© 2005 European Society for Medical Oncology
The outcome of elderly patients with advanced urothelial carcinoma after platinum-based combination chemotherapy
Departments of 1 Clinical Therapeutics and 2 Radiology, Medical School, University of Athens, Athens, Greece
* Correspondence to: Dr A. Bamias, 31 Komninon St, Haidari, 124 62 Athens, Greece. Tel: +30-210-3381546; Fax: +30-210-3381511; Email: abamias{at}med.uoa.gr
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and methodsResultsDiscussionReferences |
|---|
Background: The majority of patients with advanced urothelial cancer are elderly, but data regarding this specific age group are limited. We compared the tolerability and efficacy of first-line platinum (cisplatin or carboplatin)-based chemotherapy in elderly patients (
70 years) with those in younger patients. Patients and methods: A total of 381 patients with advanced urothelial carcinoma received CIMV (cisplatin, ifosphamide, methotrexate, vinblastine) (n=32), MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) (n=105), DC (docetaxel, cisplatin) (n=174), CaG (carboplatin, gemcitabine) (n=64) or other regimes (n=6) and were included in this analysis.
Results: A total of 116 patients were 70 years. Elderly patients experienced more frequent neutropenia grade 3/4 (55% versus 37%, P=0.087) and renal toxicity (28% versus 10%, P=0.033) among patients treated with CIMV/MVAC, and neutropenic infections (4% versus 0%, P=0.019) among patients treated with DC. Median survival did not differ significantly between elderly and younger patients (9.3 versus 10.5 months, P=0.16). Eastern Cooperative Oncology Group performance status (PS) and haemoglobin were independently associated with prognosis. Patients with PS <2 and haemoglobin 10 g/dl had a median survival of 14 months as opposed to 5 months for patients with PS 2 or haemoglobin <10 g/dl (P <0.001).
Conclusion: Elderly patients with advanced urothelial cancer tolerate platinum-based chemotherapy well and derive the same benefit as their younger counterparts.
Key words: bladder cancer, chemotherapy, elderly, platinum
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Elderly patients with cancer represent a rapidly growing population in the USA and Europe [1
]. This increase in the numbers of elderly patients alters the demographics of cancer and highlights the need to develop more age-appropriate treatment protocols. Although elderly patients form the majority of cancer patients, few studies have focused specifically on this population and the results of these studies are, in many cases, contradictive [2].
Carcinoma of the urothelial tract is a disease primarily of elderly people, since most patients are diagnosed beyond the age of 65 years [3]. Cisplatin-based chemotherapy is effective and prolongs survival of patients with advanced urothelial cancer [4–6]. Nevertheless, the combination of MVAC (methotrexate, vinblastine, doxorubicin and cisplatin), which has long been considered as standard, as well as the recently established gemcitabine/cisplatin combination [7], have been associated with bone marrow and renal toxicity. Therefore, cisplatin-based chemotherapy is offered to few elderly patients, because of age-related renal function impairment and frequent comorbidities preclude adequate hydration required for cisplatin administration [2]. The non-nephrotoxic platinum analogue, carboplatin, has been frequently substituted for cisplatin in patients who are unfit to receive cisplatin [8–10]. In both cases, there is limited information regarding the tolerability of treatment with cisplatin or carboplatin by elderly patients with advanced urothelial carcinoma and their outcome, since they form only a small percentage of patients included in clinical trials.
Between 1995 and 2003 we conducted four clinical studies in patients with advanced urothelial cancer. All patients included in these studies received first-line treatment with combinations containing cisplatin or carboplatin. We present here an analysis of our database from these studies in order to examine the relationship between age and the outcome in patients receiving platinum-based combination chemotherapy for advanced urothelial cancer. The purpose of this analysis was to determine whether elderly patients (70 years) do worse than their younger counterparts in terms of tolerance, disease control and survival.
