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Annals of Oncology Advance Access originally published online on November 2, 2006
Annals of Oncology 2007 18(2):282-287; doi:10.1093/annonc/mdl401
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© 2006 European Society for Medical Oncology

gynecologic tumors

Feasibility, toxicity and quality of life of first-line chemotherapy with platinum/paclitaxel in elderly patients aged ≥70 years with advanced ovarian cancer—a study by the AGO OVAR Germany

F Hilpert1,*, A du Bois2, ER Greimel3, J Hedderich4, G Krause1, L Venhoff1, S Loibl5 and J Pfisterer1,6

1 Klinik für Gynäkologie und Geburtshilfe, Campus Kiel, Universitätsklinikum Schleswig-Holstein, Kiel
2 Klinik für Gynäkologie und gynäkologische Onkologie, HSK Dr Horst Schmidt Klinik, Wiesbaden, Germany
3 Universitätsklinik für Frauenheilkunde und Geburtshilfe, Medizinische Universität Graz, Graz, Austria
4 Institut für Medizinische Informatik und Statistik, Campus Kiel, Universitätsklinikum Schleswig-Holstein, Kiel
5 Klinik für Gynäkologie und Geburtshilfe, Klinikum der J.W. Goethe-Universität, Frankfurt/M.
6 Frauenklinik, Universitätsklinikum Mannheim, Mannheim, Germany

* Correspondence to: Dr F. Hilpert, Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Michaelisstrasse 16, D-24105 Kiel, Germany. Tel: +49-431-597-2100; Fax: +49-431-597-2146; E-mail: fhilpert{at}email.uni-kiel.de


   Abstract
Top
 Abstract
introduction
 patients and methods
 toxicity and QoL measures
 results
 discussion
 References
 
Background: The purpose of the study was to evaluate first-line platinum/paclitaxel (Taxol) under phase III trial conditions in ovarian cancer (OC) patients aged ≥70 years.

Patients and methods: Phase III results of 779 patients with OC International Federation of Gynecology and Obstetrics (FIGO) stage IIB/IV treated with cisplatin/paclitaxel versus carboplatin/paclitaxel were retrospectively analyzed according to feasibility, toxicity (National Cancer Institute Common Toxicity Criteria) and quality of life (QoL) [European Organization for Research and Treatment of Cancer QoL questionnaire (EORTC QLQ-C30)] in patients aged <70 or ≥70 years.

Results: One hundred and three (13%) patients were aged ≥70 years. Patient characteristics (<70 versus ≥70 years) showed significant differences with regard to Eastern Cooperative Oncology Group performance status, residual disease and constitutional factors but not to FIGO stage, histology or grading. Elderly patients received 98%, 100% and 96% of the recommended paclitaxel, carboplatin and cisplatin dose, respectively, per cycle. Early discontinuation was more frequent in elderly, although QoL, nonhematological and hematological toxicity were comparable between elderly and younger patients, except for febrile neutropenia (5% versus <1%, P = 0.005). There were no significant differences with regard to cycle delays, dose reductions or the use of granulocyte colony-stimulating factor and antibiotics.

Conclusion: Platinum/paclitaxel appeared to be feasible and tolerable in elderly patients under clinical trial conditions, but there seems to be a different investigators' estimation of toxicity and less intention to maintain trial treatment in elderly.

Key words: elderly patients, ovarian cancer, phase III trial, platinum/paclitaxel


   introduction
Top
 Abstract
 introduction
patients and methods
 toxicity and QoL measures
 results
 discussion
 References
 
Epithelial ovarian cancer (OC) is the fifth most frequent cause of cancer death in women and remains the leading cause of gynecologic cancer-related deaths in the United States and Europe. Median age of patients at diagnosis of OC is ~63 years (http://seer.cancer.gov/cgi-bin/csr/1975_2002/search.pl#results). The highest incidence of OC occurs in the seventh and eighth decades of life, and due to the increasing life expectancy of women in the Western world, elderly patients are the fastest-growing segment of patients with OC [1, 2]. Despite optimization of OC treatment, age remains a negative prognostic factor for survival which is attributed not only to multiple factors such as high-grade and advanced-stage disease but also to the suboptimal application of surgical and chemotherapeutical treatment [3–7].

