101, this doesn’t interest me so much-maybe I should look at something else. So, I decided to go into medicine. But I have always kept my interest in writing, and I think I actually have a fairly good writing skill. So, whereas other people sometimes struggle with putting their clinical studies or their research into manuscripts, I actually love to do it. I edit manuscripts for many, many other people. So, I have been able to blend my writing skills into my medical career. I’ve published almost 400 peer-reviewed articles and hope to do more.Î½

 The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

ONCOLOGY® recently sat down with David R. Gandara, MD, director of the thoracic oncology program and senior advisor to the director of the University of California (UC) Davis Comprehensive Cancer Center, to discuss the impact of the pandemic on the current management and treatment of patients with lung cancer, as well as the future of education and patient care in a post–COVID-19 world.

Forging Ahead in a Time of Crisis

A 56-year-old white man with a 74 pack-year smoking history presented with macroscopic hematuria and a significant weight loss of 45 pounds in 6 months. His clinical laboratory tests indicated iron deficiency anemia and a computed tomography (CT) scan showed a left kidney tumor, mediastinal lymph nodes, and multiple lung metastases. A percutaneous CT-guided kidney biopsy revealed grade 3 clear cell renal carcinoma based on World Health Organization/International Society of Urologic Pathology classification.

The patient started first-line systemic treatment for intermediate-risk metastatic renal cell carcinoma (mRCC) with combination immunotherapy with nivolumab plus ipilimumab. After 10 days of the first cycle, he presented with a pruritic maculopapular rash covering 20% of his body surface.

The patient started first-line systemic treatment for intermediate-risk metastatic renal cell carcinoma (mRCC) with combination immunotherapy with nivolumab plus ipilimumab.

After 10 days of the first cycle, he presented with a pruritic maculopapular rash covering 20% of his body surface (

). In consensus with the Dermatology Department, we considered this to be a grade 2 cutaneous immune-related adverse event (irAE) based on the Common Terminology Criteria for Adverse Events (CTCAE).2 He received topical steroids and an oral antihistamine for 1 week; however, due to lack of clinical improvement, the patient was reevaluated and clinical laboratory tests were performed. Results showed a creatinine increase of grade 2 per CTCAE (his baseline creatinine was 1.1 mg/dL, which increased 2.3 times) (

). Nephrology was consulted for work-up of this acute kidney injury.  Urinary tract infection and urinary tract obstruction were ruled out and a bland urinary sediment was found. The patient was diagnosed with tubulointerstitial nephritis related to immune checkpoint inhibitors (ICIs).

Our patient had irAEs involving multiple organ sites; therefore, systemic steroids (prednisone 40 mg once daily) were initiated for the grade 2 irAE and ICIs were held. Ten days later, the grade 2 rash resolved (

, and renal failure improved to grade 1 with decreased creatinine levels. He started a slow steroid taper over 4 weeks.

Which of the following are true about irAEs with ICIs?

. irAEs are more common when an ICI combination is given

 The incidence of irAEs at multiple sites is at least 10% 

 irAEs usually develop within weeks to 3 months after initiation of ICIs 

 irAEs may be associated with better clinical outcomes

ICIs are associated with a distinctive class of adverse events (AEs), denominated irAEs. The management of these events remains challenging, and most recommendations are based on expert opinion and guidelines for the management of irAEs from several oncology societies.

irAEs could be explained by T-cell function disinhibition; however, the exact mechanisms remain unknown. Some studies suggest that these events are due to a combination of autoreactive T cells, autoantibodies, and cytokine secretion.

The frequency of irAEs varies according to tumor type, disease stage, and agent or agents prescribed. The incidence of irAEs is estimated to be lower with anti-programmed cell death protein 1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) monotherapy (any grade, 58%-85%; grades 3-4, 7%-20%)

 compared with anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monotherapy (any grade, 60%-85%; grades 3-4, 10%-27%).

 The highest rates of irAEs have been observed with anti–PD-L1 and anti–CTLA-4 combinations (any grade, 93%-95%; grades 3-, 40%-55%).

 Fatal irAEs are relatively uncommon, with an incidence of 0.3% to 1.3%.