|
Patients and methods |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Patients and treatment
From 1995 to 2003, 381 consecutive patients treated with first-line, platinum-based chemotherapy were entered into our database. These patients were included in four prospective clinical trials: (1) phase II study CIMV (1994–1995): cisplatin 30 mg/m2 days 1–3, ifosfamide 1.5 g/m2 days 1–3, methotrexate 30 mg/m2 day 1, vinblastine 3 mg/m2 every 3 weeks supported with granulocyte colony-stimulating factor (G-CSF) (32 patients) [11
]; (2) phase II study DC (1995–1997): docetaxel 75 mg/m2 and cisplatin 75 mg/m2 every 3 weeks supported with G-CSF (66 patients) [12]; (3) randomized phase III study MVAC versus DC (1997–2002): both supported with G-CSF (220 patients) [13]; (4) carboplatin AUC 5 on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8, every 3 weeks (62 patients). Three patients in study 3 did not receive treatment due to early death but were included in the survival analysis on an intention-to-treat basis. Ten patients did not receive allocated treatment but were included in this analysis because they all received platinum-based chemotherapy. The treatment received by the 381 patients is shown in Table 1.
|
All studies included patients older than 18 years, with histologically proven inoperable locally advanced, metastatic or recurrent cancer of the urothelial tract with adequate bone marrow and liver function. Patients with PS 0–3 were included in all studies except for study 3, which included patients PS 0–2. Normal serum creatinine was required in the first three studies. The only study with an upper age limit (75 years) was the randomised study [13
]. Creatinine clearance was calculated according the Cockroft formula [14], while the carboplatin dose was calculated according to the Calvert formula [15].
Efficacy and toxicity analysis
Survival was calculated from the day of the initiation of treatment until date of death or last contact for patients still alive at the time of follow-up. Our database was updated in October 2003. Tumour assessment was performed every three cycles of treatment. Patients with bidimensionally measurable disease, who received protocol treatment and had at least one follow-up tumour assessment were eligible for response evaluation. Standard WHO criteria [16] were used for classifying response. In an intention-to-treat analysis all patients were included in the analysis; non-evaluable patients were considered as non-responders. Toxicity was evaluated at each chemotherapy visit according to National Cancer Institute Common Toxicity Criteria. All patients who received at least one cycle of chemotherapy were included in toxicity analysis. Relative dose intensity (RDI) was defined as the percentage of the expected dose administered to the patient (per unit of time expressed in mg/m2/week).
Statistical analysis
All analyses were performed using the SPSS statistical software (SPSS for Windows, version 10, SPSS Inc., Chicago, IL). Differences between elderly and younger patients were examined with a 
2 test for categorical variables, whereas the t-test was used for continuous variables. Survival curves were produced with the Kaplan–Meier method and compared between arms with the stratified log-rank test. For univariate and multivariate analyses of survival, the Cox proportional hazards model was used. Throughout the analysis a level of 5% was used to denote statistical significance.
|
Results |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Patients
Patients' characteristics according to age are shown in Table 1. Median creatinine clearance and baseline median hemoglobin were significantly lower in the elderly group (69 versus 52 ml/min, P <0.001; 12.5 versus 11.9 g/dl, P=0.017). Disease site distribution did not differ significantly between the two groups, except from lymph node metastases, which were more frequent in the younger patients group (66% versus 59%, P=0.006). Nevertheless, there was no significant difference in the percentage of patients with visceral metastases between the two groups (49% versus 55%, P=0.243).
Chemotherapy administration and toxicity
RDI was analyzed for studies 3 and 4, since this parameter was not reported in the first two studies. The median number of cycles and RDI did not differ significantly between the two age groups irrespective of the treatment received (Table 2).
|
In patients treated with DC, neutropenic infections were significantly more frequent among elderly patients (0% versus 4%, P=0.019) (Table 2). Grade 3 or 4 neutropenia was also more frequent among elderly patients treated with CIMV or MVAC (37% versus 55%) but this difference did not reach statistical significance (P=0.087). Grade 3 or 4 renal toxicity was rare. Grade 1 or 2 toxicity was more frequent among elderly patients receiving CIMV or MVAC (10% versus 28%, P=0.033).
The toxic death rates were similar between the two age groups: 1.7% in the elderly group (two patients) and 1.5% among younger patients (four patients). All deaths were due to neutropenic sepsis.
