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Journal of Clinical Oncology, Vol 22, No 2 (January 15), 2004: pp. 262-268
© 2004 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2004.08.039
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Outcome of Elderly Patients With Recurrent or Metastatic Head and Neck Cancer Treated With Cisplatin-Based Chemotherapy

Athanassios Argiris, Yi Li, Barbara A. Murphy, Corey J. Langer, Arlene A. Forastiere

From the Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Dana-Farber Cancer Institute, Boston, MA; Vanderbilt University, Vanderbilt-Ingram Cancer Center, Nashville, TN; Fox Chase Cancer Center, Philadelphia, PA; and Johns Hopkins Oncology Center, Baltimore, MD

Address reprint requests to Athanassios Argiris, MD, 676 North St Clair, Suite 850, Division of Hematology-Oncology, Northwestern University, the Feinberg School of Medicine, Chicago, IL 60611; e-mail: a-argiris{at}northwestern.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors’ Disclosures of...
 REFERENCES
 
PURPOSE: To evaluate the outcome of elderly patients with head and neck cancer undergoing palliative chemotherapy.

PATIENTS AND METHODS: We analyzed combined data from two mature phase III randomized trials conducted by the Eastern Cooperative Oncology Group (ECOG; trial E1393, which compared cisplatin plus paclitaxel at two dose levels, and trial E1395, which compared cisplatin plus fluorouracil to cisplatin plus paclitaxel) to evaluate the toxicity, objective response rates, and survival of patients 70 years or older versus their younger counterparts. All patients had previously untreated recurrent or metastatic squamous cell carcinoma of the head and neck and ECOG performance status 0 or 1.

RESULTS: Fifty-three elderly patients were enrolled from a total of 399 eligible participants (13%). Elderly patients had similar objective response rates (28% v 33%) and median time to progression (5.25 v 4.8 months) compared with younger patients. The median survival was 5.3 v 8 months (Wilcoxon P = .06; log-rank P = .17) and the 1-year survival 26% v 33% for elderly and younger patients, respectively. Elderly patients had a significantly higher incidence of severe nephrotoxicity, diarrhea, and thrombocytopenia. A higher rate of toxic deaths was noted in the elderly but did not reach statistical significance (13% v 8%; P = .29).

CONCLUSION: Elderly patients were underrepresented in these studies. Fit elderly patients with recurrent or metastatic head and neck cancer sustained increased toxicities with cisplatin-based doublets but had comparable survival outcomes compared with younger patients. Strategies to ameliorate toxicities should be pursued in the elderly.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors’ Disclosures of...
 REFERENCES
 
Almost half of the approximately 40,000 new cases of head and neck cancer diagnosed annually in the United States occur in individuals older than 65 years [1]. As life expectancy increases, clinicians increasingly face the challenge of treating elderly patients with cancer, including head and neck cancer. It is estimated that by year 2030, 20% of the U. S. population will be 65 years or older [2]. However, only a small percentage of elderly patients participate in clinical trials [3,4]. No studies have yet focused on the outcome of elderly patients with head and neck cancer treated with chemotherapy.

Cisplatin or cisplatin-based regimens have been widely employed treatments for recurrent or metastatic head and neck cancer. A small randomized study showed that cisplatin monotherapy is superior to best supportive care [5]. Cisplatin-based combination chemotherapy, despite yielding higher response rates, has not been shown to produce a survival benefit compared with single agents in randomized comparisons in recurrent or metastatic head and neck cancer [6,7]. Overall, the outcome of patients with recurrent or metastatic head and neck squamous cell carcinoma is poor and the median survival reported in randomized studies ranges from 6 to 9 months [6-9].

The Eastern Cooperative Oncology Group (ECOG) conducted two consecutive randomized studies with cisplatin-based doublets in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. These two randomized trials (E1393 and E1395) compared cisplatin doublets (cisplatin and paclitaxel at two dose levels, and cisplatin and paclitaxel v cisplatin and fluorouracil [FU]) but failed to show statistically significant survival differences between the treatment arms [8,9]. Considerable toxicities were observed in both studies. In the palliative care setting, toxicities of therapy may worsen quality of life and need to be thoroughly examined. Data from other retrospective clinical studies suggest that older age increases the rate of some complications of chemotherapy [10,11]. The importance of age as a parameter affecting the tolerability and efficacy of chemotherapy for recurrent or metastatic head and neck cancer warrants investigation. Therefore, we analyzed data from these two randomized studies employing cisplatin-based combination chemotherapy for the treatment of patients with recurrent or metastatic head and neck cancer (studies E1393 and E1395) to evaluate the outcome of older patients.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors’ Disclosures of...
 REFERENCES
 
