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10.1245/s10434-006-9229-z
Annals of Surgical Oncology 14:968-976 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Incidence and Treatment of Tracheal Cancer: A Nationwide Study in The Netherlands

Jimmie Honings, MS1, Jos A. A. M. van Dijck, PhD2,3, Ad F. T. M. Verhagen, MD, PhD4, Henricus F. M. van der Heijden, MD, PhD5 and Henri A. M. Marres, MD, PhD1

1 Dept. Oto-rhino-laryngology and Head & Neck Surgery, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
2 Comprehensive Cancer Center East, Nijmegen, The Netherlands
3 Department of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
4 Department of Cardiothoracic Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
5 Department of Pulmonary diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Correspondence: Address correspondence and reprint requests to: Henri A. M. Marres, MD, PhD; E-mail: h.marres{at}kno.umcn.nl


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background: The aim of this study was to assess the incidence, characteristics, treatment, and survival of patients with tracheal malignancies in the Netherlands.

Methods: All cases of tracheal cancer entered into the database of the Netherlands Cancer Registry in the period 1989–2002 were selected. Data on histological type, age at time of diagnosis, treatment, and survival were analyzed retrospectively.

Results: The annual incidence was 0.142 per 100,000 inhabitants (308 cases, of which 15 were found incidentally at autopsy). Of these, 72% were men. In 52.9%, the histological type was squamous cell carcinoma and in only 7.1% adenoid cystic carcinoma (ACC). Mean age at time of diagnosis was 64.3 years. Of the 293 patients diagnosed while alive, 34 patients underwent surgical resection (11.6%), 156 patients received radiotherapy (53.2%), and 103 patients neither (35.4%). Median survival of all 293 patients was 10 months (mean 28 months) with 1-year, 5-year, and 10-year survival rates of 43%, 15%, and 6%, respectively. The prognosis of patients with ACC was significantly better. The 5-year survival rate in patients who underwent surgical resection was 51%, and the 10-year survival rate in these patients was 33%.

Conclusion: The prognosis of patients with a tracheal malignancy is usually poor. Surgical treatment, however, can lead to good survival rates; still, this is currently only used in selected patients, even though it would seem to be possible in more cases in view of the technical advances in the field of tracheal surgery. Centralizing the care and treatment of tracheal cancers and implementing a more assertive attitude towards this disease could make surgery accessible to a larger number of patients. Data from the literature show that this would lead to better survival in patients with a tracheal malignancy.

Key Words: Tracheal cancer • Nationwide study • Epidemiology • Treatment of tracheal cancer • Survival of patients with tracheal cancer


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Primary tracheal cancer is rare and its incidence is very low compared with laryngeal or bronchial cancer. The annual incidence of tracheal cancer is approximately 0.1 per 100,000 persons,1,2 accounting for only 0.2% of malignant neoplasms of the respiratory tract3,4 and only 0.02–0.04% of all reported malignancies.1,5 Because of its low incidence, knowledge of the epidemiology, etiology, prognostic factors, and methods of treatment is limited. Tracheal cancer is more common in men and patients with a history of smoking, the latter group making up 77–86% of all patients with tracheal cancer. Median age at the time of diagnosis is 67 years.5,6 The prognosis of patients diagnosed with tracheal cancer is poor, the 5-year survival rate being 5–35%.2,5–8

Surgery with or without irradiation is considered to be the treatment of choice2,6,9–12 for two histological types of primary tracheal carcinoma, with different characteristics: squamous cell carcinoma (SCC) and adenoid cystic carcinoma (ACC).6,7,10,11,13

Licht et al. (2001) concluded that a nihilistic attitude exists based on ignorance of the surgical treatment of tracheal cancers. In Denmark, less than 10% of all patients with tracheal cancer were treated surgically, whereas patients undergoing this type of treatment had better survival rates compared with patients undergoing other types of treatment.5 These findings are in line with those of Manninen et al. in 1993.6 If ignorance of surgical treatment is so widespread, the management of tracheal cancer could certainly be improved. A more aggressive approach towards tracheal cancer might lead to improved survival in patients diagnosed with this disease.

In the Netherlands, all hospitals are associated with one of the nine regional cancer registries (Comprehensive Cancer Centers), which submit their data to the national database of the Netherlands Cancer Registry (NCR), thus creating a systematic collection of data on all malignant neoplasms occurring in the Netherlands since 1989. This provides the prerequisites for a reliable nationwide study on tracheal cancer.

The goal of this study was to assess the incidence, characteristics, treatment modalities, and treatment outcome of tracheal cancer in the Netherlands.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
In the Netherlands, a population-based cancer registry exists. Nine regional cancer registries gather data on patient characteristics, topography, morphology, stage, and treatment of cancer. The main source of notification is a national archive of pathology reports. This is completed with data from the National Hospital Discharge Registry. After notification, specially trained registrars collect data from the patient files in the hospitals.

