Best Practices in Urothelial Carcinoma: Utilizing Nonsurgical Options for Low-Grade Upper Tract Urothelial Carcinoma (LG-UTUC)

Panelists:

Sandip M. Prasad, MD, MPhil

Urology Oncology & Minimally Invasive Urology Specialist
Garden State Urology
Whippany, NJ

Cristina McKeen, RN, BSN

Occupational Medicine
Atlantic Health System
Morristown, NJ

Janet Booher

Insurance Coordinator
Franklin Surgical
Basking Ridge, NJ

Moderator: Nicholas J. Sarlis, MD, PhD

Senior Medical Advisor
The Lynx Group
Cranbury, NJ

On April 12, 2021, a select group of healthcare professionals involved in the care of patients with urothelial carcinoma (UC) participated in a virtual multidisciplinary panel to discuss best practices in the use of Jelmyto® (mitomycin) for pyelocalyceal solution, which was approved by the US Food and Drug Administration (FDA) in April 2020 for the treatment of adult patients with low-grade upper tract urothelial carcinoma (LG-UTUC). Jelmyto is contraindicated in patients with perforation of the bladder or upper urinary tract. This paper will present a brief overview of UC and discuss treatment approaches and emerging options for managing LG-UTUC. It will also provide best practices on the logistics involved in distribution of Jelmyto and the reimbursement implications for healthcare providers treating patients with LG-UTUC.

Overview of Disease and Epidemiology

UC is a malignancy that affects the urothelial cells that line the bladder, renal pelvis, ureters, and the urethra, accounting for an estimated 164,000 cases in the United States in 2021.1 Although upper and lower tract UC possess histologic similarities, they are considered to be 2 different types of malignancies due to their varying disease characteristics and prognosis. Upper tract urothelial carcinoma (UTUC) is a rare subset of UC, comprising 5% to 10% of all urothelial cancers.2 Although urologists might encounter and treat urothelial cancers frequently, the very low incidence of UTUC (annual incidence of 2 new cases per 100,000 people in Western countries)3 highlights the importance of considering UTUC as a possible diagnosis and staying current on emerging treatment paradigms.

UTUC is assigned a tumor grade as low-grade or high-grade disease based on morphologic characteristics that are directly linked to its malignant potential, and this determines varying prognosis and treatment options.3 Approximately 30% of UTUCs are low-grade. These are cancers that in general behave in a relatively indolent or slow-growing fashion. They grow locally and can reach quite a large size while still being asymptomatic, even at a later stage of disease.4 The UTUCs that are high-grade are very different. These are tumors that can metastasize within weeks to months and have a much more aggressive behavior. According to Dr Prasad, “Therefore, their prognosis and overall management are different. So, the initial separation between high-grade and low-grade is the first step to choosing a treatment approach.”

Risk factors contributing to the development of UTUC include environmental to genetic factors.5 Although inherited traits and gene polymorphisms play a key role in defining disease risk, tobacco smoking remains one of the primary modifiable risk factors associated with UTUC and accounts for 70% of male and 40% of female disease incidence.6-8

Gross or microscopic hematuria is the most common symptom/sign of UTUC, with up to 80% of patients presenting with this finding. Flank pain and a lumbar mass are manifestations of UTUC, occurring at a rate of 20% to 40% and 10% to 20%, respectively, at the time of initial diagnosis.2 Computed tomography imaging, flexible ureteroscopy, and ureteroscopic biopsy are methods for firm establishment of a UTUC diagnosis.

Disease Burden

UTUC is more commonly seen between the 7th and 8th decades of life and is 3 times more prevalent in men than in women.2,9 Sixty percent of UTUC is invasive at diagnosis in comparison to 15% to 25% of lower tract urothelial carcinoma (LTUC) and has a worse prognosis with a 5-year recurrence rate of 28% and 5-year mortality rate of 23%.10 Factors that contribute to the grim prognosis for UTUC include the presence of advanced disease at the time of initial diagnosis (due to the lack of effective screening modalities) and the thin composition of the ureter wall (allowing for locoregional transmucosal spread). Patient-related factors contributing to poor prognosis include advanced age, obesity, current smoking, being African American, poor Eastern Cooperative Oncology Group performance status, high tumor grade, presence of symptoms and/or hydronephrosis at presentation, and history of bladder cancer.6

