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Urothelial Carcinoma First-line Systemic Therapy in Patients Ineligible (‘Unfit’) to Receive a Cisplatin-based Regimen – Which Patients? What Needs? Maria De Santis Kaiser Franz Josef-Spital, Center for Oncology and Hematology; Ludwig Boltzmann–Institute for Applied Cancer Research (LBI–ACR); Applied Cancer Research–Institute for Translational Research (ACR–ITR), Vienna, Austria Standard Chemotherapy in ‘Fit’ Bladder Cancer Patients First-line treatment options in ‘fit’ bladder cancer patients who are able to receive platinum-based therapy include GC, paclitaxel/gemcitabine/ cisplatin (PGC), methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) with or without granulocyte colony-stimulating factor (G-CSF), or high-dose (HD)-MVAC with G-CSF. The highest level of evidence and grade of recommendation is available for all these combinations. 1,2 Some patients display long-term survival following cisplatin-based combination chemotherapy, with 5-year survival rates of approximately 15 %. Moreover, as outlined earlier, patients with lymph node (LN)-only So far, no standard chemotherapy has been established in patients who are ‘unfit’ to receive cisplatin. Approximately 50‌ % of urothelial cancer patients are not eligible to receive standard cisplatin-based chemotherapy. 17–20 Comorbidity and age concerns mean that elderly patients are often under- represented in clinical trials, which makes them unrealistic, because these are representative of a large proportion of bladder cancer patients. 21 Patients with a history of cancer have been shown to have an average of three comorbid conditions, 22 yet the importance of comorbidity has not consistently been addressed in clinical trials and clinical practice since coming to attention over 40 years ago. 23 Clinical trials have tended to exclude elderly patients and/or those with comorbidities, and metastases (i.e. no visceral metastases) have better 5-year survival rates (see Table 1). 3,4 it is therefore not established whether dosages investigated in clinical trials are safe in the elderly and comorbid population. Chronological versus Functional Age Can comorbidity, age, or sex predict risk of mortality in elderly patients? Interesting data have come to the fore, showing that age, sex and comorbidity in particular can be predictive of mortality in elderly patients. Different index scores have been developed to gauge the importance of these factors in patient outcome, but these have so far not been included in clinical trial designs (see Table 3). 5,24–27 An important reality in the treatment of bladder cancer is the fact that populations are growing older overall. The incidence of invasive cancer in patients above the age of 65 years is expected to increase dramatically in the next few years. 5 Therefore, the matter of comorbid conditions in elderly patients, which is associated with prognostic implications, will become more prominent. 6,7 Importantly, an identical chronological age may correspond to a different functional age. Age does not necessarily mean that a patient is unfit to receive platinum- based chemotherapy. Patients are not routinely categorised according to their absolute age. The treatment of bladder cancer in elderly patients is met with a series of challenges, derived from the use of cisplatin, which forms the backbone of standard treatment. Cisplatin versus Carboplatin in Bladder Cancer Patients There have been a lot of discussions about the use of cisplatin in the treatment of bladder cancer, specifically in terms of whether this agent is required as part of combination chemotherapy regimens, and whether it is necessary to separate cisplatin-eligible and -ineligible patients. 8,9 Currently, there are no data from randomised phase III studies addressing this concern. Whether cisplatin can be replaced safely by carboplatin in cisplatin-eligible patients was investigated in one randomised phase III trial comparing MVAC versus carboplatin plus paclitaxel that was closed early due to slow accrual. 10 Other randomised phase II studies compared various cisplatin- and carboplatin-based combinations in patients with recurrent or metastatic bladder cancer. The overarching impression is that carboplatin-based chemotherapy is less active, with reduced CR and survival rates (see Table 2). 11–13 Furthermore, several smaller phase II studies evaluating carboplatin in combination with paclitaxel resulted in mediocre outcomes, with OS durations of approximately 9 months and responses below 50 %. 14–16 © TO U CH MED ICA L MEDIA 2013 When deciding on chemotherapy treatment in elderly cancer patients, Wedding et al. have shown in a prospective trial that a comprehensive geriatric assessment (CGA) distinguishes fit patients from vulnerable or frail patients with more precision compared with physician’s evaluations. 28 The advantage of using the CGA in elderly patients (≥75 years) is that this assessment provides a description of physiological age. The CGA can detect reversible issues, provide a cognitive function assessment and improve anti-cancer treatment. Although it is not standard, the CGA is recommended for routine use in the older patient population with cancer by several international societies. 29,30 The CGA is, however, a time- consuming and costly approach that requires further validation. In a recent publication by Hurria et al., a score was constructed to predict chemotherapy toxicity in older adults with cancer, with more accuracy than Karnofsky performance score (KPS) and Eastern Cooperative Oncology Group (ECOG) PS. This score was presented as being short and feasible in daily practice, by assessing tumour and treatment variables, socio- demographic factors, laboratory test results and geriatric assessment variables (including function, comorbidity, cognition, psychological state, social activity/support and nutritional status). 31 Who are the ‘Unfit’ Patients Ineligible to Receive Cisplatin? In the bladder cancer population, comorbidities include renal function impairment, congestive heart failure (CHF), cardiovascular risk factors, 13