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Management of Locally Advanced Unresectable or Metastatic Urothelial Carcinoma: Expert Opinion from an Indian Panel via Delphi Consensus Method
CC BY 4.0 · Indian J Med Paediatr Oncol 2024; 45(05): 365-375
DOI: DOI: 10.1055/s-0042-1760317
Abstract
Introduction Currently, there are no guidelines for the management of locally advanced unresectable or metastatic urothelial carcinoma (mUC) from an Indian perspective. There is a lack of consensus on the utility of treatment options in first-line (1L) and second-line (2L) settings, especially in cisplatin- and platinum-unfit mUC patient subgroups.
Objective This articles aims to develop evidence-based practical consensus recommendations for the management of mUC in Indian settings.
Methods Modified Delphi consensus methodology was considered to arrive at a consensus. An expert scientific committee of 15 medical oncologists from India constituted the panel. Twelve clinically relevant questions were grouped into five categories for presentation and discussion: (1) cisplatin and platinum ineligibility criteria; (2) programmed death ligand 1 and fibroblast growth factor receptor (FGFR) testing in mUC patients; (3) treatment options in 1L settings; (4) role of switch maintenance; and (5) treatment options in 2L. Statements that reached high (≥ 80%) and moderate (60–79%) levels of consensus in the first round (electronic survey) did not undergo the second Delphi round. The questions that received a low level of consensus (< 60>
Results Renal impairment (creatinine clearance [CrCl] < 60 mL/min) and New York Heart Association class 3 heart failure are important assessment criteria for determining cisplatin ineligibility. Patients are unfit for any platinum-based chemotherapy in case of Eastern Cooperative Oncology Group performance status> 3 or severe renal impairment (CrCl < 30 mL/min). Gemcitabine and platinum with cisplatin over carboplatin were preferred in 1L settings. In patients unfit for cisplatin-based regimens, carboplatin–gemcitabine chemotherapy was preferred over immunotherapy (atezolizumab or pembrolizumab). Selected patients who are platinum ineligible may be considered for immunotherapy. Post-induction chemotherapy, those who do not progress may be strongly considered for avelumab maintenance. Experts recommended erdafitinib in FGFR-positive mUC patients in 2L settings. In FGFR-negative patients, immunotherapy (pembrolizumab, nivolumab, or avelumab) may be preferred over chemotherapy (paclitaxel, docetaxel, or vinflunine). Enfortumab vedotin and sacituzumab govitecan may be considered for further lines of therapy.
Conclusion Expert panel consensus will offer expert guidance to oncologists/clinicians on the management of mUC in Indian settings.
Key Points
In 1L settings, the experts preferred gemcitabine and platinum with cisplatin over carboplatin in mUC patients.
In patients unfit for cisplatin-based regimens, carboplatin–gemcitabine chemotherapy was preferred over immunotherapy (atezolizumab or pembrolizumab). Selected patients who are platinum ineligible (cisplatin and carboplatin) may be considered for immunotherapy (atezolizumab or pembrolizumab) in 1L. Post-induction chemotherapy, those who do not progress should be strongly considered for avelumab switch maintenance.
Erdafitinib was recommended in FGFR-positive mUC patients in 2L.
In FGFR-negative patients, platinum-based chemotherapy was suggested in 2L for those relapsing late, immunotherapy (pembrolizumab, nivolumab, or avelumab) for those who did not receive targeted immunotherapy in 1L, and single-agent chemotherapy (paclitaxel, docetaxel, or vinflunine) for other mUC patients.
Keywords
Authors' Contributions
All authors have contributed equally to the concept, design, editing, review, and finalization of manuscript.
Publication History
Article published online:
10 February 2023
© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
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Abstract
Introduction Currently, there are no guidelines for the management of locally advanced unresectable or metastatic urothelial carcinoma (mUC) from an Indian perspective. There is a lack of consensus on the utility of treatment options in first-line (1L) and second-line (2L) settings, especially in cisplatin- and platinum-unfit mUC patient subgroups.
Objective This articles aims to develop evidence-based practical consensus recommendations for the management of mUC in Indian settings.
