Posted: Monday, November 21, 2022
Early-Stage Muscle-Invasive Bladder Cancer: Role of Perioperative Systemic Treatment
Patients with stage II and III muscle-invasive bladder cancer are often treated with surgery, usually radical cystectomy.1 Bladder preservation with concurrent chemoradiotherapy is another option for these patients. Those with muscle-invasive disease at the time of radical cystectomy are at very high risk (50%) for recurrence.2 For most of those patients, disease recurrence will not be curable. “This gives us a very strong rationale for employing an adjuvant strategy,” stated Matthew I. Milowsky, MD, FASCO, The George Gabriel and Frances Gable Villere Distinguished Professor of Bladder and Genitourinary Cancer Research at the University of North Carolina School of Medicine/Lineberger Comprehensive Cancer Center in Chapel Hill. “The critical question,” he observed, “is what are the best perioperative strategies for patients with muscle-invasive bladder cancer in this setting?”
There is level 1 evidence to support the use of cisplatin-based, combination chemotherapy in the neoadjuvant setting.3 That represents best practice for patients who are eligible to receive cisplatin-based therapy. “In contrast, there is no level 1 evidence to support the use of cisplatin-based chemotherapy in the adjuvant setting.”4
Dr. Milowsky, who is also Co-Director of the Urologic Oncology Program at the Lineberger Comprehensive Cancer Center, told JNCCN 360 there has been a series of studies in the adjuvant setting, “but they have all been underpowered, in large part, due to accrual issues. The EORTC 30994 study was a large trial,5 but it, too, was underpowered. Systematic reviews of such trials suggest that overall survival is improved with adjuvant cisplatin-based therapy, but the level of evidence is not the same as for neoadjuvant treatment.”6 Moreover, about one-third of patients will not be eligible for cisplatin-based treatment in the adjuvant setting within the first 90 days after surgery because of issues that arise in the postoperative setting.7
An Alternative to Adjuvant Chemotherapy
In view of these issues in the adjuvant setting, there is an unmet need for non-cisplatin–based regimens that can decrease the risk for recurrence and improve survival outcomes for these patients after surgery. The CheckMate 274 trial was designed to evaluate adjuvant immunotherapy with nivolumab.8
Dr. Milowsky explained that the eligibility criteria for the CheckMate 274 trial were reasonable and should be part of real-world clinical decision-making. Patients with pT3/4 and/or node-positive disease; those who did not receive neoadjuvant therapy; and those who received neoadjuvant therapy but demonstrated persistent muscle-invasive disease may be considered for adjuvant treatment. In August 2021, the U.S. Food and Drug Administration approved nivolumab for the adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection.9
[Editor’s Note: Nivolumab is also indicated for patients with locally advanced or metastatic urothelial carcinoma who experience disease progression during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.]
According to Christine Liebertz, NP, MSN, AOCNP, who has been a member of the genitourinary service at Memorial Sloan Kettering Cancer Center (MSK) in New York for 27 years, “in addition to meeting eligibility criteria, the patient’s condition is an important factor. He or she needs to be in good enough condition to tolerate treatment.”
Muscle-Invasive Bladder Cancer Versus Upper Tract Disease
One of the variables in CheckMate 274 was pathologic evidence of urothelial carcinoma (originating in the bladder, ureter, or renal pelvis). “It was smart to include patients with upper tract urothelial cancer in the CheckMate 274 study,” Dr. Milowsky said. About 10% of patients will have upper tract urothelial cancer, the majority of which arise in the renal pelvis.10 Although the forest plots suggested that patients with upper tract disease may not derive as much benefit from adjuvant nivolumab as patients with bladder cancer, “we have to be very careful about making decisions on the basis of subgroup analyses, as the overall trial was positive for an improvement in disease-free survival,” Dr. Milowsky noted.
Neoadjuvant Cisplatin Plus Adjuvant Nivolumab?
Although overall the study was positive, whether patients received neoadjuvant cisplatin or not, Dr. Milowsky reported, the subgroup analysis suggests the greatest benefit was seen in those who received preoperative treatment. “In fact,” he said, “that was a stratification factor. We do not know why that was the case, and a good percentage of patients (40%–45%) had received neoadjuvant cisplatin. Could it be that chemotherapy sensitized patients to the effects of immunotherapy? We do not know.”
Conversations With Patients
“Now that we have these data” [ie, from CheckMate 274], “our conversations with newly diagnosed patients can include adjuvant immunotherapy as part of the overall plan, if pathologic findings during surgery warrant its consideration,” Dr. Milowsky told JNCCN 360. This would be in addition to starting with neoadjuvant chemotherapy, followed by radical cystectomy. [Editor’s Note: Patients who received nivolumab had a median disease-free survival of 20.8 months vs. 10.8 months with placebo.]
A ‘New Normal’ After Surgery?