Response rates and survival
Complete and overall response rates were similar between the two groups for patients receiving MVAC, CIMV or CaG (Table 3). Complete response rate was significantly higher for younger patients among patients treated with DC (15% versus 2%, P=0.009). Nevertheless, the overall response rates did not differ between the two groups.
|
Median follow-up and median survival for the whole population were 35 months and 10 months [95% confidence interval (CI) 9–12]. Median survival for patients younger than 70 years was 10.5 months (95% CI 9–12), while median survival for patients
70 years was 9.3 months (95% CI 7–12) (Figure 1). This difference was not significant (P=0.16). When patients were stratified according the treatment regime or the administration of cisplatin or carboplatin, no significant differences in survival between the two groups were observed (Table 3).
|
Prognostic factors for survival within the elderly group
During follow-up 90 patients died among patients
70 years: 83 due to bladder cancer, two due to toxicity from treatment, two due to stroke, two due to myocardial infarction and one due to pulmonary oedema. The prognostic significance of the characteristics shown in Table 1, using univariate Cox regression analysis, is shown in Table 4. PS 2 or 3, haemoglobulin <10, white blood cell count >10 000 and liver metastases were associated with worse prognosis, while there was a trend (P <0.1) for worse prognosis in patients with distant metastases and weight loss. Treatment with cisplatin-based chemotherapy (as opposed to carboplatin) was associated with longer median survival (10 versus 7 months), but this difference was not significant (P=0.260). Similarly, there was no significant difference of survival according to chemotherapy used (Table 3, P=0.327).
|
Multivariate analysis including these factors showed that PS and haemoglobulin level were independently associated with prognosis (Table 4). Based on these two factors we stratified patients in two prognostic groups: patients with no adverse prognostic factor had a median survival of 14 months (95% CI 11–16) as opposed to 5 months (95% CI 4–6) in patients who had one or two adverse prognostic features (P <0.001) (Figure 2).
|
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Although cancer is a disease of old age, there is a reluctance for inclusion of elderly patients into clinical trials [17
] or administration of anticancer treatment in general [2]. In bladder cancer, although the majority of patients are older than 65 years, data regarding elderly patients are scarce. We analysed our advanced urothelial cancer database in order to compare the efficacy and tolerability of platinum-based chemotherapy between elderly (70 years) and younger patients. To our knowledge this is the first study of this specific age subgroup in this disease. Although the retrospective nature of this analysis and the relatively small number of elderly patients included represent two limitations of this study, we believe that our results provide useful information regarding the role of combination chemotherapy in this population.
Data regarding the tolerability of chemotherapy by elderly patients have been contradictory. Several retrospective studies have shown that these patients can tolerate chemotherapy equally as well as younger patients [17, 18], while other investigators have shown poor tolerance of chemotherapy [19, 20]. Advancing age has been associated with reduced bone marrow reserve and glomerular filtration rate (GFR) [2]. Our analysis confirms these data, since elderly patients had more frequent anemia and significantly lower creatinine clearance. Renal toxicity was more frequent in elderly patients receiving MVAC or CIMV. In addition, higher grade 3 or 4 neutropenia was observed in patients receiving MVAC or CIMV, while neutropenic infections were exclusively observed in elderly patients among those treated with DC. In spite of these differences, bone marrow toxicity was acceptable and did not result in lower exposure to chemotherapy, as shown by a similar number of cycles and RDI between the two age groups. The lack of excessive bone marrow toxicity in elderly patients could be attributed to the routine use of granulocyte colony-stimulating factor in most patients included in this analysis (studies 2 and 3) [12, 13].
There is controversy regarding the efficacy of chemotherapy in elderly patients. Old age is a predictor of poor survival in non-Hodgkin's lymphoma [21] and ovarian cancer [22]. Few data in patients with advanced urothelial cancer have been published. Our study showed that chemotherapy had similar efficacy in elderly and younger patients. This was true for cisplatin and carboplatin-based treatment, although the number of patients receiving carboplatin was too low for definite conclusions. Because our patients have been treated with different chemotherapy regimes, we stratified them according to treatment in all analyses of toxicity and efficacy. Again, no differences were detected between the two age groups. As expected, stratification lowered the statistical power of our results. Nevertheless, median survival of the two age groups was very similar in all subgroups, making the possibility of a true difference unlikely. Our results are in concert with other retrospective analyses [23, 24], which showed a lack of prognostic significance of age in patients with advanced urothelial cancer. Another study showed that patients older than 60 years had a better outcome than younger patients [25]. Nevertheless, that result may have reflected the selection of elderly patients with physical condition and prognostic factors better than the average patient in this age group, in order to avoid excessive toxicity from MVAC administration.
