Abstract
Background: This retrospective study aimed to determine the efficacy and toxicity of a combined chemotherapeutic regimen of gemcitabine and cisplatin (GC) for the treatment of metastatic urothelial carcinomas (UCs) in patients 80 years of age and over. Patients and Methods: Twelve patients who were at least 80 years old and had been diagnosed with metastatic UC were treated with GC. The patient cohort consisted of 9 men and 3 women, with a median age of 83 (range 80-84) years. The median follow-up was 54 (range 14-80) months. Results: Five out of the 12 patients (42%) showed an objective response, with two achieving a clinically complete response and three a partial response with GC. The median time to progression was 6 months, and the median overall survival was 14 months. The grade 3 and 4 toxicities of the regimen were primarily hematological, including anemia (33%), neutropenia (58%), and thrombocytopenia (50%). No grade 3 or 4 non-hematological toxicities were found. Conclusion: GC appears to be an effective and well-tolerated regimen for the treatment of metastatic UCs in very old patients.
Bladder cancer is the 9th most commonly diagnosed cancer in men, the 17th most frequently diagnosed cancer in woman and accounted for approximately 6200 deaths in Japan in the year 2007 (1). Urothelial carcinoma (UC) is the most common form of bladder cancer. UC can also be found in other sites such as the renal pelvis, ureter, and urethra.
Although metastatic UC is generally a chemosensitive disease, the prognosis for patients with metastatic UC remains poor. Cisplatin-based chemotherapy is the only modality that provides the potential for long-term survival. To date, the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) has been accepted as the gold-standard therapy for metastatic UC. It was recently demonstrated that the two-drug regimens with gemcitabine and cisplatin (GC) provided a similar survival advantage as M-VAC with a better safety profile and tolerability (2). Gemcitabine was approved in Japan for UC in 2008 and will soon be widely used. Our experience in Japanese patients using GC showed the clinical response rate to be 44%, with complete responses seen in 15% of patients (3).
The population of people over 65 years old is now increasing rapidly in Japan, and the ratio of elderly people in comparison to the rest of the population is also increasing. Accordingly, there is an expected rise in the need to treat elderly patients presenting with metastatic UC, because the median age of those patients is >70 years. Since there is a lack of both clinical trial data and any consensus on how to evaluate and manage elderly cancer patients, physicians' practices may be based on extrapolation from existing data in younger patients, and/or influenced by physicians' experiences and personal beliefs. Although it is important to focus on the survival benefit of chemotherapy for UC, estimating the benefit of chemotherapy simply by the survival or disease-free interval may not be appropriate for elderly patients because chemotherapy may disturb their activities of daily living (ADL). Many elderly patients have pulmonary and/or cardiovascular diseases due to smoking as an associated risk factor. In addition, many elderly patients have impaired renal function, which hampers safe administration of this type of chemotherapy. Even in patients in good condition, cisplatin-based chemotherapy can sometimes cause clinical myelosuppression, mucositis, or drug-related death. Unfortunately, these toxicities are occasionally very severe in Japanese patients, with a concomitant long-term hospital stay and disturbance of quality of life. From the viewpoint of safety, GC is generally thought to be superior to M-VAC, however, there is insufficient information available to determine whether this is also the case for elderly patients.
Patient characteristics.
There is a need to review the existing results of the outcomes of treatment of elderly patients and to tailor treatment accordingly, and not to completely rely on the results from randomized trials, since these may not always be applicable to our practice. We herein report a retrospective analysis of the safety and efficacy of GC in patients 80 years of age or older.
Patients and Methods
From July 2002 to June 2009, 71 patients with metastatic UC were treated. Eligible patients were required to have either histological or cytological proof of UC and at least one measurable lesion diagnosed by computed tomography (CT) or magnetic resonance imaging (MRI). An Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2 and an estimated life expectancy of at least 3 months was also required. Patients with an inadequate liver function as shown by the total bilirubin level >1.5 mg/dl or inadequate renal function with creatinine clearance <30 ml/min were excluded. Prior to the start of treatment, all patients were examined by high-resolution CT, and those with interstitial pneumonia were excluded. Written informed consent was obtained from all patients, and this clinical study was approved by the Ehime University Hospital Ethical Committee.
Dose adjustment of cisplatin based on the level of creatinine clearance.