Today, there is evidence that despite several improvements of general health care and supportive therapies, elderly patients with advanced OC are still not treated with the currently recommended standard carboplatin/paclitaxel, established by several large phase III trials during the past 10 years [4, 6, 8–11]. Several reports showed that only about half of the elderly women with advanced OC were treated with platinum-based chemotherapy, although they seem to benefit from combination therapy [12, 13]. The inadequate cytostatic treatment of the elderly is usually attributed to toxicity, comorbid conditions, physiologic changes and considerations regarding quality of life (QoL) [14].

There is concern about the representativeness of study results for the elderly, as only a minority of patients participating is older than 65 years [15–17]. This problem has been focused on by several study groups. All groups indicated old age or associated reasons as the predominant factor for nonenrolment into clinical trials [18–20]. Additionally, common inclusion criteria, such as history of prior malignancies, adequate hematological and renal functions or Eastern Cooperative Oncology Group (ECOG) status, predominantly affect the participation of elderly patients and attribute to the age-related bias of study participation [1, 20].

The 3rd International Consensus Meeting of the Gynecologic Cancer Intergroup recently confirmed the recommendation of carboplatin/paclitaxel as standard arm for future phase III trials in primary OC [21] and, therefore, the question needs to be answered if the recommended standard is feasible and safe for the elderly under phase III trial conditions.

Many previous reports on elderly patients based their results on an age split of <65 or >65 years and concluded that platinum-based chemotherapy is tolerated by elderly patients up to the age 70 years [4, 12, 22]. Patients aged ≥70 years, however, account for most of the underrepresentation of the elderly in clinical trials. Nevertheless, some evidence showed that chronological age ≥70 years does not adversely influence the ability to receive aggressive treatment [17, 23].

The present retrospective exploratory analysis of a phase III first-line trial in advanced OC evaluates the feasibility, toxicity and QoL in patients aged ≥70 years treated with platinum/paclitaxel under clinical trial conditions.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
toxicity and QoL measures
 results
 discussion
 References
 
patients
This analysis was carried out on the basis of the data of a phase III trial [Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group 3 (AGO OVAR-3) protocol] with 798 patients [9]. All patients were enrolled from 1995 to 1997 after receiving cytoreductive surgery. Patients were then randomly assigned to receive paclitaxel (Taxol) (Brystol-Myers Squibb, Germany) plus carboplatin (TC) or paclitaxel plus cisplatin (PT). Inclusion and exclusion criteria did not contain any age limits, but required adequate organ functions, good performance status and a glomerular filtration rate (GFR) of at least 60 ml/min (details see [9]). The GFR was estimated using the Jelliffe formula [24].

The OVAR-3 study was designed in accordance with good clinical practice guidelines, German drug laws and the Declaration of Helsinki. German and Austrian centers participated in this study, and it was approved by the local ethics committee of each participating center. The OVAR-3 study was also certified by the German Cancer Society. All patients provided written informed consent before participation.

treatment
All patients for this age-specific evaluation of feasibility, toxicity and QoL of platinum/paclitaxel had to have received at least one cycle of the assigned treatment. In the TC arm, paclitaxel (185 mg/m2) was administered intravenously (i.v.) for 3 hours followed by carboplatin area under the curve (AUC) 6 [dose in milligrams = AUC mg·min/ml x (GFR + 25)] administered i.v. for 30–60 minutes. In the PT arm, paclitaxel (same dose and schedule) plus cisplatin 75 mg/m2 were administered i.v., both given for six courses every 3 weeks. Regardless of calculated doses, the maximal absolute dose that was given to each patient was limited to 400 mg for paclitaxel, 880 mg for carboplatin and 165 mg for cisplatin.

Dose reductions were allowed depending on predefined levels of hematological or nonhematological toxicity. These levels were as follows: carboplatin AUC mg·min/ml 5 (level 1) or AUC mg·min/ml 4 (level 2), cisplatin 60 mg/m2 (level 1) or 50 mg/m2 (level 2) and paclitaxel 160 mg/m2 (level 1) or 135 mg/m2 (level 2). Any subsequent treatment cycle was delayed when the patient's absolute neutrophil count (ANC) was <1.5 g/l or platelet count was <100 g/l.