Analysis of baseline characteristics of elderly patients showed that PS 2 or 3 and significant anaemia (haemoglobulin <10 g/dl) were independent predictors of poor prognosis. The prognostic significance of PS has been shown in all previous studies studying prognostic factors in advanced urothelial cancer [23–25], while anaemia was also shown to be an independent prognostic factor in one of these studies [23]. Surprisingly, the presence of visceral metastases did not have a significant impact on survival in this analysis, although patients with visceral metastases had a shorter median survival (13 versus 8 months). Our study cannot specify whether this represents a true difference of this population compared with younger patients, or whether this is a result of the small number of patients included in this analysis. The first speculation is supported by the fact that the presence of visceral metastases was associated with poor prognosis in our phase III study, where elderly patients represented a small proportion of the population included [13]. Although this study was included in this analysis, the prognostic significance of this factor was not maintained when only elderly patients were analysed. On the other hand, lack of prognostic significance was also shown in two other studies [24, 25]. One of these studies also included a relatively small number of patients (n=92) [25], while the other study included a non-homogeneously treated population [24]. On the contrary, both studies that showed the prognostic significance of the presence of visceral metastases included patients who had all received the same treatment (MVAC or GC) [23, 26].
The combination of the two prognostic factors defined two groups of distinctly different prognosis. The ability of identifying groups of different prognosis by combining prognostic factors has also been shown for patients treated with MVAC [23]. Patients who had one or two adverse prognostic factors had a median survival of only 5 months. It seems that these patients do not benefit from platinum-based combination chemotherapy and they should be candidates for symptomatic treatment, non-toxic monotherapy or novel non-chemotherapeutic agents.
Cisplatin-based chemotherapy is considered the standard treatment for patients with advanced urothelial cancer who have good PS, adequate renal function and no comorbidities precluding sufficient hydration [27]. In contrast, carboplatin-based chemotherapy has generally produced inferior results [28–30] and is reserved for unfit patients. Survival was inferior for carboplatin-based chemotherapy among elderly patients in our study, although this did not reach statistical significance. This lack of significance may be due to the relatively small number of patients included in this analysis. Since elderly patients tolerated cisplatin-based chemotherapy equally as well as younger patients, we recommend that this treatment should be offered to elderly patients with good PS and no contraindications for cisplatin administration.
In conclusion, elderly patients with advanced urothelial cancer tolerate well and benefit from platinum-based chemotherapy and, therefore, should be offered this treatment option and should be included in clinical trials. Nevertheless, the use of prognostic factors is strongly recommended in order to select patients unlikely to benefit from combination chemotherapy and to avoid unnecessary toxicity.
Received for publication April 21, 2004. Revision received July 23, 2004. Accepted for publication August 26, 2004.
|
References |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
1. Yancik R, Ries LA. Aging and cancer in America: demographic and epidemiologic perspectives. Hematol Oncol Clin North Am 2000; 14: 17–24.[CrossRef][Web of Science][Medline]
2. Balducci L, Extermann M. Management of cancer in the older person: a practical approach. Oncologist 2000; 5: 224–237.
3. Herr HW, Shipley WU, Bajorin DF. Cancer of the bladder. In DeVita VT, Hellman S, Rosenberg SA (eds): Cancer. Principles and Practice of Oncology, 6th edition. Philadelphia, PA: Lippincott Williams and Wilkins 2001; 1396.
4. Sternberg C, Yagoda A, Scher HI et al. Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) for transitional cell carcinoma of the urothelium. J Urol 1985; 133: 403–407.[Web of Science][Medline]
5. Sternberg C, Yakoda A, Scher HI et al. M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) for advanced transitional cell carcinoma of the urothelium. J Urol 1988; 139: 461–469.[Web of Science][Medline]
6. Sternberg CN. The treatment of advanced bladder cancer. Ann Oncol 1995; 6: 113–126.
7. Von der Maase H, Hansen SW, Roberts JT et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced metastatic bladder cancer: Results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2001; 17: 3068–3077.
8. Carles J, Nogue M, Domenech M et al. Carboplatin-gemcitabine treatment of patients with transitional cell carcinoma of the bladder and impaired renal function. Oncology 2000; 59: 24–27.[CrossRef][Web of Science][Medline]
9. Shannon C, Crombie C, Brooks A et al. Carboplatin and gemcitabine in metastatic transitional cell carcinoma of the urothelium: effective treatment of patients with poor prognostic features. Ann Oncol 2001; 12: 947–952.