Methods Modified Delphi consensus methodology was considered to arrive at a consensus. An expert scientific committee of 15 medical oncologists from India constituted the panel. Twelve clinically relevant questions were grouped into five categories for presentation and discussion: (1) cisplatin and platinum ineligibility criteria; (2) programmed death ligand 1 and fibroblast growth factor receptor (FGFR) testing in mUC patients; (3) treatment options in 1L settings; (4) role of switch maintenance; and (5) treatment options in 2L. Statements that reached high (≥ 80%) and moderate (60–79%) levels of consensus in the first round (electronic survey) did not undergo the second Delphi round. The questions that received a low level of consensus (< 60>
Results Renal impairment (creatinine clearance [CrCl] < 60 mL/min) and New York Heart Association class 3 heart failure are important assessment criteria for determining cisplatin ineligibility. Patients are unfit for any platinum-based chemotherapy in case of Eastern Cooperative Oncology Group performance status> 3 or severe renal impairment (CrCl < 30 mL/min). Gemcitabine and platinum with cisplatin over carboplatin were preferred in 1L settings. In patients unfit for cisplatin-based regimens, carboplatin–gemcitabine chemotherapy was preferred over immunotherapy (atezolizumab or pembrolizumab). Selected patients who are platinum ineligible may be considered for immunotherapy. Post-induction chemotherapy, those who do not progress may be strongly considered for avelumab maintenance. Experts recommended erdafitinib in FGFR-positive mUC patients in 2L settings. In FGFR-negative patients, immunotherapy (pembrolizumab, nivolumab, or avelumab) may be preferred over chemotherapy (paclitaxel, docetaxel, or vinflunine). Enfortumab vedotin and sacituzumab govitecan may be considered for further lines of therapy.
Conclusion Expert panel consensus will offer expert guidance to oncologists/clinicians on the management of mUC in Indian settings.
Key Points
In 1L settings, the experts preferred gemcitabine and platinum with cisplatin over carboplatin in mUC patients.
In patients unfit for cisplatin-based regimens, carboplatin–gemcitabine chemotherapy was preferred over immunotherapy (atezolizumab or pembrolizumab). Selected patients who are platinum ineligible (cisplatin and carboplatin) may be considered for immunotherapy (atezolizumab or pembrolizumab) in 1L. Post-induction chemotherapy, those who do not progress should be strongly considered for avelumab switch maintenance.
Erdafitinib was recommended in FGFR-positive mUC patients in 2L.
In FGFR-negative patients, platinum-based chemotherapy was suggested in 2L for those relapsing late, immunotherapy (pembrolizumab, nivolumab, or avelumab) for those who did not receive targeted immunotherapy in 1L, and single-agent chemotherapy (paclitaxel, docetaxel, or vinflunine) for other mUC patients.
Keywords
bladder cancer - metastatic urothelial carcinoma - locally advanced - India - management - consensus - DelphiIntroduction
Carcinoma of the urinary bladder is a common urological malignancy that causes substantial morbidity and mortality. As per the Global Cancer Observatory: CANCER TODAY (GLOBOCAN) statistics, bladder cancer (BC) ranked 10th in incidence, with approximately 573,000 new cases and 213,000 deaths in 2020.[1] Urothelial carcinoma (UC) is the predominant histologic type of BC and accounts for nearly 90% of all BC cases globally.[2] BC has a wide spectrum of disease severity from low-grade non–muscle-invasive BC (NMIBC) to muscle-invasive disease stage and metastatic lesions associated with poor outcomes.[3] The majority of muscle-invasive tumors are high-grade UCs. A high probability of local/systemic recurrences of muscle-invasive tumors within 36 months after local treatment of primary tumor has been observed.[4] BC diagnosed at earlier stages carry a greater chance of 5-year relative survival compared to later disease stages ([Table 1]).[5] Overall, 5-year relative survival rate for patients diagnosed with distant metastatic UC (mUC) is roughly 6%.[5] In India, BC is ranked 17th in incidence and 19th in mortality, with significant heterogeneity in incidence rates across different regions of India.[6] The overall incidence rate of BC in India as per the National Cancer Registry Programme report is 2.25 per 100,000 annually (males: 3.67 and females: 0.83).[7] In India, BC patients are more often diagnosed with locally advanced diseases, resulting in poor outcomes. A study by Prakash et al assessed the stage distribution of patients presenting with BC (N = 419) to a tertiary care cancer center in Mumbai.[8] The median age of patients at diagnosis was 59 (18–88) years.[8] Around 47% of patients had NMIBC, 36% had muscle-invasive and locally advanced disease, and 17% had metastatic disease.[8] The most common sites of distant metastasis were bone, lung, liver, pelvic peritoneum, adrenal glands, and nonregional lymph nodes.[8]