Supportive treatment with granulocyte colony-stimulating factor (G-CSF) was allowed if after dose reduction in the previous courses the ANC nadir was ≤0.5 x 109/l [Common Toxicity Criteria (CTC) grade 4] lasting for >5 days, or in case of neutropenic fever, or infection, or if recovery of ANC took >36 days. Prophylactic antibiotics were allowed at the investigator's discretion if ANC was <0.5 x 109/L. All patients received standard premedication including hydration for cisplatin, antiallergic and antiemetic medication (details see [9]).


   toxicity and QoL measures
Top
 Abstract
 introduction
 patients and methods
 toxicity and QoL measures
results
 discussion
 References
 
Adverse events and toxic effects were graded by study investigators according to the National Cancer Institute CTC version 2.0. All observed toxic effects were recorded continuously; blood chemistry parameters were measured before each treatment cycle and hematological parameters were measured weekly. Data were checked by source verification by on-site monitors. QoL was evaluated using global health status/QoL score of the European Organization for Research and Treatment of Cancer (EORTC) QoL questionnaire (EORTC QLQ-C30, version 2.0). No specific QLQ module for OC was used in this trial because none was available at this time. Patients assessed their own health-related QoL every other treatment cycle, after the last treatment cycle and 3 and 6 months after cessation of treatment. QoL responses were evaluated according to the EORTC guidelines [25]. A detailed analysis of QoL with respect to the two treatment regimens has recently been published [26].

statistics
For this age-specific retrospective exploratory analysis, patients were dichotomized according to the age split of <70 or ≥70 years. The age was defined as age at time of study randomization.

The primary end point of this study was to evaluate the feasibility and toxicity of platinum/paclitaxel as first-line chemotherapy in elderly patients with advanced OC under clinical trial conditions. Secondary end points were the evaluation of QoL and of the factors influencing feasibility criteria such as early discontinuation, cycle delays and dose reductions.

All statistical tests were exploratory in nature. The selected variables within each age group were evaluated by the analysis of contingency tables (Fisher's exact test, chi-square test) and by comparing means (± standard deviation, t-test). Although P values were stated in all tables, a general level of significance for P < 0.05 was used.


   results
Top
 Abstract
 introduction
 patients and methods
 toxicity and QoL measures
 results
discussion
 References
 
patients
The intention-to-treat population of the AGO OVAR-3 trial included 783 patients. Four patients did not receive any treatment. Therefore, 779 patients were assessable for this analysis. Six hundred and seventy-six patients (87%) were <70 years and 103 patients (13%) ≥70 years. Median age in the younger group was 55.6 (±9.4, range 21–69 years) and 73.5 (±2.7, range 70–85 years) in the elderly group. Patient's characteristics of each group are given in Table 1. There were no significant differences with regard to International Federation of Gynecology and Obstetrics (FIGO) stage, histology or tumor grading between both groups. ECOG score 2 and measurable disease occurred significantly more often in patients ≥70 years (17% versus 8%, P = 0.011 and 34% versus 23%, P = 0.019, respectively). With regard to constitutional factors, there was a significant difference for body height (161 versus 164 cm, P < 0.001) and body surface (1.68 versus 1.73 m2, P = 0.035) in patients ≥70 or <70 years, respectively. Serum creatinine levels were comparable between both groups, but the estimated GFR was significantly lower in the elderly patients (72 versus 89 ml/min, P < 0.001).


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  		Table 1. Patient characteristics

 
feasibility
In the elderly group, 53 (52%) patients received carboplatin/paclitaxel and 50 (49%) patients cisplatin/paclitaxel. In the younger group, 342 (51%) patients received carboplatin/paclitaxel and 334 (49%) patients cisplatin/paclitaxel. The elderly received 98%, 100% and 96% of the recommended paclitaxel, carboplatin and cisplatin dose, respectively. Although significant, the mean dose of cisplatin was only slightly lower in the elderly patients (73.7 versus 72.1 mg/m2, P = 0.01), while there was no significant difference for carboplatin (AUC 5.7 versus 6.0) and paclitaxel (182 versus 182 mg/m2).