10. Bellmunt J, de Wit R, Albanell J et al. A feasibility study of carboplatin with fixed dose of gemcitabine in ‘unfit’ patients with advanced bladder cancer. Eur J Cancer 2001; 37: 2212–2215.[CrossRef][Web of Science][Medline]
11. Kyriakakis Z, Dimopoulos MA, Kostakopoulos A et al. Cisplatin, ifosfamide, methotrexate and vinblastine combination chemotherapy for metastatic urothelial cancer. J Urol 1997; 158: 408–411.[CrossRef][Web of Science][Medline]
12. Dimopoulos M, Bakoyiannis C, Georgoulias V et al. Docetaxel and cisplatin combination chemotherapy in advanced carcinoma of the urothelium: a multicenter phase II study of the Hellenic Cooperative Oncology Group. Ann Oncol 1999; 10: 1385–1388.
13. Bamias A, Aravantinos G, Deliveliotis Ch et al. Docetaxel and cisplatin with granulocyte-colony stimulating factor (G-CSF) versus M-VAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomised, phase III study conducted by the Hellenic Cooperative Oncology Group. J Clin Oncol 2004; 22: 220–228.
14. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41.[Web of Science][Medline]
15. Calvert AH, Newell DR, Gumbrell LA et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989; 7: 1748–1756.[Abstract]
16. Miller AB, Hoogstraten B, Staquet M. Reporting results of cancer treatment. Cancer 1981; 47: 207–214.[CrossRef][Web of Science][Medline]
17. Rocha Lima CM, Henderson JE, Kosty M et al. Therapy choices among older patients with lung carcinoma. Cancer 2002; 94: 181–187.[CrossRef][Medline]
18. Sargent DJ, Goldberg RM, Jacobson SD et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 2001; 345: 1091–1097.
19. Crivellari D, Bonetti M, Castiglione-Gertsch M et al. Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: the International Breast Cancer Study Group Trial VII. J Clin Oncol 2000; 18: 1412–1422.
20. Argiris A, Li Y, Murphy BA et al. Outcome of elderly patients with recurrence or metastatic head and neck cancer treated with cisplatin-based chemotherapy. J Clin Oncol 2004; 22: 262–268.
21. Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 1998; 16: 2780–2791.[Abstract]
22. Markman M, Lewis JL, Saigo P et al. Impact of age on survival of patients with ovarian cancer. Gynecol Oncol 1993; 49: 236–241.[CrossRef][Web of Science][Medline]
23. Bajorin DF, Dodd PM, Mazudmar M et al. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of treatment. J Clin Oncol 1999; 17: 3173–3181.
24. Sengelov L, Kamby C, Schou G et al. Prognostic factors and significance of chemotherapy in patients with recurrent or metastatic transitional cell cancer of the urinary tract. Cancer 1994; 74: 123–133.[CrossRef][Medline]
25. Geller NL, Sternberg CN, Penenberg D et al. Prognostic factors for survival of patients with advanced urothelial tumors treated with methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy. Cancer 1991; 67: 1525–1531.[CrossRef][Web of Science][Medline]
26. Stadler WM, Hayden A, von der Maase H et al. Long-term survival in phase II trials of gemcitabine plus cisplatin for advanced transitional cell cancer. Urol Oncol 2002; 7: 153–157.[CrossRef][Web of Science][Medline]
27. De Wit R. Overview of bladder cancer trials in the European Organization for Research and Treatment. Cancer 2003; 97: 2120–2126.[CrossRef][Web of Science][Medline]
28. Petrioli R, Frediani B, Manganelli A et al. Comparison between a cisplatin-containing regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients. A randomized phase II study. Cancer 1996; 77: 344–351.[CrossRef][Web of Science][Medline]
29. Bellmunt J, Ribas A, Eres N et al. Carboplatin-based versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma. Cancer 1997; 80: 1966–1972.[CrossRef][Web of Science][Medline]
30. Zielinski CC, Schnack B, Grbovic M et al. Paclitaxel and carboplatin in patients with metastatic urothelial cancer: results of a phase II trial. Br J Cancer 1998; 78: 370–374.[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. V. Raj, A. Iasonos, H. Herr, and S. M. Donat Formulas Calculating Creatinine Clearance Are Inadequate for Determining Eligibility for Cisplatin-Based Chemotherapy in Bladder Cancer J. Clin. Oncol., July 1, 2006; 24(19): 3095 - 3100. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Bamias, I. Tiliakos, M.-D. Karali, and M. A. Dimopoulos Systemic chemotherapy in inoperable or metastatic bladder cancer Ann. Onc., April 1, 2006; 17(4): 553 - 561. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||