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Clinical Cancer Research Vol. 10, 1956-1962, March 2004
© 2004 American Association for Cancer Research

Clinical Trials

Competing Causes of Death and Second Primary Tumors in Patients with Locoregionally Advanced Head and Neck Cancer Treated with Chemoradiotherapy

Athanassios Argiris1, Bruce E. Brockstein1,3, Daniel J. Haraf2, Kerstin M. Stenson2, Bharat B. Mittal1, Merrill S. Kies1, Fred R. Rosen4, Borko Jovanovic1 and Everett E. Vokes2

1 The Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago; 2 University of Chicago and University of Chicago Cancer Research Center, Chicago; 3 Evanston Northwestern HealthCare, Evanston; and 4 University of Illinois, Chicago, Illinois


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: The purpose of this retrospective analysis was to evaluate the emergence of second primary malignancies and the contribution of different causes of death to the outcome of patients with locoregionally advanced head and cancer receiving primary chemoradiotherapy.

Experimental Design: We studied 324 patients with stage IV squamous cell head and neck cancer who were enrolled on five consecutive multicenter Phase II studies of concurrent chemoradiotherapy. All of the regimens included concurrent 5-fluorouracil and hydroxyurea on an alternate week schedule with radiotherapy, either alone (FHX) or with cisplatin (C-FHX) or paclitaxel (T-FHX). The cumulative incidence of second primary tumors or death from any cause was estimated using methods of competing risk analysis.

Results: Median follow-up of surviving patients was 5.2 years (2–10.6 years). The 5-year overall survival and progression-free survival of the cohort were 46% and 65%, respectively. Causes of death and median time of occurrence were as follows: disease (n = 88; 1.5 years), treatment-associated acute or late complications (n = 30; 4 months), second primary tumors (n = 18; 3.5 years), comorbidities (n = 41; 1.9 years), and unknown (n = 20; 5.1 years). Predominant causes of death from comorbidities were cardiac and respiratory illnesses. Twenty-six patients (8%) developed a second primary tumor at a median time of 2.8 years (4 months to 10 years). The cumulative incidence of second primary tumors was 5%, 7%, and 13% at 3, 5, and 10 years, respectively. The most frequent site of second primaries was the lung (n = 13), followed by the esophagus (n = 3) and head and neck (n = 2)

Conclusions: Patients with locoregionally advanced head and neck cancer treated with concurrent chemoradiotherapy are potentially curable but face significant risks of mortality from causes other than disease progression. Ameliorating toxicity, and implementing secondary screening and chemoprevention strategies are major goals in the management of head and neck cancer.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
It has been recognized that survivors of head and neck cancer have increased morbidity and mortality compared with the healthy population that relates to treatment sequelae, coexisting pulmonary, cardiac, and liver diseases secondary to smoking and alcohol use, and second primary tumors (1, 2, 3, 4, 5) . Currently, with the advent of aggressive combined modality programs disease control in patients even with stage IV head and neck cancer has been optimized; in Phase II trials progression-free survival has exceeded 60% at 3–5 years (6, 7, 8, 9, 10, 11, 12, 13) . Therefore, this group of patients is subjected to competing causes of death in addition to the primary disease. The impact of competing causes of death has been studied in long-term survivors of other potentially curable malignancies, such as Hodgkin’s disease, breast cancer, and testicular cancer (14, 15, 16, 17) . Second primary tumors, often involving the aerodigestive epithelium, are a major cause of mortality in head and neck cancer survivors (3) . It is postulated that this is the result of "field cancerization," a term that denotes that the entire aerodigestive epithelium has been exposed to chronic carcinogenic insults and is predisposed to develop multiple premalignant and malignant lesions (18) . Moreover, the utilization of induction chemotherapy and aggressive concomitant chemoradiotherapy is associated with significant treatment-related complications, which are potentially life threatening. To evaluate the different causes of death and the impact of second primary tumors on the long-term outcome of patients treated primarily with nonsurgical therapies, we conducted an analysis of our data from five mature Phase II chemoradiotherapy trials (8, 9, 10 , 12 , 13) . This patient population was used previously for another retrospective analysis with a different focus (19) . Common to the five protocols was the utilization of intensive chemoradiotherapy, and a high locoregional control rate and survival. Therefore, we were interested in investigating the competing causes of death in a group of head and neck patients treated in this fashion.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Between November 1989 and March 1999, 394 patients with locoregionally advanced head and neck cancer, of whom 374 (95%) had stage IV (M0) head and neck cancer, were enrolled in five phase II studies conducted at up to three academic institutions in Chicago, University of Chicago, Northwestern University, and University of Illinois, and affiliated hospitals. The study protocols were approved by each Institutional Review Board, and subjects signed informed consent. The chemoradiotherapy regimens included concurrent 5-fluorouracil and hydroxyurea on an alternate week schedule (1 week on and 1 week off) and once or twice daily radiation therapy, either alone (FHX regimen) or with cisplatin (C-FHX regimen) or paclitaxel (T-FHX regimens; see Table 1Citation ). Two of the earlier studies used cisplatin and 5-fluorouracil-based induction chemotherapy. Results from these studies and detailed methodology have been reported previously (8, 9, 10 , 12 , 13) . An analysis of prognostic factors, patterns of relapse, and long-term survival observed in these studies have also been conducted (19) .


