(UroToday.com) The 2024 American Society of Clinical Oncology (ASCO) Annual Meeting held in Chicago, IL was host to a kidney and bladder rapid oral abstract session. Dr. Jae-Lyun Lee presented the results of a multicenter phase II trial of modified FOLFIRINOX for the first-line treatment of advanced urachal cancer (ULTMA; KCSG GU20-03).
Urachal cancer is a rare malignancy accounting for <1% of bladder cancers. This is an aggressive disease with the overall survival for recurrent or metastatic disease currently less than two years.1,2 It remains a poorly understood disease, with a paucity of prospective clinical trials to inform treatment decision-making, particularly in the advanced setting, with no established standard of care available.
Current chemotherapy options are based on extrapolative evidence from other disease sites. Systemic regimens for urothelial carcinoma, including gemcitabine/cisplatin or MVAC, may be considered based on anatomical vicinity principles. Given the similar histopathology and genomic mutational profile of colorectal cancer to urachal cancer, 5-FU, S1, capecitabine, oxaliplatin, and irinotecan, have been considered for urachal cancer. Based on evidence from case report/series and systematic reviews, it appears that colorectal cancer chemotherapy regimens may be more beneficial for urachal cancer, compared to regimens for urothelial cancer.1,3
The modified FOLFIRINOX regimen consists of the combination of 5-FU/LV, oxaliplatin, and irinotecan which have synergistic mechanisms of action, do not overlap in major side effects, and all have the potential to be effective in urachal cancer. This regimen has proved to be a significant advancement in the management of pancreatic cancer. To reduce serious adverse events, a modified FOLFIRINOX regimen, which reduced the dose of irinotecan and excluded 5-FU bolus infusion, was used in this study.
This study included patients meeting the following inclusion criteria:
- Histologically confirmed adenocarcinoma of bladder/urachal remnant that is clinically consistent with urachal cancer.
- Origin in the anterior wall or dome of the bladder
- Predominant invasion of muscularis or deeper tissues
- No obvious origin from the overlying urothelium (relative normal-looking urothelial mucosa)
- No primary adenocarcinoma elsewhere
- Patients with locally advanced, recurrent, or metastatic disease not amenable to surgery, radiotherapy, or combined modality therapy with curative intent
- Measurable disease according to RECIST v1.1
- ECOG performance status 0–1
- Adequate bone marrow, hepatic, and renal function
The modified FOLFIRINOX was administered as follows:
- Oxaliplatin 85 mg/m2 over two hours, Irinotecan 150 mg/m2 over 1.5 hours, Leucovorin 400 mg/m2 over two hours, and 5-FU 2,400 mg/m2 over 46 hours)
- Prophylactic pegteograstim 6 mg subcutaneously on day 3
- Prophylactic antibiotics mandatory for the first two cycles (levofloaxcin750 mg orally daily from days 4 to 7)
- Antiemetics, per investigator’s discretion
- Repeated every two weeks up to 12 cycles (or until progression or unacceptable toxicities). Study drugs can be administered after 12 cycles to the subjects deriving a benefit from the study medication.
The primary study outcome was overall response rate. The secondary outcomes included:
- Progression-free survival
- Overall survival
- Incidence of febrile neutropenia
- Genomic aberrations (targeted next generation sequencing)
The study outcome measures included responses evaluation every six weeks for the first 24 weeks, then every 9 weeks between weeks 25 and 48, and every 12 weeks thereafter.
Between April 2021 and November 2023, 21 patients were enrolled from five cancer centers. The baseline patient characteristics are summarized below. The median patient age was 50 years. 62% of patients had de novo metastatic disease. 76% had undergone prior surgery. 10% had received prior adjuvant chemotherapy. The most common sites of metastases were the lungs (48%), lymph nodes (38%), and the peritoneum (33%).
A complete response was observed in 2 (9.5%) patients, with an additional 11 (52.4%) experiencing a partial response. The remaining 38.1% of patents had stable disease, and none had progressive disease. The overall response rate was 61.9% (95% CI: 41.1 – 82.7%).
At a median follow-up of 23.3 months, 15 patients experienced disease progression and the median PFS was 9.3 months (95% CI: 6.7 –11.9). After a median follow-up of 24.7 months, 10 patients died, and the median overall survival was 19.7 months (95% CI: 14.3 – 25.1).
At the time of last analysis, 19 patients had discontinued treatment, with only two patients remaining on therapy. As of May 2024, a total of 241 cycles had been administered, with a median of 12 cycles per patient. Dose reductions occurred in seven patients (33.3%) and 45 cycles (18.7%). A dose delay was experienced by five patients (23.8%), and 9/220 cycles (4.1%).
The adverse events are summarized below. There was one grade 3 neutropenic event; however, none of the patients experienced febrile neutropenia. The most common grade 1-2 adverse events were peripheral neuropathy, nausea/abdominal pain, ALT elevation, thrombocytopenia, and fatigue. The most common grade 3 event was anemia (9.5%). There was no grade ≥4 adverse events.
Dr. Lee concluded that:
- The ULTIMA study, the first prospective study in advanced urachal cancer, showed that a modified FOLFIRINOX showed an encouraging objective response rate (62%) and progression-free survival (9.3 months).
- This regimen is well tolerated with no febrile neutropenic events using prophylactic long-acting G-CSF
- Modified FOLFIRINOX should be considered for the 1st line treatment of advanced urachal cancer
Presented by: Jae-Lyun Lee, MD, PhD, Professor, Asan Medical Center and University College of Medicine, Seoul, South Korea
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, May 31 – Tues, June 4, 2024.
References:
- Siefker-Radtke AO, Gee J, Shen Y, et al. Multimodality management of urachal carcinoma: the M. D. Anderson Cancer Center experience. J Urol. 2003;169(4): 1295-8.
- Chen M, Xue C, Huang R, et al. Treatment Outcome of Different Chemotherapy in Patients With Relapsed or Metastatic Malignant Urachal Tumor. Front Oncol. 2021:11:739134.
- Szarvas T, Modos O, Niedworok C, et al. Clinical, prognostic, and therapeutic aspects of urachal carcinoma-A comprehensive review with meta-analysis of 1,010 cases. Urol Oncol. 2016;34(9): 388-98.