Some patients have recently undergone both neoadjuvant chemotherapy and extensive surgical procedures, Ms. Liebertz told JNCCN 360. “They may still be adjusting to their postchemotherapy, postoperative bodies, so we need to be mindful of those changes. By the time we are at the point of initiating adjuvant systemic therapy (perhaps 6 to 8 weeks after surgery), patients will have become at least somewhat familiar with whatever changes surgery has wrought. They may have an ileal conduit, or there may be a change in urinary function or sexual function. We need to recognize that patients are individual in their abilities to adjust to these changes.”
Adjuvant systemic treatment is one approach to improving the patient’s outcomes, but additional emphasis on healthy living—ie, good nutrition, activity/exercise, preventive health screenings and maintenance—will enhance any benefits associated with therapy.
“As providers,” Ms. Liebertz continued, “we not only evaluate patients at baseline and monitor for potential treatment-related toxicities, but also should be encouraging healthy lifestyles and strategies to help regain normal function and well-being. Adjuvant systemic treatment is one approach to improving the patient’s outcomes, but additional emphasis on healthy living—ie, good nutrition, activity/exercise, preventive health screenings and maintenance—will enhance any benefits associated with therapy."
At MSK, after a medical oncologist makes the recommendation for adjuvant treatment and explains the rationale to the patient, the outpatient nurse begins the initial patient education on the therapy, Ms. Liebertz explained. With any therapy, but particularly with immunotherapy, this should be an ongoing process that requires reinforcement and monitoring.
Treatment Administration: Clinical Trial Versus Real Life
Unlike the clinical trial setting, in practice, “we don’t routinely measure PD-L1 levels nor use them to determine therapy for patients with muscle-invasive bladder cancer,” Dr. Milowsky said. “The PD-L1 story is complicated, but it just has not panned out the way we hoped it would.”
In addition, the CheckMate 274 protocol administered 240 mg of nivolumab every 2 weeks for 12 months. “In practice, we often give 480 mg monthly, which generally enhances the convenience of the regimen and reduces the impact on patients’ everyday lives and schedules,” Dr. Milowsky explained. Ms. Liebertz confirmed that adjuvant nivolumab is also administered monthly at MSK rather than every 2 weeks.
“We do not usually give any pretreatment medications—unless the patient has previously experienced an infusion reaction,” Ms. Leibertz said. Patients are seen every 4 weeks for infusion and are closely monitored. Laboratory testing evaluates blood cell counts, and comprehensive panels are performed looking at liver and renal function. Another standard evaluation is for thyroid function. And, “of course, the patient meets with the clinician for a physical exam before each infusion.”
“When we talk with patients,” Ms. Liebertz told JNCCN 360, “our key message is that anything out of the norm should be reported. It might be completely fine, but if patients have a question or concern, we want to know. There’s no symptom too small to advise us about. We reassure patients that most individuals tolerate the therapy very well,” she continued, “with no or minimal toxicity, but there are a few high-risk adverse effects for which early intervention is critical.” Much has been learned about how to safely administer immunotherapies, but “there’s always that one patient out of hundreds who may develop a significant toxicity,” cautioned Ms. Liebertz.
We need to be proactive by knowing what to look for in terms of adverse events.
Unlike with chemotherapy, where symptoms may appear rapidly, toxicities with immunotherapy may develop over time. For patients treated with nivolumab or any checkpoint inhibitor, the MSK team has a very low threshold for referring patients to the appropriate specialist (eg, pulmonologist, gastroenterologist, endocrinologist, dermatologist). “If we note a potential risk for a serious adverse event, we refer,” Ms. Liebertz observed.
Because fatigue is a common symptom, “we look for endocrinopathies, such as abnormal thyroid or adrenal function, or another potential cause, such as anemia.” Ms. Liebertz also recommended that patients keep skin hydrated and well moisturized to prevent common skin rashes. These skin symptoms, such as pruritus, are usually treated aggressively, “because they can significantly affect the patient’s quality of life,” she pointed out.
Of note, “we deliberately do not recommend over-the-counter treatments for common discomforts such as diarrhea, for example, precisely because we want patients to report those symptoms. Diarrhea may be just a passing issue, or it could be a sign of something more serious, such as inflammation or colitis. We want the opportunity to investigate anything out of the ordinary. This is one of the biggest lessons we’ve learned about using immunotherapy: We need to be proactive by knowing what to look for in terms of adverse events.”
According to Dr. Milowsky, the incidence of grade 3 or 4 adverse effects in the nivolumab arm of CheckMate 274 was less than 20%. “That’s pretty reasonable,” he told JNCCN 360. “Our experience with checkpoint inhibitors is that they are well tolerated…, until they’re not. And, of course, oncologists have become better at recognizing and managing the less common adverse events associated with checkpoint inhibitors. The more common side effects, such as mild fatigue, perhaps some rash, loose bowel movements, are manageable. The treatment-related adverse events are also manageable if we educate our patients, recognize them quickly, and initiate treatment. Of note, the quality-of-life data from this study showed no detriment in the experimental arm, which is important in the adjuvant setting.
