UC

Systemic anticancer therapy for urothelial carcinoma: UK oncologists’ perspective

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Abstract

Urothelial carcinoma (UC) is a common cancer associated with a poor prognosis in patients with advanced disease. Platinum-based chemotherapy has remained the cornerstone of systemic anticancer treatment for many years, and recent developments in the treatment landscape have improved outcomes. In this review, we provide an overview of systemic treatment for UC, including clinical data supporting the current standard of care at each point in the treatment pathway and author interpretations from a UK perspective. Neoadjuvant cisplatin-based chemotherapy is recommended for eligible patients with muscle-invasive bladder cancer and is preferable to adjuvant treatment. For first-line treatment of advanced UC, platinum-eligible patients should receive cisplatin- or carboplatin-based chemotherapy, followed by avelumab maintenance in those without disease progression. Among patients unable to receive platinum-based chemotherapy, immune checkpoint inhibitor (ICI) treatment is an option for those with programmed death ligand 1 (PD-L1)–positive tumours. Second-line or later treatment options depend on prior treatment, and enfortumab vedotin is preferred after prior ICI and chemotherapy, although availability varies between countries. Additional options include rechallenge with platinum-based chemotherapy, an ICI, or non–platinum-based chemotherapy. Areas of uncertainty include the optimal number of first-line chemotherapy cycles for advanced UC and the value of PD-L1 testing for UC.

Future perspectives

In the UK, only 30% of patients with advanced UC receive 1L treatment [87]; across global real-world studies, ≈40% of patients receive 1L treatment, with only 15–20% receiving 2L or later treatment [88,89,90,91]. Therefore, a significant unmet need remains, particularly in the 1L setting.

Two novel agents have been approved for later-line treatment of advanced UC outside Europe based on single-arm studies. Firstly, sacituzumab govitecan (ADC targeted to trophoblast cell-surface antigen 2), which has shown activity in patients with advanced UC following disease progression with platinum-based chemotherapy and ICI therapy [92]; an ongoing Phase 3 trial is assessing sacituzumab govitecan vs chemotherapy. Secondly, erdafitinib has shown significantly improved efficacy vs chemotherapy in the randomised Phase 3 THOR trial in a cohort of patients with prior treatment including an ICI [76]. Other ongoing Phase 3 trials of systemic anticancer therapy that are registered on ClinicalTrials.gov are summarised in Table 2. A Phase 3 trial that assessed nivolumab + ipilimumab (anti–cytotoxic T lymphocyte antigen-4) vs platinum-based chemotherapy as 1L treatment for patients with advanced UC did not meet its primary endpoint of prolonged OS in patients with PD-L1–positive tumours [93]. However, as discussed previously, in a substudy from this trial, significantly improved OS and PFS were reported with 1L nivolumab + cisplatin-based chemotherapy followed by nivolumab monotherapy vs cisplatin-based chemotherapy [46]. Considerable improvements in OS and PFS were seen with EV + pembrolizumab vs platinum-based chemotherapy in the Phase 3 EV-302 trial, which enrolled platinum-eligible patients [58]. Results from these trials have the potential to provide additional options in the 1L setting, but the relevance of these regimens to UK clinical practice will depend on regulatory and economic assessments.Table 2 Ongoing Phase 3 trials in UC registered on ClinicalTrials.gov.

Full size table

Conclusions

The information summarised in this review provides an overview, from a UK perspective, of key data and clinical developments that support the current standard of care for systemic treatment in patients with UC. Platinum-based chemotherapy remains the cornerstone of systemic treatment for patients with UC. However, the treatment landscape has and continues to evolve rapidly with the development of several new treatments, including different ICIs and ADCs, which have been shown to provide long-term clinical benefits in different populations. Although treatment options available in the UK and other countries depend on local approvals and reimbursement decisions, these developments have improved the prognosis for patients with UC. Despite this, outcomes remain poor overall, particularly in patients with advanced UC; therefore, it is imperative that eligible patients receive optimal treatment at each decision point.

Glucose control complicates therapy for UC patients with type 1 diabetes.

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Treating ulcerative colitis in patients with type 1 diabetes presents numerous challenges as commonly prescribed corticosteroids can affect glucose control, and the diseases share other comorbidities.

Researchers surveyed existing studies and discussed shared complications — including hepatic steatosis, neuropathy, osteoporosis and venous thrombosis — and treatment strategies for UC patients with type 1 diabetes.

“It is still unknown whether coexistence of these diseases may increase their occurrence,” the researchers wrote, and added that genetic links invite further study, and that hyperglycemia also can cause postoperative complications.

According to researchers, type 1 diabetes is the third most common comorbidity in UC patients after psoriasis and rheumatoid arthritis. Because corticosteroids are the preferred treatment for UC patients with type 1 diabetes, clinicians must be mindful of the potential for increased blood glucose levels. Researchers wrote that patients with severe UC should be hospitalized and treated with 60 mg methylprednisolone daily or 100 mg hydrocortisone four times daily for 7 to 10 days. They said that higher doses are no more effective, and lower doses are less effective. About 67% of patients respond favorably to treatment, and secondary treatment could include colectomy, cyclosporine, infliximab or tacrolimus.

Patients with diabetes should be monitored closely for hyperglycemia, dehydration and electrolyte imbalance to avoid complications such as hyperosmolar hyperglycemic state or diabetic ketoacidosis. Similar factors also can complicate postoperative healing in UC patients. Hypokalemia and hypomagnesemia are potential morbidities caused by poorly controlled blood sugar, and increase the risk for toxic megacolon.

Researchers said patients with type 1 diabetes with mild to moderate UC symptoms are likely to experience favorable UC outcomes with administration of topical mesalazine. Other treatments such as beclomethasone dipropionate, budesonide multimatrix system, fluticasone or prednisolone metasulphobenzoate also are discussed in the review, along with UC complications related to drugs such as metformin often administered for diabetes.

Review article: delivery and efficacy of topical 5-aminosalicylic acid (mesalazine) therapy in the treatment of ulcerative colitis

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The use of topical therapy in the treatment of ulcerative colitis has declined in recent years despite evidence of good efficacy.

Aims  To review US prescription trends for 5-aminosalicylic acid (5-ASA) since the US approval of Asacol extended-release oral mesalazine (mesalamine) in 1992; to estimate the optimal level of 5-ASA exposure in the distal colon; to determine factors influencing distal colonic exposures; and to compare the effectiveness of different 5-ASA formulations (oral, topical suspension, foam, suppositories) in clinical trials.

Methods  Review of clinical trials, physiologic studies and prescription trends of various mesalazine formulations for treatment of distal ulcerative colitis.

Results  Between 1992 and 2009, prescriptions for oral mesalazine increased sixfold, whereas topical suspensions declined by 10%. In clinical trials, topical therapy resulted in higher remission and clinical response rates than oral therapy, with trends to earlier improvement. The mucosal concentrations of 5-ASA achieved by topical agents in the distal colon were up to 200-fold higher than those achieved by oral administration alone. Despite active colitis, over 40% of a topically administered 4 g 5-ASA suspension (equal to 1.6 g) reached the sigmoid colon. This likely represents a therapeutic exposure of 5-ASA. Although topical therapies are less convenient than oral medications, treatment algorithms have failed to take into account quality of life improvements resulting from more rapid and complete treatment response.

Conclusions  Topical mesalazine therapy is superior to oral therapy in distal ulcerative colitis for both therapeutic response and drug delivery. Practice patterns should be re-evaluated in light of this information.

Source: Alimentary Pharmacology & Therapeutics.