Patient Population
ECOG is a national cooperative group (funded by the National Cancer Institute) that conducts cancer-related studies in adults. For this analysis, we reviewed data from two consecutive phase III randomized trials conducted by the ECOG (E1393 and E1395) that compared cisplatin doublets in patients with recurrent or metastatic head and neck cancer [8,9]. A total of 428 patients (210 patients in E1393 and 218 patients in E1395) were enrolled onto the two studies, of whom 399 patients (201 patients in E1393 and 198 patients in E1395) were eligible and were included in this report. For our analysis, we used a cutoff of 70 years of age to define the elderly, which has been used in previous analyses of cancer patients receiving cisplatin-based chemotherapy [10].

Eligibility and Study Design
Eligibility criteria were similar between study protocols E1393 and E1395. All patients had squamous cell carcinoma of the head and neck from any site, except the nasopharynx, deemed incurable with surgery or radiotherapy; ECOG performance status of 0 or 1; and no prior chemotherapy for the treatment of recurrent or metastatic disease. However, patients could have received chemotherapy as part of initial curative therapy, if administered more than 6 months before study entry. In E1395, paclitaxel or FU had to have been given more than 12 months before study entry. Additional eligibility criteria were measurable disease in E1393 and measurable or assessable disease in E1395; adequate end-organ function, including serum creatinine of <= 1.5 mg/dL (<= 1.2 mg/dL in E1395), total bilirubin less than 1.5 mg/100 mL, absolute neutrophil count >= 1,500/µL, platelets >= 100,000/µL, and hemoglobin of >= 10 g/dL; recovery from major surgery; no active infections; no history of congestive heart failure, and no history of myocardial infarction in the last 6 months; and age 18 years or older. All patients provided written informed consent in accordance with institutional guidelines. The sample size calculation for both trials was based on the major end point, which was overall survival. Secondary end points included response rate and toxicities, whereas event-free survival was also a primary end point in E1393, and quality-of-life analysis and pain intensity were included as secondary end points in E1395. Standard ECOG solid tumor response criteria were used for tumor response assessment. Patients were randomly assigned to treatment equally between arms in both trials and stratified for disease status (newly diagnosed v recurrent) and performance status (0 v 1). In April 1999, the Southwest Oncology Group (SWOG) was added as a participant in E1395. SWOG institutions enrolled 24 patients onto this study.

Treatment Plan and Overall Results in E1393 and E1395
In the first randomized study (E1393), high-dose paclitaxel (200 mg/m2) as a 24-hour infusion plus cisplatin 75 mg/m2 with granulocyte colony-stimulating factor support was compared with low-dose paclitaxel (135 mg/m2) as a 24-hour infusion, plus cisplatin 75 mg/m2 [8] (Table 1). The study was conducted from June 1993 to June 1995. A total of 210 patients were randomly assigned to treatment equally between the two arms. No significant differences in outcome were observed. The response rate was 35% v 36% and the median survival was 7.6 v 6.8 months, in the high-dose versus low-dose paclitaxel arms, respectively. Grade 4 neutropenia was seen in 61% to 71% of patients and the incidence of febrile neutropenia with hospitalization was also high (27% v 39%). The toxic death rate was 10% (12% v 9%). It was concluded that the 24-hour paclitaxel infusion was associated with unacceptable toxicity when combined with cisplatin. Instead, a 3-hour paclitaxel infusion was substituted for the 24-hour infusion and combined with cisplatin for additional testing. In a subsequent randomized trial (E1395), the combination of paclitaxel 175 mg/m2 as a 3-hour infusion and cisplatin 75 mg/m2 was compared with a standard cisplatin and FU regimen [9] (Table 1). The study opened in March 1997 and concluded accrual in January 2000. A total of 218 patients were enrolled. There was no statistically significant difference in either response rates or survival between the two regimens. The median survival was 8.8 months and the 1-year survival was 41% in patients receiving FU and cisplatin versus 9.1 months and 34%, respectively, in patients receiving paclitaxel and cisplatin.