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  		Table 1 Consecutive Phase II trials with FHX-based regimensa

Patients were randomized to receive or not erythropoietin 40,000 international units SQ once weekly for 14 weeks starting with the first treatment week of cycle 1 and continue for 4 weeks after treatment completion.

 
After the completion of therapy, patients were followed with computed tomography scans of the chest, and the head and neck. In the three most recent protocols, it was recommended that follow-up computed tomography scans are performed every 6 months for the first 5 years. For this analysis, to examine a more homogeneous population, we excluded patients with stage III disease, unknown primary tumors, nasopharyngeal or paranasal sinus primaries, and nonsquamous histology. After excluding 70 patients for one or more of the above reasons, 324 patients were analyzed. In one of these study protocols (6950; Ref. 9 ), patients were offered to receive adjuvant chemoprevention for up to 1 year consisting of IFN-{alpha} and cis-retinoic acid. Compliance with this chemoprevention regimen was extremely poor; only 6 patients received it for the intended period of 1 year. These patients have been included in this analysis. The definition of a second primary tumor was not strictly defined in the protocol. A metachronous malignancy was designated as a recurrence or second primary tumor by the local investigator. In general, a tumor of a different histology or of a tumor of the same histology (i.e., squamous cell) but involving a different anatomical site was considered as second primary. Multiple lung lesions were usually considered metastatic.