In addition to the poor prognosis for this malignancy based on the aforementioned factors, there also exists significant associated morbidity due to complications that arise from renal function decline through either long-standing obstructive uropathy or loss of a renal unit to radical nephroureterectomy (RNU; see next section). Thus, some UTUC patients are at risk for severe renal insufficiency and consequently, cardiovascular complications. UTUC patients with chronic kidney disease (CKD) have an overall mortality that is almost 3 times that of patients without CKD and have a >50% rate of hospitalization per patient-year.11

Treatment Modalities
Radical Nephroureterectomy

The gold standard treatment for UTUC has been RNU.12-15 When performing RNU, open procedure was the preferred treatment until the past decade or so, but laparoscopic technique has gained significant predominance as the procedure of choice, especially as it has recently been shown to have short- to mid-term oncologic outcomes that are comparable to an open surgical approach. Laparoscopic RNU is also associated with lower blood loss and shorter hospital stays at 5 years compared with open techniques.16

Even though RNU promises overall satisfactory oncologic outcomes, treatment approaches that are organ-sparing are the preferred method for low-grade tumors in general, and that adage certainly applies to LG-UTUC. Multiple studies have demonstrated the decrease in estimated glomerular filtration rate with no recovery over time for patients who have lost a kidney due to RNU.17,18

The financial burden that results from losing a renal unit is also a major factor to consider, with a 3- to 10-fold increase in cost associated with an RNU versus a nephron-sparing treatment.2 According to Dr Prasad, “Patients are arriving into surgery with advanced kidney disease subsequent to the procedure associated with a loss of a renal unit. So, many of them progress on to stage 4 or 5 CKD, which means that patients are dialysis-dependent and/or in need of renal transplantation. Taking patients to dialysis versus keeping them off dialysis has tremendous implications for the patients, as well as for society.” Studies have shown the financial impact associated with RNU to be significant, with the initial procedural costs ranging from $11,793 to $23,235 per patient, readmission/retreatment costs of $31,697 per patient, and long-term costs (up to 5 years out and also associated with CKD) ranging from $41,474 to $385,164 per patient. In comparison, kidney-sparing treatment approaches were associated with cost-savings of $252,272 per patient over a 5-year period.19

Endoscopic Management

Nephron-sparing endoscopic management is a minimally invasive treatment strategy that offers outcomes in survival and oncologic measures that are comparable to the standard of therapy (laparoscopic or open RNU) in a select patient population.2 Endoscopic management of UTUC has primarily been reserved for patients with solitary kidneys or bilateral disease, or those who are not candidates for RNU. Limited retrospective case studies have shown no short- and mid-term differences in overall or cancer-specific survival between endoscopic management and RNU, with long-term renal complications occurring less frequently with endoscopic management.2,20 This strategy is primarily reserved for patients who are readily available for frequent and regular follow-up, as they are prone to high local recurrence rates (up to 50% in 5 years post-procedure). The rate of recurrence is associated with the size of the initial primary tumor, with lesions smaller than 1.5 cm having a low likelihood of recurrence.6

Topical Intracavitary Therapy with BCG or Soluble Mitomycin

Even though RNU remains the gold standard approach for the management of LG-UTUC, a 70% risk of subsequent recurrence still exists following this procedure. To reduce the risk of recurrence, topical administration of chemotherapeutic and immunotherapy agents has been used as an adjuvant therapy post-RNU or endoscopic tumor extirpation to prevent or delay recurrences. These agents can be administered through a ureteric catheter in a retrograde manner or through a percutaneous nephrostomy tube in an antegrade fashion. The 2 most common agents used for this treatment are bacillus Calmette-Guérin (BCG) immunotherapy and mitomycin-C.21 BCG has been used for UTUC in doses similar to those given for bladder cancer therapy, with volumes ranging from 40 mL to 250 mL. Rates of response range from 63% to 100%, with a recurrence rate of up to 50%.11 Use of BCG, which is approved for non–muscle-invasive bladder cancer, in patients with UTUC has demonstrated good outcomes but lacks sufficient long-term follow-up data, and the monitoring of recurrence is burdensome to both the patient and the healthcare system.