Evolving Data, Better Markers
A major criticism of the CheckMate 274 study is that an overall survival benefit was not observed. The IMvigor010 study, another adjuvant study, looked at atezolizumab vs surveillance.11 This trial, which did not use a placebo, did not show a benefit for atezolizumab. Finally, data from the AMBASSADOR study by the National Cancer Institute trials group, [ClinicalTrials.gov identifier NCT03244384] are pending. “So, there’s one positive study and one negative study,” Dr. Milowsky commented.
There was an analysis of the IMvigor010 study that looked specifically at circulating tumor DNA (ctDNA).12 “It showed that ctDNA could be potentially both prognostic and predictive with regard to the use of checkpoint inhibitors in the adjuvant setting for muscle-invasive bladder cancer,” Dr. Milowsky reported. As a result, the IMvigor011 study is using ctDNA to guide the use of adjuvant atezolizumab.
“There’s a lot more to come,” Dr. Milowsky stated. “For instance, if we can better select patients based on the presence or absence of ctDNA as a biomarker—because PD-L1 is not great—we can get closer to treating patients who really will benefit from adjuvant treatment and avoid the potential toxicities of treatment in those who are destined to have excellent outcomes. A colorectal cancer study looking at ctDNA to guide adjuvant therapy was just published in The New England Journal of Medicine.13 It is an exciting story,” he noted.
Does the Use of Adjuvant Treatment Affect Choices of Later-Line Therapies?
With regard to the use of a checkpoint inhibitor for more advanced disease, Dr. Milowsky commented: “Until we have evidence-based information, we may have to choose an arbitrary time point, after which we can rechallenge. In other words, if a certain period (perhaps 6 months, 1 year) has elapsed since adjuvant therapy with a checkpoint inhibitor was discontinued, it may be reasonable to use such treatment again in the metastatic setting, if it becomes necessary.”
Moving Toward Health and Life After Surgery
In the adjuvant setting, as previously noted, “we try to emphasize strategies to move patients back to health and normalcy,” Ms. Liebertz said. Because previous chemotherapy and/or surgery may have curtailed their ability to be active, patients often gain weight. Thus, even after they have healed from surgery, they may have less energy and feel less able to do things they had previously enjoyed. “We encourage exercise, social interactions, healthful eating, and positive engagement. Adjuvant treatment is a little extra insurance, but patients should be urged to resume a fulfilling life.”
Matthew I. Milowsky, MD, FASCO, has reported stock and other ownership interests in Pfizer, Merck, and Gilead. He also has served as a consultant or advisor to Loxo/Lilly and has financial relationships with Elsevier and Medscape. Dr. Milowsky’s institution has received research funding from Merck, Roche/Genentech, Bristol Myers Squibb, Mirati Therapeutics, Incyte, Seagen, GI Therapeutics, Alliance Foundation Trials, Alliance for Clinical Trials in Oncology, Clovis Oncology, Arvinas, and Regeneron.
Christine Liebertz, NP, MSN, AOCNP, has reported no conflicts of interest.
- Flaig TW, Spiess PE, Abern A, et al. NCCN Clinical Practice Guidelines in Oncology. Bladder Cancer. Version 2.2022—May 20, 2022. To view the most recent version, visit NCCN.org.
- Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patient. J Clin Oncol 2001;19:666–675.
- Advanced Bladder Cancer (ABC) Meta-analysis Collaboration, Vale C. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 2003;361:1927–1934.
- Raghavan D, Bawtinhimer A, Mahoney J, et al. Adjuvant chemotherapy for bladder cancer—why does level 1 evidence not support it? Ann Oncol 2014;25:1930–1934.
- Sternberg CN, Skoneczna I, Kerst JM, et al. Immediate versus deferred chemotherapy after radical cystectomy in patients with PT3-pT4 or N+M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomized phase 3 trial. Lancet 2015;16:76–86.
- Advanced Bladder Cancer (ABC) Meta-analysis Collaborators Group. Adjuvant chemotherapy for muscle-invasive bladder cancer: a systematic review and meta-analysis of individual participant data from randomized controlled trials. Eur Urol 2022;81:50–61.
- Donat SM, Shabsigh A, Savage C, et al. Potential impact of postoperative early complications on the timing of adjuvant chemotherapy in patients undergoing radical cystectomy: a high-volume tertiary cancer center experience. Eur Urol 2009;55;177–185.
- Bajorin DF, Wittes A, Gschwend Je, et al. Adjuvant nivolumab versus placebo in muscle-invasive carcinoma. N Engl J Med 2021;384:2102–2114.
- S. Food and Drug Administration. FDA approves nivolumab for adjuvant treatment of urothelial carcinoma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-adjuvant-treatment-urothelial-carcinoma. Accessed October 18, 2022.
- Richards KA, Jarrard DF, Schwartz BF (ed). Urothelial tumors of the renal pelvis and ureters. Available at https://emedicine.medscape.com/article/452449-overview. Accessed October 16, 2022.
- Bellmunt J, Hussain M, Gschwend JE, et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomized, phase 3 trial. Lancet Oncol 2021;22:525–537.
- Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature 2021;595:432–437.
- Tie J, Cohen JD, Lahouel K, et al. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer. N Engl J Med 2022;386:2261–2272.