The patients were divided into two groups: those aged 80 years old and over (group 1; n=12) and those younger than 80 years of age (group 2; n=59). The median age of patients was 72 (range 45-84) years, while corresponding ages for group 1 were 83 (80-84) and group 2 were 70 (45-79) years. The clinical characteristics of the patients in each group are shown in Table I. The median follow-up of all patients was 42 (range: 5-82) months, and that of the patients in group 1 was 54 (range: 14-80) months. The median serum creatinine and creatinine clearance (CCr) in patients in group 1 was 1.2 (range: 0.7-1.6) mg/dl and 41 (range: 30-58) ml/min, respectively, while that in group 2 was 1.0 (range: 0.6-1.4) mg/dl and 65 (range: 38-112) ml/min, respectively.
Treatment. The treatment schedule was 1000 mg/m2 gemcitabine on days 1, 8, and 15; and 70 mg/m2 cisplatin on day 2. The patients received pre-treatment with dexamethasone before each administration of gemcitabine. A 5-hydroxytryptamine receptor antagonist was administered on days 2 and 3 to prevent chemotherapy-induced nausea and vomiting. The courses were repeated every 28 days. A detailed medical interview, clinical examination, and laboratory studies were carried out before drug administration was initiated. The dose adjustment of cisplatin was based on the assessment of CCr (Table II). When granulocytes measured <500/μl or platelets 5.0×104/μl, administration of gemcitabine was skipped until the levels recovered. The treatment was carried out for a maximum of 6 cycles in the responding patients but was discontinued when disease progression was observed.
The median number of cycles of GC was 3 (range 2-6). The preventive administration of granulocyte colony-stimulating factor (G-CSF) was also prohibited based on the American Society of Clinical Oncology (ASCO) 2006 guidelines (4). However, according to the decision made by the physician in charge, the following administration criteria were accepted: (a) fever (38°C) development with granulocytes <1000/μl or granulocytes <500/μl after the completion of drug administration; (b) the subsequent drug administration was started when granulocytes were <1000/μl.
Evaluation of response and toxicity. The primary endpoint of the study was to determine the overall (complete plus partial) response rate. The secondary endpoint was overall survival.
All patients who completed at least two therapy cycles were included in the analysis for chemotherapeutic efficacy until there was evidence of progressive disease. All assessments of efficacy were made in accordance with the General Rules for Clinical and Pathological Studies on Bladder Cancer (5) and on Renal Pelvic and Ureteral Cancer (6) by the Japanese Urological Association and the Japanese Society of Pathology. Responses for all patients were reviewed by two independent radiologists.
The overall response rate and response rate for each group.
Toxicity of GC regimen.
The Mann-Whitney U-test was used for comparison of responses between the groups. After treatment discontinuation, the patients were evaluated every month to assess survival status. Survival was measured from the time of chemotherapy initiation until death or the last follow-up. The survival distributions were estimated using the Kaplan-Meier method, and the log-rank test was used to compare survival curves. Two-sided p-values of <0.05 were considered to be statistically significant.
At least one measurement per cycle was required for assessing hematological and biological parameters. The toxic effects were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 (7).
Results
Response. All 71 patients received at least two courses of GC, and therefore all of the patients were evaluated for response and toxicity. The overall response rate in each group is shown in Table III. Five (42%) of the 12 patients in group 1 (aged 80 years and over) showed an objective response, with 2 achieving a complete response (CR) and 3 achieving a partial response (PR). One patient (8%) showed disease progression on this regimen. Twenty-six (44%) out of the 59 patients in group 2 (less than 80 years of age) showed an objective response, with 9 achieving a CR and 17 achieving a PR. Eighteen patients (29%) showed disease progression in group 2. The duration to response in all responders was within a month of initiating treatment. There was no significant difference in the response between groups 1 and 2 (p>0.05). The median time to progression in the 12 patients in group 1 was 6 (range: 2-76) months, and their median overall survival was 14 (range 8-76) months at a median follow-up of 54 (range 14-80) months. With a median follow-up of 54 months, only one patient (8%) remains alive and progression-free in group 1. The median time to progression in the 59 patients in group 2 was 5 (range: 2-79) months, and their median overall survival was 11 (range: 2-79) months. Figure 1 shows the overall survival curves for each group.
Overall survival in each group.