A single intravesical instillation of soluble mitomycin-C, an antibiotic isolated from the broth of Streptomyces caespitosus which has been shown to have antitumor activity, post-RNU can reduce the risk of recurrence by 40%.16 A retrospective review demonstrated that treatment with adjuvant mitomycin was associated with a cancer-free survival rate of 65%, with a recurrence of 35% at the mean follow-up of 24 months. None of the patients with low-grade disease required nephroureterectomy and maintained a stable kidney function.22 Doses for mitomycin for intracavitary instillation have varied, with 40 mg being dissolved in 30, 40, or 1000 mL of saline or 5 mg in 20 mL of saline.11

Chemotherapy as a Primary Treatment Option: Jelmyto

As discussed above, endoscopic management has historically involved the use of a chemotherapeutic agent as a preventive measure after tumor ablation. However, a new approach is to use chemotherapy as a primary treatment modality to treat LG-UTUC. Jelmyto for pyelocalyceal solution was approved by the FDA in April 2020 and indicated for the treatment of adult patients with LG-UTUC.23 It is the first chemo-ablative agent—formulated in a unique fashion for optimal local delivery—to be FDA-approved for use in LG-UTUC. The FDA granted priority review and breakthrough therapy designation for Jelmyto based on the fact that it is the first drug to demonstrate significant improvement over other available frontline therapies for a diagnosis of LG-UTUC, which remains a serious and life-threatening malignancy. Given that there was no previously approved therapy for this serious condition, it was also granted a fast-track designation by the FDA. Its orphan drug designation also provided further impetus for its successful clinical development as a treatment aimed at a rare disease.24

One of the main challenges for traditional instillation of mitomycin has been assuring sufficient drug contact time with the tumor and surrounding transitional epithelium at the site of administration due to the difficulty of reaching the highly complex anatomical structures of the renal pelvis, as well as constant wash-off of the soluble chemotherapeutic due to the steady, continuous production of urine by the kidney (an effect further accentuated by gravity). Jelmyto offers a solution by utilizing a novel reverse-thermal technology (RTGel™) combining mitomycin with a sterile hydrogel that allows it to fill and conform to the anatomically complex structure of the renal collecting system and, thus, deliver a sustained exposure of mitomycin for up to 4 to 6 hours post-gel application.23

Mechanism of action

Jelmyto inhibits the synthesis of DNA. It also suppresses cellular RNA and protein synthesis at high concentrations.23

Clinical data
Efficacy

The OLYMPUS study, an open-label, single-arm, multicenter trial enrolled 71 patients with treatment-naïve or recurrent noninvasive LG-UTUC with ≥1 measurable papillary tumors (0.5-1.5 cm) located above the ureteropelvic junction. Patients were treated with Jelmyto 4 mg/mL to a total volume sufficient to completely fill the renal pelvis, once weekly for a total of 6 weeks. Patients who had complete response (CR) after the initial treatment period entered maintenance therapy consisting of once-monthly additional Jelmyto instillations for a maximum of 11 such administrations.23

Efficacy was measured as rate and durability of CR at 12 months based on ureteroscopic and pathology assessments. CR was defined as a complete absence of tumor lesions in the ipsilateral pyelocalyceal system 3 months post-initiation of Jelmyto treatment. A total of 41 patients (58%) achieved CR in the study (95% confidence interval [CI], 45-69; Figure 1).23 Of the patients who achieved CR, 23 patients (56%) achieved durability of CR at 12 months.23