Statistical Methods.
Overall survival was calculated from the date of treatment initiation to the date of death or last follow-up. Progression-free survival was calculated from the time of treatment initiation to the time of disease recurrence, death, or last follow-up, not including toxic deaths or second primaries as events. Survival curves were constructed using the Kaplan-Meier method (20) . Fisher’s exact test or {chi}2 test was used to compare groups with respects to dichotomous end points. We analyzed the competing risks of second primary tumors and death from other causes using cumulative incidence functions to calculate the fraction of patients suffering from each event over time. The Kaplan-Meier methodology, which treats event occurrences of one risk and considers as censored observations occurrences of all other events, does not provide a correct estimation of risk in the presence of multiple competing risks. Therefore, when multiple potential events may occur, methodologies using cumulative incidence functions have been applied (14 , 21, 22, 23, 24, 25, 26) . In our analysis, we grouped events into 5 groups: (a) death due to disease; (b) death secondary to treatment complications; (c) development of second primary tumor; (d) death due to comorbidities; and (e) unknown cause of death. Patients alive and without a second primary tumor at last follow-up were censored. The definition of treatment-related deaths included late events and deaths secondary to surgical complications. We used NCSS 2000 for cumulative incidence analysis and the SPSS version 11.5 (SPSS Inc., Chicago, IL) for other statistical analysis.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Characteristics of all 324 patients who fulfilled the inclusion criteria and of the subset of 26 patients who developed a second primary tumor are displayed in Table 2Citation . The median follow-up period of the 127 surviving patients was 5.2 years (2–10.6). The 5-year overall survival rate was 46%, and the 5-year progression-free survival rate was 65%. Eighty percent and 90% of the 123 patients who suffered relapses did so within 1.5 years and 2.5 years, respectively. After 4 years, only 6 patients relapsed, 1 locally, 1 regionally, and 4 distantly. A total of 197 deaths occurred; 88 deaths (45%) were due to disease progression, 30 (15%) due to treatment-related complications, of which 18 (9%) were early deaths, i.e., during the first 6 months from treatment initiation, and 12 (6%) were late deaths, i.e., occurring >6 months from treatment initiation, 18 (9%) due to second primary tumors, 41 (21%) due to comorbid illnesses, and 20 (10%) due to unknown causes. On the basis of the median time of occurrence, deaths occurred first due to treatment-related complications followed by disease, comorbidities, and second primaries (see Table 3Citation ). All of the treatment-related deaths occurred within 1 year from treatment initiation with the exception of two events; a death that occurred 3.4 years later due to postoperative vascular complications from treatment-related tracheal fistula repair and a death that occurred 1.7 years later due to cisplatin-induced renal failure. Eighteen of 30 deaths (60%) occurred within the first 6 months after treatment initiation, i.e., the early toxic death rate was 6% in a total of 324 patients. The treatment-related death rate, including early and late events, decreased over time from 10–12% in the first three protocols to 5.5–7.5% in the last two protocols with T-FHX (P = 0.2). The cumulative incidence of second primary tumors and competing causes of death are displayed in Table 4Citation and Fig. 1Citation . A breakdown of the 30 treatment-related deaths and the 41 deaths due to comorbidities is listed in Table 5Citation . Infectious complications, such as sepsis (n = 8) and endocarditis (n = 3) were common causes of treatment-related death. In some cases the relationship to treatment was indirect. Four treatment-related deaths were the result of surgical complications after salvage surgery or biopsies that may be considered part of multimodality treatment. Cardiac diseases (n = 8), pneumonia (n = 8), chronic obstructive pulmonary disease and other respiratory causes (n = 7), and complications of drug use (n = 5) accounted for the majority of deaths from comorbid illnesses. We could identify no potential risk factors, such as gender, performance status, or site of primary, predicting toxic death or death from comorbidities. However, an association between smoking and death from comorbidities was suggested: none of 21 never-smokers died from comorbidities versus 31 (13%) of 247 smokers (P = 0.068; Fisher exact test; 1-sided).


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  		Table 2 Patient characteristics and smoking and alcohol use

 

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  		Table 3 Categories of death and time of occurrence

 

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  		Table 4 Cumulative incidence with 95% confidence intervals of second primary tumors and death from disease, and comorbidities

 


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  		Fig. 1. Cumulative incidences (n = 324) of death due to disease (category = 1, A), development of second primary tumors (category = 3, B), and death due to comorbidities (category = 4, C). Time is in years.

 

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  		Table 5 Causes of death

 
Second Primary Tumors.
Twenty-six patients (8%) developed 27 second primary tumors. One patient was diagnosed with two second primaries, of lung and rectal origin. The site and histology of the second primary tumors and patient outcomes are listed in Table 6Citation . The majority of second primary tumors (19 of 27) involved the aerodigestive epithelium, lung (n = 14), esophagus (n = 3), and head and neck (n = 2). Of 14 patients with lung cancer, 12 died from progressive disease; 1 patient died from an unrelated cause 8.2 years after the diagnosis of second primary lung cancer; another patient was censored alive 1.9 years after diagnosis of lung cancer. In 1 case, a patient died of respiratory failure and was found at autopsy to have locally advanced lung cancer. The actuarial risk of developing a second primary tumor per year varied over time; from the first to the tenth year the annual risk and total number of second primary events per year/number of patients at risk at the beginning of each year was 0.9% (3 of 324), 0.8% (2 of 256), 5% (10 of 207), 3% (6 of 173), 1.5% (2 of 134), 1% (1 of 99), 1.5% (1 of 66), 0% (0 of 41), 0% (0 of 23), and 7% (1 of 15). On cumulative incidence analysis that accounts for patients lost to competing causes of death, the cumulative incidence of second primary tumors was 5% at year 3, 7% at year 5, and 13% at year 10 (Table 4)Citation . On univariate analysis, no patient or tumor characteristics were predictive for the development of a second primary tumor (Table 1)Citation . There were no significant differences in smoking or alcohol usage habits between patients who developed a second primary tumor and the rest of the patients.