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  		Table 1. Treatment Plan and Overall Results

 
Statistical Analysis
Survival data were analyzed using the Kaplan-Meier method [12]. The log-rank test was used to assess the significance of univariate associations. Fisher’s exact test or {chi}2 test was used to compare groups with respect to dichotomous end points (eg, response rates and toxicities). Logistic regression analysis was performed to evaluate associations between the dichotomized outcomes (eg, toxicities) and the covariates of interest (age) while controlling for the other potential confounders (eg, treatment group). All P values reported are two-sided.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors’ Disclosures of...
 REFERENCES
 
Patient characteristics according to age group are listed in Table 2. Fifty-three patients (13%) of a total of 399 eligible patients were 70 years or older. The elderly group had a median age of 73 years (range, 70 to 84 years) and the younger group had a median age of 59 years (range, 22 to 69 years). One hundred nine patients (30%) were 65 years or older; only three patients (0.8%) were older than 80 years, and 10 patients (2.5%) were younger than 40 years. An increase in the percentage of elderly patients from E1393 to the more recent E1395 trial was noted, from 10% to 17% (P = .055). There was no statistically significant difference in the median number of cycles received between the elderly and the younger patients. A higher percentage of elderly patients were treated with cisplatin and FU versus cisplatin and paclitaxel in E1395 (Table 2).


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  		Table 2. Patient Characteristics and Univariate Analysis

 
Response and Survival
The objective response rates (complete plus partial) were similar among older (28%) and younger patients (33%; {chi}2, P = .58; Table 3). Three patients (6%) in the older group and 27 patients (8%) in the younger group were noted to have a complete response. The median time to progression was 5.25 months among older versus 4.8 months among younger patients (log-rank P = .69; Fig 1). Elderly patients were noted to have a lower median survival (5.3 v 8 months), but the difference did not reach statistical significance (Wilcoxon P = .06; log-rank P = .17; Fig 2). The higher number of deaths occurring in the first few months in the elderly was due partially to an increased number of toxic deaths in that group, a difference that did not reach statistical significance (see Toxicity). However, the actuarial 1- and 2-year survival rates were identical between the two groups: 26% among the elderly versus 33% among younger patients at 1 year, and 11% among older versus 12% among younger patients at 2 years. Similar results in terms of antitumor activity and survival were obtained when a cutoff of 65 years was used to define the elderly (data not shown).


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  		Table 3. Treatment Efficacy in Older (n = 53) and Younger Patients (n = 346)

 


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  		Fig 1. Kaplan-Meier survival curves for elderly (n = 53) and younger patients (n = 346); log-rank P = .17; Wilcoxon P = .06.

 


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  		Fig 2. Kaplan-Meier estimates of time to progression for elderly (n = 53) and younger patients (n = 346); log-rank P = .69.

 
Toxicity
The frequency of toxicities in the two groups is listed in Table 4. The definition of renal toxicity included elevations in creatinine or blood urea nitrogen, hematuria, or proteinuria. Elderly patients had a higher incidence of grade 3 to 5 thrombocytopenia (26% v 12%; P = .0097), diarrhea (17% v 3%; P = .0002), renal complications (8% v 2%; P = .04), and stomatitis (19% v 8%; P = .019). After we adjusted for the unequal distribution of elderly and younger patients between treatment arms using a logistic regression analysis model, the differences in severe stomatitis incidence between the elderly and younger patients were no longer statistically significant (P = .25); however, differences in the rates of severe thrombocytopenia (P = .0003), diarrhea (P < .0001), and renal complications (P = .02) retained their statistical significance. The rate of other toxicities was comparable between the two groups. Similar results were obtained when a cutoff of 65 years was used to define the elderly (data not shown). A total of 35 deaths were attributed to treatment-related complications; seven patients (13%) died as a result of toxicity in the elderly group and 28 patients (8%) died as a result of toxicity in the younger group (P = .29). The causes of toxic death for elderly patients were as follows: infection (three patients), renal (one patient), pulmonary (one patient), cardiac (one patient), and sudden death of unknown etiology (one patient). These events occurred at a median time of 33 days from treatment initiation (range, 17 to 41 days), and in all patients were believed to be related to treatment. Six of these seven patients were males and one was female; four patients were treated on E1393 (two patients in each arm) and three were treated on E1395 (two patients in the cisplatin and FU arm and one patient in the cisplatin and paclitaxel arm).