|
Stage at diagnosis |
5-year relative survival (%) |
|---|---|
|
Stage 0: Noninvasive papillary carcinoma and carcinoma in situ |
96 |
|
Stage 0–I: Localized (confined to primary sites) |
70 |
|
Stage III–IV: Regional (spread to regional lymph nodes) |
38 |
|
Stage IV: Distant (metastasis to lungs, liver, or bones) |
6 |
|
(A) Cisplatin/platinum ineligibility criteria: Summary of expert recommendations |
|---|
|
Expert recommendations on cisplatin-ineligibility criteria |
|
• ECOG PS ≥ 2 (LOE: 1a; GOR: ++; LOC: 66.7%). |
|
• CrCl < 60 mL/min (LOE: 1a; GOR: ++; LOC: 86.7%) |
|
• Grade ≥ 2 peripheral neuropathy (LOE: 2c; GOR: ++; LOC: 60%) |
|
• NYHA class 3 heart failure (LOE: 2c; GOR: ++; LOC: 80%) |
|
• Grade ≥ 2 hearing loss (LOE: 2c; GOR: +; LOC: 80%) |
|
Expert recommendations on platinum (cisplatin and carboplatin)-ineligibility criteria |
|
• ECOG PS > 3 (LOE: 2c; GOR: ++; LOC: 80%) |
|
• CrCl < 30 mL/min (LOE: 2c; GOR: ++; LOC: 80%) |
|
• Grade > 3 peripheral neuropathy (LOE: 2c; GOR: ++; LOC: 60%) |
|
• NYHA class > 3 heart failure (LOE: 2c; GOR: ++; LOC: 60%) |
|
• ECOG PS 2 and CrCl < 30 mL/min are important criteria for determining platinum ineligibility in patients with mUC (LOE: 2c; GOR: ++; LOC: 66.7%) |
|
• Grade ≥ 2 hearing loss (LOE: 2c; GOR: +; LOC: 80%) |
|
(B) Biomarker testing in mUC: Summary of expert recommendations |
|
PD-L1 testing before 1L systemic therapy can be performed in mUC patients who are ineligible to receive cisplatin chemotherapy. PD-L1 testing before 1L systemic therapy is not required for those who are ineligible to receive any platinum-based chemotherapy (LOE: 1a; GOR: +; LOC: 80%) |
|
PD-L1 testing is not required when assessing eligibility for ICI maintenance in patients who have not progressed with platinum-containing chemotherapy (LOE: 2b; GOR: +/− ; LOC: 80%) |
|
PD-L1 testing is not required when assessing eligibility for treatment in 2L settings. According to current knowledge, a general recommendation cannot be given (LOE: 1a; GOR: +/− ; LOC: 80%) |
|
FGFR mutation testing has not shown benefit for mUC patients in 1L settings. A general recommendation regarding FGFR testing before 1L systemic therapy cannot be given (LOE: 2b; GOR: +/− ; LOC: 80%) |
|
It is important to screen mUC patients for FGFR alterations before 2L systemic therapy to plan for optimal treatment (LOE: 1a; GOR: ++; LOC: 80%) |
|
(A) 1L systemic therapy for locally advanced unresectable UC or mUC: Summary of expert recommendations |
|
Treatment of cisplatin-ineligible mUC patients with positive PD-L1 status Carboplatin–gemcitabine chemotherapy is preferred over ICI monotherapy (atezolizumab or pembrolizumab) in mUC patients with positive PD-L1 status deemed unfit for cisplatin-based therapy in 1L settings (LOE: 2b; GOR: ++; LOC: 80%) Treatment of mUC patient ineligible for any platinum-based chemotherapy (cisplatin and carboplatin ineligible) • ICI monotherapy (atezolizumab or pembrolizumab) can be preferred over BSC in patients ineligible for any platinum-based chemotherapy (LOE: 2b; GOR: ++; LOC: 80%) • BSC is strongly preferred over ICI therapy in patients with: (1) poor performance status; (2) multiple uncontrolled comorbidities; and/or (3) poor access to immunotherapies (LOE: 2c; GOR: ++; LOC: 80%) Scope of immunotherapy–chemotherapy combination in 1L treatment settings • Immunotherapy (atezolizumab or pembrolizumab) plus platinum–gemcitabine chemotherapy is not suitable in mUC patients in 1L treatment settings (LOE: 1b; GOR: −; LOC: 80%) |
|
(B) Switch maintenance for locally advanced unresectable UC or mUC patients after 1L platinum-containing chemotherapy: Expert recommendations |
|
Switch maintenance in the general population • Avelumab switch maintenance plus BSC is strongly recommended in mUC patients with the nonprogressive disease after 4–6 cycles of 1L platinum-containing chemotherapy (LOE: 1b; GOR: ++; LOC: 100%) • Pembrolizumab switch maintenance is not suitable after 1L platinum-containing chemotherapy due to no OS benefit in mUC patients (LOE: 2b; GOR: −; LOC: 80%) • BSC instead of switch maintenance can be considered in patients with poor performance status and lack of access to immunotherapies (LOE: 2c; GOR: +/− ; LOC: 80%) |
|