Early discontinuation occurred in 26% of the elderly patients and 13% of the younger patients (P = 0.001), resulting in a higher proportion of elderly patients (23%) who received only one to four cycles (P < 0.001). The distribution of cycle numbers is given in Table 2. The reasons for early discontinuation differed between both groups: Early discontinuation due to toxicity (19% versus 8%, P < 0.001) and patients' withdrawal (10% versus 3%, P < 0.001) was significantly more frequent in the elderly. Other reasons such as progressive disease or death showed no significant differences.


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  		Table 2. Number of cycles and reasons for early discontinuation

 
The exploratory analysis of toxic effects responsible for early discontinuation indicated fatigue, myelotoxicity and renal toxicity to occur more often in the elderly and peripheral neurotoxicity, cardiovascular and gastrointestinal (GI) toxic effects and hypersensitivity reactions to be more frequent in the younger group (Table 3). In the elderly group, only one patient's treatment was stopped due to infection/febrile neutropenia.


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  		Table 3. Toxic effects associated with early discontinuation

 
Cycle delays for ≥7 days at least once during the treatment period were observed in 37% versus 33% of the elderly and younger patients (P = 0.493), respectively (Table 4). There were no differences with regard to the reasons for cycle delay between both age groups.


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  		Table 4. Cycle delays and associated reasons

 
Dose reductions occurred more often in the younger patients' group without reaching statistical significance: 12% of the younger patients and only 6% of the elderly patients received a dose reduction at least once during treatment (P = 0.105). The frequency distribution of the reasons for dose reductions, e.g. hematological or nonhematological toxicity, was comparable between both age groups. In detail, dose reductions in the elderly were due to one (1%) patient's hematotoxicity and due to five (5%) patients nonhematological toxicity.

There was no significant difference for the usage of G-CSF and antibiotics between both age groups: G-CSF was applied to 7% and 10% (P = 0.4) and antibiotics to 10% and 8% (P = 0.393) of the elderly and younger patients, respectively. Solely red blood transfusions tended to be more frequent in the elderly (21% versus 13%, P = 0.059).

toxicity and QoL
Hematological toxicity did not differ significantly between both age groups with regard to anemia, thrombocytopenia, leucopenia and neutropenia (Table 5). Febrile neutropenia was significantly more frequent in the elderly (5%) than in the younger (<1%) patients (P < 0.001).


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  		Table 5. Hematological toxicity (worst cycle per patient)

 
Nonhematological toxic effects are shown in Table 6. The incidence of grade 3/4 nonhematological toxic effects was generally low in both age groups. There were no significant differences with regard to the rate of GI and neurological toxic effects or hypersensitivity reactions between both groups. Only grade 3/4 infections tended to occur more often in elderly patients (P = 0.077), while younger patients tended to suffer more frequently from grade 3/4 myalgia (P = 0.074).


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  		Table 6. Nonhematological toxicity (worst cycle per patient)

 
QoL assessment according to the EORTC QLQ-C30 showed no significant differences between both age groups with regard to the global health status/QoL scale during the treatment period (Figure 1). The differences in the global health/QoL status score did not exceed five points within the time points.


Figure 1
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  		Figure 1. Quality-of-life (QoL) assessment according to European Organization for Research and Treatment of Cancer QoL questionnaire (EORTC QLQ-C30).

 

   discussion
Top
 Abstract
 introduction
 patients and methods
 toxicity and QoL measures
 results
 discussion
References
 
This retrospective analysis is based on the data of the AGO OVAR-3 phase III trial which showed an advantage in tolerability and QoL without compromises in efficacy of carboplatin/paclitaxel versus cisplatin/paclitaxel in a homogenous population of advanced OC patients [9].