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  		Table 6 Second primary tumors (n = 27)

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We studied in a systematic manner the impact of competing causes of death on the outcome of patients with locoregionally advanced head and neck cancer treated with multiagent chemoradiotherapy regimens. These patients were selected for participation into a clinical trial and, therefore, were in general of good performance status and without major medical comorbidities at baseline. As expected, the vast majority of patients were smokers and/or alcohol drinkers. With combined data from five Phase II trials of chemoradiotherapy, a progression-free survival of 65% was achieved at 5 years; the overall survival rate was 46% implying that causes other than disease contributed to patient demise. Approximately half of the deaths that occurred could not be linked to disease progression. Curing disease is only one of the multifaceted problems that patients with head and neck cancer face. Treatment-related toxicity was the major cause of death other than disease during the first year in our patient population. Subsequently, second primary tumors and comorbidities gradually emerged as major cause of morbidity and mortality. Due to the high disease control rate observed, patients were exposed to the risks of late, primary-disease unrelated, competing causes of death. The application of competing risk analysis for the evaluation of the outcome of patients with head and neck cancer is a novel concept but has been used previously for survival analysis in other malignancies (14 , 21) . The cumulative incidence of second primary tumors increased to 5% at 3 years, 7% at 5 years, and 13% at 10 years. Respiratory, cardiovascular, alcohol-related causes, and drug overdose were the most common causes of death from comorbid conditions. This spectrum of comorbidities is characteristic of the population of patients with head and neck cancer that is plagued by high rates of tobacco and other substances use. Hall et al. (4) demonstrated that within the first 5 years from diagnosis ~1 of 5 patients dies from increased comorbidities. Skarsgard et al. (5) calculated that the excess mortality (i.e., expected survival in the general population minus observed survival) for patients registered in the Ontario Cancer Registry in Canada and the Surveillance, Epidemiology, and End Results database in the United States who survived up to 5 years from diagnosis was >50%, whereas the excess mortality for patients who survived beyond the first 5 years was in the order of 20–40%. The major impact of noncancer-related causes of death in head and neck cancer is reminiscent of similar findings in patients undergoing chemotherapy for other potentially curable diseases, such as Hodgkin’s disease and germ cell tumors (14, 15, 16) .

The development of second primary tumors in patients with head and neck cancer treated primarily with surgery and radiation therapy has been described in multiple studies. Metachronous malignancies develop in approximately 10–20% of patients with head and neck cancer at a median interval of 31–43 months (27, 28, 29, 30, 31, 32) . The annual rate of second primary tumors is estimated to be 3–5%, and it may remain constant over time (27 , 28 , 33 , 34) . However, the reported risk of second primary tumors may vary according to the site of the original tumor, continued tobacco exposure, curability of the primary tumor, and the length and quality of follow-up (3) . In a large retrospective analysis of patients with various stages of head and neck cancer treated with radiation therapy as single-modality therapy, the estimated risk of developing a second primary tumor within 3 years of radiotherapy was 10%, within 5 years 15%, and within 8 years 23%(28) . In a preliminary analysis of a randomized placebo-controlled chemoprevention trial with cis-retinoic acid that enrolled a total of 1191 eligible patients with stage I-II head and neck cancer, second primary tumors developed in 14% of patients, at an annual rate of 5% (34) . Sixty-six percent of second primary tumors developed in the aerodigestive tract, of which 50% developed in the lung, 44% in head and neck, and 5% in the esophagus (34) . The incidence of second primary tumors related to the site of primary (pharynx more than oral cavity and larynx), stage of disease (stage II more than I), and smoking status (current smokers more than former and never smokers; (34) . Many studies have also reported that the amount of tobacco use and smoking continuation correlate with the risk of a second primary tumor (35 , 36) . Data regarding smoking continuation were not included in our study. However, we found no correlation between smoking and alcohol habits at baseline and the development of a second primary tumor.