Currently, ICIs are the preferred first-line therapy for mRCC,

 either in combination with tyrosine kinase inhibitors

 The phase 3 CheckMate 214 study evaluated nivolumab plus ipilimumab versus sunitinib in patients with untreated mRCC. Among the 550 patients who received nivolumab plus ipilimumab, 46% experienced grade 3 to 4 AEs, 35% required high-dose systemic steroids (≥40 mg of prednisone per day), and 22% of patients developed treatment-related AEs leading to discontinuation. The most common irAEs were increased liver enzymes (2%-3%) and diarrhea (3%).

Although it is generally accepted that patients receiving ICIs and combination ICIs may experience irAEs affecting multiple organ sites, the exact incidence of concurrent or sequential irAEs in the same patient has not been reported in the kidney cancer population. However, in a retrospective study of 559 patients with non–small cell lung cancer (NSCLC) given nivolumab or pembrolizumab, 231 (41%) developed irAEs, and 40 (17.4%) presented multiple-site irAEs. These were defined as immune-related events occurring in different systems/organs in the same patient. The most frequent irAEs of any grade were classified as endocrine, cutaneous, and gastrointestinal (GI). In contrast, the most common grades 3 to 4 irAEs were GI and pulmonary. In the multivariate analysis, no factor was associated with the development of single- or multiple-site irAEs. Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were higher among patients with AEs compared with those who did not experience AEs (

 <.0001), but no significant differences were observed among those who presented multiple-site events compared with those who had single-site irAEs. Among patients with irAEs, 32 (6.1%) discontinued treatment due AEs, and no statistical differences were found in ORR, PFS, and OS when compared in those who did not discontinue treatment.

The data regarding the incidence of multiple irAEs in the same patient is very scarce. It comes from heterogenous populations (ie, different tumor types and stages) and retrospective studies. The Table includes data from studies that report the frequency of multiple-site irAEs, which varies from 13% to 53%.

 Therefore, answer B is a correct statement. 

Similar to incidence, the onset of irAEs highly depends of the type of ICI and whether the ICI is used as monotherapy or in combination. The toxicities associated with ipilimumab appear within the first 2 to 12 weeks of treatment, usually during the induction phase. The onset of AEs with anti–PD-1 drugs is slightly longer, occurring 5 to 15 weeks after the first dose of treatment. Finally, with ICI combinations,  toxicities occur earlier and over a more prolonged period of time.

 Concerning the development of multiple-site irAEs, the mean time since ICI initiation to their development was similar to single-site irAEs (62 vs 78 days, 

Steroids are the mainstay management strategy for irAEs and can be used in conjunction with other immunosuppressive agents according to the evolution and severity of the event. For grade 2 toxicities, ICIs are held, and corticosteroids are initiated at an initial dose of 0.5 to 1 mg/kg per day (prednisone or equivalent). For grade 3 toxicities, ICIs are held, and high-dose corticosteroids are initiated at an initial dose of 1 to 2 mg/kg day (prednisone or equivalent). For grade 4 toxicities, ICIs are permanently discontinued, and high-dose corticosteroids are initiated. Upon response to treatment, corticosteroids are tapered over 4 to 6 weeks.  If there is no response, corticosteroids are used in conjunction with other immunosuppressive agents, such as infliximab or mycophenolate, depending on site of irAE and severity.

irAEs may affect more than 1 organ simultaneously (as in our case) or sequentially. Therefore, immunosuppressive treatment may require a longer duration or to be given at different periods of time. In the case of multiple-site AEs, the MD Anderson Cancer Center experience indicates that treatment type, its duration, and associated complications were comparable between patients with single and multiple irAEs.

In 2 retrospective studies in patients with mRCC treated with nivolumab after receiving a prior tyrosine kinase inhibitor, OS and PFS were significantly longer in those with irAEs than in those without irAEs. Multivariable analyses revealed a protective association with irAEs in both outcomes in each study.

 In addition, an Italian study analyzed patients with NSCLC treated with nivolumab and found that individuals who developed at least 2 irAEs (43%) had longer median PFS and OS compared with those with a single or no irAEs (

 <.0001). Among patients with irAEs, 14% (n = 12) discontinued immunotherapy because of AEs, and at the time of analysis, 11 were alive without disease progression or subsequent treatment.

 In lieu of this evidence, there is some suggestion that irAEs may be associated with better clinical outcomes. Therefore, answer D is a correct statement. 