Toxicity. The toxicities are listed in Table IV. Treatments were generally well tolerated in both groups. There were no treatment-related deaths. Overall, myelosuppression, pariticularly thrombocytopenia and neutropenia, was the most common serious (grade 3-4) toxicity. In group 1, six (50%) and seven (58%) patients experienced grade 3 thrombocytopenia and neutropenia, respectively. Compared with the patients in group 2, the hematological toxicities were more frequent in group 1. There was one grade 4 anemia. Grade 3 febrile neutropenia occurred in one patient (2%) in group 2. Four patients (33%) developed grade 3-4 anemia. Two patients of group 1 required a red blood cell (RBC) transfusion. However, nonhematological toxicities were less frequent and not severe in either group. Nausea, anorexia, and mucositis were generally mild. Duodenal obstruction by the tumor was observed in one patient in group 2 during chemotherapy, and the obstruction was released with bypass surgery.
There were no cases of grade 3-4 biochemical toxicity in terms of aspartate aminotransferase (AST)/alanine aminotransferase (ALT), alkaline phosphatase, or bilirubin levels, and no transient elevations of these values were observed. In addition, none of the patients had a grade 3-4 elevation of serum creatinine or blood urea nitrogen levels.
Discussion
The median age of patients presenting with metastatic UC is >70 years. Elderly patients with metastatic UC are often not managed according to treatment guidelines, since these patients frequently have disease- or age-related comorbidities. Only recently has more attention been paid to chemotherapy in the elderly (8). A standard of care for elderly patients has not yet been established. The treatment of elderly patients, therefore, is generally modified to account for considerations of age and the subjective evaluation of the patient's general status (9). When treating elderly patients with UC, urologists should pay careful attention to the treatment procedure and consider dose modification depending on the drugs being used (10). In particular, renal function impairment increases with age (11). A common misconception is that elderly patients are cisplatin-ineligible and cannot receive platinum-based treatment. However, advanced age does not necessarily exclude a patient from receiving cisplatin-based therapy, and age alone should not be used as a generalized adverse prognostic factor (12). The dose of cisplatin should be adjusted before chemotherapy based on the assessment of renal function using CCr as a marker. Carboplatin is often substituted for cisplatin for patients with moderately insufficient renal function (30<CCr<60 ml/min), and this should also be considered for elderly patients. As all 12 patients in group 1 of our study had moderately insufficient renal function, dose-adjusted cisplatin was administered for the treatment of all patients.
In this study, we did not observe any substantial differences in the response rate between the elderly and younger groups, although the number of patients 80 years of age and over was limited. The overall response rate was 42% in the patients aged 80 years and over. The median survival in those patients was 14 months at a median follow-up of 54 months. These results were similar to those of the patients aged younger than 80 years. Our previous data have revealed that the overall response rate was 63% in the patients who received GC as first-line chemotherapy (3). The response rate in the present study is satisfactory in comparison with previous data, since the 12 elderly patients in the present study included 7 patients who had received prior chemotherapy. It is likely that the relatively favorable results may be attributed to the fact that there were only a few metastatic lesions in each patient, or that there were only limited metastatic lesions, such as the isolation in the lungs and lymph nodes. Treatment with GC had a greater impact on the disease response in the lungs and lymph nodes than in the liver or bone (3).
Our results show that GC can be safely used to treat elderly patients with metastatic UC. Neither unexpected nor cumulative toxic effects were found in the present study, and no life-threatening complications were seen. Moreover, no significant renal or liver dysfunctions occurred at any point. The most frequent grade 3/4 toxicity associated with GC was myelosuppression. Only one patient with grade 4 anemia was observed in the elderly group, and two patients overall required RBC transfusion. None of the 12 patients in our study experienced grade 3 or 4 non-hematological toxicities. Nevertheless, this study has some limitations because of its retrospective nature and the limited number of patients. There may be selection bias for patients who received chemotherapy. However, our results demonstrate that elderly patients also benefit from treatment with the GC regimen, with only mild toxicities.
The treatment of elderly patients with metastatic UC represents a challenge. However, our results from the present study are very encouraging. This better risk-benefit ratio may lead to the introduction of the GC regimen as a standard chemotherapeutic approach for elderly patients with metastatic UC. Larger-scale clinical trials have to be designed to conclusively demonstrate the beneficial effect for these patients and to rule out any potential toxicities.
Footnotes
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Conflict of Interest Statement
N. Tanji received honoraria for lectures from Eli Lilly Japan K.K. The other authors have no potential conflict of interest to report.
- Received May 14, 2010.
- Revision received June 24, 2010.
- Accepted July 1, 2010.
- Copyright© 2010 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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