Although no age limits were set, the age distribution in the study still showed an underrepresentation of elderly patients. Mean age in our study was 56 years in contrast to the expected age peak of 63 years according to the Surveillance Epidemiology and Results database. Consequently, the percentage of patients ≥70 years was lower as could be expected. The avoidance of any age-based selection bias in the inclusion criteria did not compensate for the underrepresentation of elderly patients as mentioned previously for randomized clinical trials in OC [15–18]. The reasons for the low participation of elderly patients in this trial remain unclear. It could be assumed that the predominant reasons for nonenrolment (e.g. low GFR, secondary malignancies and concomitant diseases) as mentioned in the original publication of the AGO OVAR-3 trial apply to a higher frequency in elderly patients [9]. Additionally, there might be an investigator's discretion on the basis of a subjective higher threshold for study participation in old age. This stands in line with recently published studies from the AGO OVAR and the Gynecologic Oncology Group which identified age as the predominant reason for the investigator's decision for nonenrolment [18, 20]. Therefore, the results from this age-specific analysis are inevitably limited by a study-participation-related bias. This is also indicated by the fact that the present study basically gives information about ‘young old’ patients (65–75 years of age) according to the three-group classification proposed by Balducci et al. [27]. Financial reasons as a barrier for participation of elderly can be excluded for Germany, since the costs of clinical trial treatment are covered so far. The latter problem, however, was evident in the United States and led to the initiation of a Medicare policy change which increased older patient participation in clinical trials since the year 2000 [28].

Hematological toxicity in general and nonhematological toxic effects showed no significant differences to the detriment of elderly patients which confirms a number of previous reports for platinum-based and platinum/paclitaxel-based chemotherapy in the elderly [22, 23, 29, 30]. Febrile neutropenia, however, occurred more frequently in the elderly, but the absolute incidence was rather low and within an acceptable range. Additionally, QoL in the elderly was not affected immoderately in comparison to their younger counterparts. Similar observations were reported for carboplatin/paclitaxel-treated elderly with non-small-cell lung cancer [29]. The comparable results of QoL in both age groups did not confirm any disadvantage in principle for chemotherapy in the elderly which might be due to the comparable toxicity in both age groups. This observation, however, gets even more relevance since patient-reported outcomes are not necessarily in agreement with objective assessments. Calhoun et al. [31] found that physicians rated severe toxicity health states induced by chemotherapy more favorably than patients.

Overall, platinum/paclitaxel was feasible and safe for treatment of the elderly in this trial. The dosages of platinum and paclitaxel per cycle were comparable between both age groups, which is consistent with previous age-related observations [5, 32, 33]. Early discontinuation, however, occurred significantly more often, and 23% of elderly patients received no more than four cycles. The reasons for shorter treatment duration among age groups are hard to explain. One major reason was increased patients' withdrawal which might be attributable to a higher rate of skepticism toward clinical trials in elderly patients. The second-most frequently quoted reason was toxicity. It, however, must have been rather anticipated toxicity than experienced toxicity. The latter did not occur in a higher proportion of elderly patients. We cannot rule out that an ability to foresee toxicity and treatment discontinuation avoided excessive toxicity in this subgroup. The other way round, however, might be true as well. The inconsistencies between the toxicity and QoL assessment on the one hand and the higher early-cessation rate on the other hand might be explained by different investigators' estimation of toxicity in elderly patients. This is also indicated by the observation that the investigators did not exploit all instruments to maintain treatment since there were no differences with regard to dose reductions or cycle delays between both age groups. Conclusively, there might be a certain reservation to use all options for the completion of treatment which led to continuation of deficient representativeness of study results for the older population.

These results indicate that investigators' policy regarding treatment modification in case of toxicity tends toward treatment delay ± supportive care in younger patients but treatment cessation in elderly patients. Neither toxicity nor QoL data, however, support this strategy. On the other hand, the results from this age-specific subgroup analysis should be interpreted carefully: it is accompanied with an inevitable study-participation-related bias, the original trial was designed for other aims and a specific geriatric assessment was not available. Therefore, new prospective trials devoted to explore the best treatment of elderly patients are recommended. Potential strategies include the evaluation of the recommended standard carboplatin/paclitaxel against potentially less toxic regimens in elderly and the geriatric assessment of elderly patients who participate in clinical trials [34].

The results of our study, however, should encourage physicians to apply standard therapy for young old patients (65–75 years of age) who fulfil the common criteria for clinical trial participation and to recruit elderly patients for future clinical trials to improve the representativeness of study results for the whole OC population.

Received for publication June 15, 2006. Revision received September 11, 2006. Accepted for publication September 18, 2006.


   References
Top
 Abstract
 introduction
 patients and methods
 toxicity and QoL measures
 results
 discussion
 References
 
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