Data from the CheckMate 214 study of mRCC treatment in the first-line setting revealed that in the ICI arm, 25% of patients discontinued treatment due to irAEs (median duration of treatment 2.1 months). These patients generally had higher ORRs, complete response rates, and 24-month OS compared with sunitinib. These efficacy outcomes were also similar to the intention-to-treat population in the nivolumab plus ipilimumab arm. The latter suggests that oncological outcomes remain comparable with immunotherapy despite the need for treatment suspension due to toxicity.

In this case, we decided to continue with a second cycle of the ICI combination while the patient was tapering off steroids (at dose of prednisone 15 mg/day) after 35 days of treatment delay.

Is Re-Treatment With Immunotherapy in this Patient an Option?

Currently, the correct answer remains unclear because the benefit in survival with re-treatment is uncertain and some consider that patients with irAEs experience enhanced ICI efficacy and that re-treatment may be not be necessary. The current guideline recommendations state that for grade 2 and 3 irAEs, when symptoms and/or laboratory values return to grade 1 or less, cautious rechallenge with ICIs may be offered. However, ICIs should be permanently discontinued if patients have grade 4 irAEs, with the exception of endocrinopathies that are controlled with hormone replacement.

 Another option following combination nivolumab and ipilimumab therapy would be a rechallenge with nivolumab only.

In the mRCC setting, there is 1 retrospective cohort analysis where 80 patients with clinically significant irAEs, defined as those requiring treatment interruption or discontinuation, were evaluated. The most common irAEs were transaminitis, colitis, and pneumonitis. In 36 (45%) patients, ICI treatment was restarted. Eleven (30.5%) patients were receiving nivolumab plus ipilimumab (like our patient); 7 (63.5%) patients were switched to nivolumab monotherapy and 4 (36.3%) patients restarted the combination. The initial grade of irAE did not predict whether the patient would be rechallenged with monotherapy or the combination.

 After ICI retreatment, 12 (33.3%) patients developed a new type of irAE and 6 (16.6%) experienced the same one. This implied that 50% of patients with mRCC developed a new or recurrent irAE after restarting treatment, similar to results in patients with NSCLC and melanoma.

Regarding  posttreatment AEs, 39% of  irAEs were grade 3 with there were no grade 4 or 5 events. Colitis was the most frequent irAE after rechallenge. The median time to an irAE was 2.8 months (range, 0.3-13.8 months), 6 (33.3%) patients required hospitalization, 11 (61.1%) required systemic steroids, and 13 (72%) patients required a therapy interruption for at least 1 week (10 (77%) of which permanently discontinued treatment). The median duration of immunotherapy after retreatment was 5.3 months (range: <1.0 to 21.3 months).

Two  significant predisposing factors for developing irAEs after rechallenge have been identified in patients with metastatic melanoma given combined anti–CTLA-4 and anti–PD-1 therapy. The first is a shorter duration between final dose of combination therapy to resumption of an ICI, and the second is the use of steroids at the time of restart.

In conclusion, ICIs can cause irAEs involving multiple organ sites in the same patient, concurrently or sequentially. Careful monitoring and dose interruption of ICIs, and early initiation of corticosteroids when needed, are important. Rechallenge with ICIs may be appropriate for some patients but continued monitoring for new or recurrent irAEs is critical.

 is associate professor, head of the Urologic Oncology Clinic, national researcher. Instituto Nacional de Ciencias MÃ©dicas y NutriciÃ³n Salvador ZubirÃ¡n. Mexico City, Mexico. She is also a member of ASCO’s IDEA Working Group.

 is chairman, Prostate Conditions Education Council; editor in chief, Grand Rounds in Urology; and professor of Urology, University of California San Diego, La Jolla, California.

1.     Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. 

. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126.

2.     Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline.

Experts discuss the case of a 56-year-old white man who presents with multiple immune-related adverse events

ONCOLOGY Vol 34 Issue 5 | Oncology

Navigating Uncharted Waters

Fighting 2 Enemies: Cancer and COVID-19

Managing Prostate Cancer Surgical Patients during the COVID-19 Pandemic: A Brief Report of the Duke Cancer Institute’s Initial Experience

A Rational Approach to Managing Prostate Cancer in an Irrational Time

Forging Ahead in a Time of Crisis

Immune-Related Adverse Events Involving Multiple Organ Sites in a Patient Treated With Nivolumab Plus Ipilimumab

Novel Neoadjuvant Treatment Strategies for Triple-Negative Breast Cancer

76-Year-Old Woman With a Bluish-Purple Lump in her Left Upper Medial Leg