Approximately 30–50% of second primary tumors develop in the head and neck (27 , 34 , 37) . Because these tumors are uniformly squamous and despite the implementation of strict criteria, it is in many cases uncertain whether the presumed second primaries actually represent local recurrences. In our series, only 7% (2 of 27) of the second primary tumors developed in the head and neck. We have reported previously that 0 of 25 patients with head and neck cancer from an occult primary treated on similar chemoradiotherapy programs developed a metachronous mucosal malignancy (38) . An intriguing hypothesis that merits further study is that the low rate of head and neck second primaries reported is due to an in-field effect of chemoradiotherapy, i.e., the addition of chemotherapy to radiation therapy contributes to the eradication of occult in-field primaries or even premalignant lesions. It is also possible but unlikely that a number of the late local relapses reported were actually second primaries. Moreover, despite the use of cumulative incidence analysis, the high rates of failure from other causes may have obscured the true incidence of second primary tumors in our series. Newer strategies of adjuvant therapies aimed at reducing the incidence of recurrence and second primaries are being investigated (39) .

Finally, a significant number of deaths in our series were treatment-related; overall, 9% of patients died due to acute or chronic treatment-related events although this number was lower in the last two T-FHX trials at 5.5% and 7.5%, respectively. Sixty-percent of these events (18 of 30) occurred within the first 6 months, and 40% (12 of 30) were late events. Conventional radiation therapy plus cisplatin 100 mg/m2 every 3 weeks for locoregionally advanced unresectable head and neck cancer resulted in 4% treatment-related deaths in a cooperative group study (40) . However, these authors considered treatment-related deaths only those occurring within 30 days of treatment completion (40) . Because we used a broader definition and included late deaths as well as surgery-related deaths, we may have overestimated treatment-related mortality. Nevertheless, toxicities with intensive concurrent chemoradiotherapy are considerable, and appropriate patient selection and supportive care are paramount. Longer follow-up, >5 years, will be required to fully assess late toxicities and functional outcomes from combined modality therapy.

In conclusion, our study reveals the magnitude of the multiple problems involved in the management of head and neck cancer. Efforts to improve the outcome of patients with head and neck cancer should focus not only on disease control but also on treatment-related complications, second primary tumors, and comorbidities.


   ACKNOWLEDGMENTS
 
We thank Alfred W. Rademaker, Louis Portugal, Harold Pelzer, and Barry Wenig for serving as investigators in the study protocols.


   FOOTNOTES
 
Grant support: University of Chicago/Northwestern University Oral Cancer Center Grant P50 DE11921–04, University of Chicago Cancer Research Center Grant P30 CA14599, The Francis Lederer Foundation, The Geraldi Norton Memorial Corporation, The Robert and Valda Svendsen Memorial, and Bristol-Myers Squibb, Princeton, NJ.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Notes: M. Kies is presently at the M.D. Anderson Cancer Center, Houston, TX.

Requests for reprints: Athanassios Argiris, Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 676 North St. Clair, Suite 850, Chicago, IL 60611. Phone: (312) 695-4441; Fax: (312) 695-6189; E-mail: a-argiris{at}northwestern.edu

Received 7/23/03; revised 11/10/03; accepted 12/ 7/03.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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M. S. Choe, X. Zhang, H. J. C. Shin, D. M. Shin, and Z. Chen
Interaction between epidermal growth factor receptor- and cyclooxygenase 2-mediated pathways and its implications for the chemoprevention of head and neck cancer
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