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Figure

Safety

In the OLYMPUS study, ureteric obstruction (a composite term covering ureteric stenosis, hydronephrosis, urinary tract obstruction, pelvi-ureteric obstruction, ureteric obstruction, and obstructive uropathy) was reported as an adverse event (AE) in 58% (N = 41) of patients receiving Jelmyto, including 17% (N = 12) of patients who experienced grade 3 obstruction (Figure 2).23 The median time to first onset of this AE was 72 days (range, 15-462). Remedial interventions in the 41 patients experiencing ureteric obstruction included ureteral stent placement (88%), balloon dilatation (29%), and nephroureterectomy (4.9%). In the 36 patients who required ureteral stent placement, the median duration of indwelling stents was 52 days (range, 1-292). Ureteric obstruction did not resolve or resolved with sequelae in 44% (N = 18) of these patients. Of the 41 patients who experienced ureteric obstruction, 17% (N = 7) experienced Grades 1-2 increase in serum creatinine.23 Bone marrow suppression was also a notable adverse reaction in the OLYMPUS trial. Grade 3 thrombocytopenia occurred in 3 patients, grade 3 anemia in 1 patient, and grade 3 neutropenia in 1 patient.23

Click Image to Enlarge
Figure

Warnings and precautions

Given the safety profile of Jelmyto (Table),23 it is recommended to monitor patients for signs and symptoms of ureteric obstruction, including flank pain, fever, and alterations in kidney function. Withholding or permanently discontinuing Jelmyto might be necessary based on the severity of the ureteric obstruction. Patients may also require temporary or long-term ureteral stents to alleviate ureteric obstruction.23

Click Image to Enlarge
Figure

Patients on Jelmyto treatment should be monitored for bone marrow suppression. Prior to each treatment, the following laboratory tests should be performed: platelet count, white blood cell count differential, and hemoglobin. Jelmyto instillations should be withheld for grade 2 thrombocytopenia or neutropenia and permanently discontinued for grade 3 or greater thrombocytopenia or neutropenia.23

Dosing and administration

Jelmyto is administered as a 4-mg/mL pyelocaliceal instillation via ureteral catheter or a nephrostomy tube with a total instillation volume not to exceed 15 mL (60 mg of mitomycin). It is instilled once weekly for 6 weeks and the frequency adjusted to once a month for a maximum of 11 additional instillations in patients who have a CR after 3 months of Jelmyto treatment.23

Practical considerations

Patients should take 1.3 g of sodium bicarbonate orally the evening prior to, the morning of, and 30 minutes prior to the instillation procedure for a total of 3.9 g for adequate urine alkalinization. The latter dose of sodium bicarbonate should be omitted if the patient will be anesthetized for the procedure.23

General anesthesia, local anesthesia, sedation, and prophylactic antibiotics and/or antihistamines may be used at the discretion of the treating urologist.23

How supplied

Jelmyto single-dose carton contains 2 40-mg single-dose vials as a sterile lyophilized powder and 1 20-mL single-dose vial of sterile hydrogel to be used as a vehicle for reconstitution.23

Instillation

Jelmyto is to be reconstituted by a pharmacy and delivered to the facility where instillation of the drug will take place. Jelmyto is indicated for instillation by retrograde or antegrade (through a nephrostomy tube) approach. The reconstituted Jelmyto will appear as a semisolid gel requiring chilling in an ice bath to a temperature of 27°F to 41°F for at least 10 minutes, but no longer than 1 hour, to convert it to a viscous liquid ready for instillation. Even in a chilled liquid state, Jelmyto will have a viscous composition that will require a Uroject12 Syringe Lever to instill it into the pyelocalyceal cavity. This syringe lever is a multi-use device and must be sterilized or disinfected prior to use (Figure 3).23

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Figure

The instillation volume will be equal to the patient’s kidney volume. The latter determined volume or 15 mL, whichever is lower, will be the final instillation volume. Once the chilled Jelmyto vial is removed from the ice bath for instillation, it should be drawn into a syringe within 4 minutes to avoid solidification. After the 4-minute time point, the components should be recapped and placed in the ice bath for no more than 15 minutes to allow for liquification.23

When ready for instillation, the syringe adaptor should be removed from the administration syringe. The administration syringe will then be connected to the ureteral catheter’s Luer Lock port by rotating the syringe only. For the majority of doses administered in the OLYMPUS study, a 7 French catheter was used for administration of Jelmyto, but a 5 French catheter can also be used if the use of the former is challenging. After confirming through fluoroscopy that the ureteral catheter is in the appropriate position, Jelmyto can be instilled into the patient by turning the knob at a rate of 1 to 2 seconds per stroke. The entire syringe must be emptied within 1 minute (Figure 3).23

General anesthesia is not required for the instillation; however, it was used in 37% of patients for at least 1 instillation during the treatment period during the clinical trial.23 Local anesthesia or sedation was used on the remainder of patients. Based on the experience of Dr Prasad, some patients “are getting Jelmyto instillation without anesthesia, and although in many cases mild sedation can be used, they are back to work or their usual activities the same day...”