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  		Table 4. Worst Toxicities (N = 399)

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors’ Disclosures of...
 REFERENCES
 
Despite a decrease in overall cancer death rates, the expansion of the aged population and its inherent increased risk for cancer is expected to increase the burden of cancer in the United States [13]. Therefore, it is becoming increasingly important to recognize age-specific differences in cancer outcomes [2]. We demonstrated that fit elderly patients, almost all between the ages of 70 and 80 years, with recurrent or metastatic head and neck cancer carry a higher risk for chemotherapy-related toxicities, namely nephrotoxicity, diarrhea, and thrombocytopenia. Nevertheless, antitumor activity was maintained in the elderly: objective response rates and time to progression were identical between older and younger patients. Another striking observation was the small percentage of elderly participants (13% were 70 years or older and 30% 65 years or older) in these two large phase III clinical trials in head and neck cancer. Older age has been recognized as a barrier to participation in clinical trials and cancer treatment in general [14-19]. Analyses of two databases, the SWOG trials from 1993 to 1996 [3] and cooperative group phase II and III trials from 1997 through 2000 [4], have found that the proportion of elderly participants, defined as 65 years or older, in head and neck cancer clinical trials was 24% to 29% compared with the proportion of elderly of 48% to 49% in the US population of patients with cancer [3,4]. A number of reasons may explain the underrepresentation of the elderly in clinical trials [19,20], including a therapeutic nihilistic attitude toward the elderly, lack of social and financial support, and comorbidities that result in ineligibility.

A major observation of our study was that the antitumor activity of chemotherapy for head and neck cancer is similar between younger and elderly patients. However, the efficacy of anticancer therapy in the elderly is surrounded by controversy. A worse outcome has been reported for the elderly with cancer in a European study, which was due partly to more advanced stage at presentation [21]. In a small randomized trial that compared cisplatin, bleomycin, or the combination with best supportive care in patients with recurrent or metastatic head and neck cancer, Morton et al [5] found that increasing age was a predictor of worse survival. Age-dependent differences in the biology of acute myeloid leukemias, including an increased incidence of unfavorable cytogenetic abnormalities in the elderly, have been documented [22]. Furthermore, older age is an established poor prognostic factor in lymphomas [23]. In solid tumors, there are sparse data suggesting age-related biologic differences [24,25]. However, multiple retrospective studies in solid tumors, including in non-small-cell lung cancer [10,11], breast cancer [26], and colon cancer [27], have failed to show consistently inferior response rates or survival in elderly treated with chemotherapy.

We found that severe nephrotoxicity, thrombocytopenia, and diarrhea were more common in the elderly than in younger patients. The observance of increased toxicities in the elderly in this study may partially be a function of the use of cisplatin-based regimens, but may also be related to other factors. Advancing age is associated with metabolic changes, higher incidence of comorbidities, and polypharmacia [28-30], which may increase treatment-related toxicities. A well-described change with age is the decline in the glomerular filtration rate [31], which may potentially increase toxicities of cisplatin-based chemotherapy. In addition, the hematopoietic reserve is reduced in the elderly, which renders them more susceptible to chemotherapy-induced myelosuppression [29,32]. In the limited available literature data on pharmacokinetics in the elderly, no major age-related differences in drug clearance could be demonstrated for etoposide and paclitaxel [33,34]. It is possible that underlying biologic differences occurring with age predispose the elderly to increased susceptibility to similar drug exposure levels [34]. However, the tolerability of chemotherapy by the elderly has been a matter of controversy. A number of retrospective studies in solid tumors have reported that toxicities are not increased in the elderly [26,27,35-37], whereas other studies suggested that the elderly suffer increased treatment-associated toxicities [10,11,38-40]. The intensity of treatment and the toxicity profile of the chemotherapy drugs used may be a differentiating factor. Dose-intense therapy is generally poorly tolerated by the elderly. Intensive chemotherapy regimens (eg, for small-cell lung cancer [40] or hematologic malignancies [41-43]) are clearly toxic for elderly patients. Cisplatin-based combinations, as used in this and other studies [10,11,38,44], may also be particularly difficult to tolerate by the elderly.

Participation of the elderly in cancer trials has been scarce [3,4]; few randomized trials have exclusively enrolled elderly patients [45-47]. No randomized trial has yet prospectively compared the outcome of young and older patients with cancer. In the United States, no elderly-specific trials have been conducted or planned in squamous cell carcinoma of the head and neck. Nevertheless, our results strengthen the notion that toxicities are increased in this patient group and indicate that studies aimed at ameliorating toxicities and improving supportive care are warranted in the elderly. The unique features and needs of the gradually expanding older population will need to be addressed in prospective studies.


   Authors’ Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors’ Disclosures of...
REFERENCES
 
The authors indicated no potential conflicts of interest.


   NOTES
 
This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, Chair).

Authors’ disclosures of potential conflicts of interest are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors’ Disclosures of...
 REFERENCES
 
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Submitted August 6, 2003; accepted November 7, 2003.


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