Patient profiles suitable for avelumab switch maintenance therapy PD-L1 status • Avelumab switch maintenance plus BSC is strongly recommended in PD-L1-positive mUC patients with the nonprogressive disease after 4–6 cycles of 1L platinum-containing chemotherapy (LOE: 1b; GOR: ++; LOC: 86.7%) • Avelumab switch maintenance plus BSC can be performed in PD-L1-negative mUC patients with the nonprogressive disease after 4–6 cycles of 1L platinum-containing chemotherapy (LOE: 2b; GOR: ++; LOC: 80%) Prior chemotherapy regimen • Avelumab switch maintenance therapy is beneficial and can be recommended in mUC patients not progressed on 1L gemcitabine–carboplatin or gemcitabine–cisplatin-based chemotherapy (LOE: 1b; GOR: ++; LOC: 93.3%) Response to chemotherapy • Avelumab switch maintenance therapy is beneficial and recommended in mUC patients with partial and complete response after 1L platinum-containing chemotherapy (LOE: 1b; GOR: ++; LOC: 86.7%) • Avelumab maintenance therapy is also recommended in mUC patients with stable disease after 1L platinum-containing chemotherapy (LOE: 1b; GOR: ++; LOC: 66.7%) Type of metastases • Avelumab switch maintenance therapy is beneficial and can be recommended in mUC patients with nonvisceral metastasis after 1L platinum-containing chemotherapy (LOE: 1b; GOR: ++; LOC: 86.7%) • Avelumab switch maintenance therapy is beneficial in mUC patients with visceral metastasis after 1L platinum-containing chemotherapy (LOE: 1b; GOR: ++; LOC: 73.3%) ECOG status Avelumab switch maintenance therapy is beneficial and can be recommended in mUC patients with ECOG status 0/1 (LOE: 1b; GOR: ++; LOC: 93.3%) CrCl Avelumab switch maintenance therapy is beneficial and can be recommended in mUC patients regardless of CrCl (< 60> Age • Avelumab switch maintenance therapy is beneficial and can be recommended in mUC patients with age < 65 years (LOE: 1b; GOR: ++; LOC: 100%) • Avelumab switch maintenance therapy is beneficial and can be recommended in mUC patients with age ≥ 65 years (LOE: 1b; GOR: ++; LOC: 66.7%) |
2L systemic therapy for locally advanced unresectable UC or mUC: Expert recommendations |
|---|
|
• Erdafitinib is recommended in FGFR-positive mUC patients in 2L settings (LOE: 2b; GOR: ++; LOC: 80%) • In FGFR-negative patients, ICI (pembrolizumab, nivolumab, or avelumab) may be preferred over chemotherapy (paclitaxel, docetaxel, or vinflunine) in 2L settings. Pembrolizumab has strong phase 3 data in terms of OS and can be preferred (LOE: 1b; GOR: ++; LOC: 80%) over nivolumab (LOE: 2b; GOR: +; LOC: 80%) in 2L settings • Enfortumab vedotin is a suitable treatment option in mUC patients who have previously received platinum-containing chemotherapy and progressed during or after treatment with a PD-1 or PD-L1 inhibitor (LOE: 1b; GOR: ++; LOC: “moderate”). Currently, enfortumab vedotin is available only on a compassionate basis in India • Sacituzumab govitecan is another treatment option in patients who have previously received platinum-containing chemotherapy and progressed during or after treatment with a PD-1 or PD-L1 inhibitor (LOE: 2b; GOR: ++; LOC: “low”) |
|
Patient profiles suitable for ICI in 2L settings • ECOG PS status: ICI therapy (pembrolizumab, nivolumab, or avelumab) is suitable and can be recommended in patients with ECOG status 0/1 in 2L settings (GOR: ++; LOC: 86.7%) • PD-L1 status: ICI therapy (pembrolizumab, nivolumab or avelumab) can be considered in PD-L1 (IC 2/3 [GOR: ++; LOC: 60%] and IC 1 [GOR: +; LOC: 73.3%]) in 2L settings • First-line chemotherapy: ICI therapy (pembrolizumab, nivolumab, or avelumab) is suitable in patients with prior cisplatin chemotherapy in 2L settings (GOR: ++; LOC: 73.3%) • Extent of involvement: ICI therapy (pembrolizumab, nivolumab, or avelumab) can be considered in patients with visceral disease in 2L settings (GOR: ++; LOC: 60%) |
|
OS improvement from the start of therapy: Expert recommendations |
|
1L platinum-based chemotherapy (4–6 cycles) followed by avelumab switch maintenance with BSC is most useful in terms of OS improvement from the start of 1L therapy and can be recommended (GOR: ++; LOC: 100%) |
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- Powles T, Rosenberg JE, Sonpavde GP. et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med 2021; 384 (12) 1125-1135
- Tagawa ST, Balar AV, Petrylak DP. et al. TROPHY-U-01: A phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol 2021; 39 (22) 2474-2485
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Publication History
Article published online:
10 February 2023
© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
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