Storage and handling

Jelmyto should be stored at room temperature (68-77°F). It is a cytotoxic drug requiring special handling and disposal procedures.23,25

Pharmacy handling and preparation

Jelmyto is prepared in a pharmacy with specific instructions and under aseptic conditions. Because reconstituted Jelmyto has to be prepared under chilled conditions, a UroGen Pharma Chilling Block is also provided to the pharmacy. The Chilling Block must be placed in the freezer at –4°F to 10.4°F the night before preparation. Jelmyto cannot be prepared using other methods of chilling. Specific reconstitution and preparation instructions are included within the Jelmyto single-dose carton provided by the manufacturer. After completion of preparation, the “discard after” date should be affixed to the admixture label, which is 8 hours from the completion of the preparation at room temperature. The Jelmyto preparation should then be placed in a light-protective bag and transported to the treatment facility.26

Ordering and distribution

UroGen Support provides a dedicated team to help manage and coordinate drug acquisition, preparation, and delivery with the pharmacy and the facility at which the drug will be administered (Figure 4).27,28 To initiate the ordering of Jelmyto, the provider must complete a pre-enrollment form, which is a signed declaration by the provider to acquire the product solely through Cardinal Health Specialty Pharmaceutical Distribution.27 After this Declaration Letter is submitted, the provider will then have to enroll the patient in the UroGen Support Program by completing and signing the enrollment form. Once received, UroGen Support conducts the necessary research on benefit qualifications (benefits verification) and financial support eligibility of the patient. This investigative report, along with the patient’s insurance coverage information and potential prior authorization requirements, will be shared with the provider. After completion, UroGen Support coordinates with the prescriber on product acquisition, preparation, and delivery.28 The UroGen team members supporting the clinic/practice will then call the provider to confirm the patient’s appointment and coordinate the ordering and delivery of the product to the UroGen-designated pharmacy and drug administration facility with each scheduled instillation.27

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Figure

For Cristina McKeen and her colleagues in her practice, the experience with their first instillation was made easy through initial educational sessions received from the UroGen clinical nurse educator. Moreover, consistent coordination was maintained throughout the treatment regimen of patients. Ms McKeen stated, “Prior to the first procedure, I received a phone call to verify the day and time of the procedure for the patient. Then, on the day of the procedure, the UroGen Support team member would call me again to ensure that the drug was received and also confirm the date of the next instillation. This was done weekly for 6 weeks. I would get a phone call both before the procedure (to set up the delivery and ensure timely delivery), as well as after the procedure (to make sure Jelmyto was delivered, and that the instillation went well).”

Reimbursement

Billing and coding requirements for Jelmyto are determined based on the patient’s insurance type, benefit type under which Jelmyto is covered, and administration site of the drug. Jelmyto can be administered at a physician’s office, hospital outpatient department (HOPD), or an ambulatory surgical center (ASC).29

As of January 1, 2021, a permanent J code has been approved for use for Jelmyto: J9281. Jelmyto has pass-through status in both HOPD and ASC settings for beneficiaries of Medicare. It is both recommended and appropriate to report any drug wastage when billing for Jelmyto using the modifier JW “Drug Amount Discarded, Not Administered to Any Patient.”29,30

The most prevalent payer for patients who receive Jelmyto is Medicare. Medicare usually covers and separately reimburses for the drug itself and required associated services. This encompasses instillation of Jelmyto in a physician’s office, HOPD, as well as ASC. Commercial insurance carriers may also cover Jelmyto and the associated medical expenses. In this case, restrictions on coverage will likely apply, ranging from special requirements for distribution and precertification. Medicaid coverage for Jelmyto varies by state and the specific state-managed Medicaid plan. Therefore, it is essential to check with the specific program or plan.29

Even though Jelmyto is covered through a large number of plans, the UroGen Support Copay Program also offers patient assistance programs for eligible patients. Eligible patients with commercial health insurance enrolled in the support program can qualify to pay as little as $50 per dose of Jelmyto for the cost of the drug with a maximum benefit of $4000 per dose. Providers will bill the support program as a secondary insurance after the primary insurance benefit is utilized.31

For patients without health insurance, the UroGen Support Patient Assistance Program may be able to support eligible patients. Eligibility requirements include use of Jelmyto for an on-label indication and an adjusted gross income of ≤400% of the Federal Poverty Level based on household income.31

More specific terms and conditions for these support programs can be attained through the UroGen Support group. According to Janet Booher, Jelmyto offers an economical option in comparison to costs associated with previously used alternative treatment options. Ms Booher stated that “When we were deciding to do this procedure at our center, we made sure that we knew ahead of time of the pricing and whether the insurance company would handle and cover everything at 100% level; further, we had a lot of help from UroGen by making sure they educated our billing and coding departments. We have been receiving our payments within about 45 days.”

Patient counseling points

It is important to stay cognizant of what patients may experience after Jelmyto instillation and, hence, it is appropriate to educate them on certain key points to ensure an optimal therapeutic experience for the patients and their caregivers. Patients should be informed that following instillation of Jelmyto, their urine may be discolored to a violet to blue color; this is expected and should not alarm the patients. Patients are also advised to avoid contact with their own urine for at least 6 hours post-instillation, void urine sitting on a toilet, and flush the toilet several times after use. Clothing that comes in contact with a patient’s urine should be washed right away and separately from other apparel.23

According to Ms McKeen, “It is very important for the patient post-procedure that the nursing staff provide education. From a safety standpoint, there are standard chemotherapy precautions for the patients to abide by. Patients are given an educational pamphlet and the information is also included in their discharge instructions.”

Patients should continually be reminded about the importance of compliance to have the desired outcome with the use of Jelmyto. According to Dr Prasad, “In my experience having treated multiple patients, they are highly compliant because they understand the consequences of what happens if tumors recur or are not treated completely. If they get through the first treatment or two, they will do quite well. All of my patients have had all 6 instillations within 6 weeks without discontinuation.”

Conclusion

Jelmyto offers a nephron-sparing treatment approach that has the potential to be the mainstay of treatment used by urologists for adult patients with LG-UTUC. Utilizing an existing clinically effective drug and augmenting its capability to overcome anatomic challenges and prolonged exposure time, Jelmyto offers urologists a new treatment option with efficacy outcomes and a tolerable safety profile. According to Dr Prasad, “Jelmyto is using an existing therapy that we know has consistently shown benefit in this tumor type. Because it is being used in a novel formulation by leveraging an innovative proprietary gel technology, it allows for contact time between the chemotherapeutic (mitomycin) and the tumor. Finally, Jelmyto uses an administration technique (pyelocalyceal instillation in most cases via a ureteral catheter or in select cases a nephrostomy tube) that is very easy for urologists to replicate, while also using an agent (mitomycin) the value of which is well understood within the specialty for the treatment of transitional cell carcinomas, and that includes LG-UTUC.”

In addition to its favorable efficacy and safety profile, the procurement, distribution, and reimbursement of Jelmyto is set up to deliver a seamless process. The logistics of distribution and reimbursement of Jelmyto as described above is a collaborative process between providers, facility staff members, and the manufacturer. Detailed product preparation, handling, and administration instruction guides are provided by the manufacturer upon delivery of the product. Upon invitation from the treating physician, UroGen Support Team members are available to provide product and instillation method education to staff members at the facility site during instillation, as well as continued guidance on claim submission to help optimize reimbursement. Providers should leverage expertise from UroGen Support, which is dedicated to providing a well-coordinated and easy transaction between all stakeholders with the aim of getting Jelmyto to the patients who need it the most.

References

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