For the current study, all cases of primary tracheal cancer reported in the files of the Netherlands Cancer Registry (NCR) between 1989 and 2002 were selected. The regional cancer registries provided data on patient characteristics, clinical information, pathologic data, and treatments given with regard to the tracheal cancer as well as the occurrence of other malignant tumors before or after the diagnosis of tracheal cancer. For these other tumors, the localization, histological type, and date of diagnosis were recorded. Furthermore, the date of death was recorded and, if not applicable, the date of the most recent follow-up. All data were stored in a database designed especially for the study.

The annual incidence as an average over the 14-year period was calculated using data from Statistics Netherlands (Centraal Bureau voor de Statistiek, CBS). During the period of the study, the number of inhabitants in the Netherlands increased from 14.8 million in 1989 to 16.1 million in 2002. The average size of the population in this period was 15.4 million. Survival was calculated from the time of diagnosis until the last follow-up and analyzed using the Kaplan-Meier procedure with the log-rank test to compare survival functions.

Statistical analysis was performed using the statistical program SPSS 12.0.1.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
During the 14-year period between 1989 and 2002, 312 cases of tracheal cancer were reported in the files of the Netherlands Cancer Registry. After reviewing the tumor localization, four patients were excluded, of which two had a lymphoma, one a laryngeal carcinoma and one a bronchial carcinoma. Finally, 308 cases were regarded as true cases of primary tracheal cancer and included for further investigation. These cases accounted for 0.034% of all recorded malignancies in this period. The calculated annual incidence in this period is 0.142 per 100,000 inhabitants.

Seventy-two percent of all tracheal cancers were diagnosed in men (n = 223) and 28% in women (n = 85). The most common histological type was SCC, which was observed in 52.9% of all patients (n = 163). The distribution of all histological types is shown in Table 1Go. In patients with ACC, the male/female ratio was 1:1, but all other histological types of tracheal cancer were found predominantly in males.


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  		TABLE 1. Histological types in 308 tracheal cancer cases in the Netherlands
 
Fifteen cases (4.9%) were found incidentally at autopsy and 293 were diagnosed while the patients were alive and confirmed by histopathological examination. This latter group was used for a more detailed analysis and investigation of the age characteristics, treatment modalities, and survival outcome.

The mean age at diagnosis was 64.3 years (range 30–95 years). An analysis of the relationship between histological type and age revealed a lower age at diagnosis for ACC (mean 59.5 years) compared to patients with SCC (mean 64.7 years, Table 2Go); this difference was almost significant (P = 0.054).


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  		TABLE 2. Age according to gender and histological type
 
Thirty-four (11.6%) of the 293 patients underwent surgical resection as the primary treatment; of these, 23 received additional radiotherapy. One of the 23 cases also underwent endobronchial laser therapy. Radiotherapy as the primary treatment was given to 156 (53.2%). Additionally, 12 of these 156 patients received some form of endobronchial treatment, focused mainly on tumor reduction, and another 12 patients received chemotherapy. Of the remaining 103 patients (35.2%) who did not receive either radiotherapy or surgery, 20 patients were treated with chemotherapy and 10 received endobronchial treatments, such as laser therapy, with palliative intent.

Eighty-five patients (29%) had a total of 101 other primary malignancies (Table 3Go) before or after their tracheal cancer were diagnosed (a mean of 1.2 other primary malignancies per person). Of these tumors, 56% were SCC and 12% were adenocarcinoma. Seventy-three of these other primary tumors were found before the carcinoma in the trachea, 20 were diagnosed in the same year and eight were discovered after the diagnosis of tracheal cancer. More than half of these second primary tumors were located in the respiratory tract.


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  		TABLE 3. Localizations of prior, concurrent and second primary tumors (n = 85)
 
The 10-year follow-up is complete in 223 of 293 patients (76.1%). The overall median survival (n = 293) was 10 months (mean 28 months) with a 1-year survival rate of 43%, a 5-year survival rate of 14%, and a 10-year survival rate of 6% (Table 4Go and Fig. 1Go).


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  		TABLE 4. Survival in tracheal cancer according to histological type and type of treatment
 

Figure 1
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  		FIG. 1. Overall survival of tracheal cancer in the Netherlands (n = 293).

 
Surprisingly, the survival of patients who had one or more other primary tumors (n = 85) was not significantly different from that of patients without other primary tumors (n = 208): median survival times of 16 months (95% CI 9–23 months) and 8 months (95% CI 5–11 months), respectively (P = 0.0896).

The survival following different methods of treatment did differ and was significantly better after surgery (P < 0.0001, Table 4Go). For surgically treated patients without radiotherapy (n = 11), the median survival was 91 months (mean 79 months). When surgery and radiotherapy were combined, median survival was 82 months (mean 80 months). Overall, for surgically treated patients (n = 34), median survival was 82 months (mean 79 months). Patients treated with radiotherapy alone had a median overall survival time of 11 months (median 24 months). In the group of patients who did not receive either surgical treatment or radiotherapy, the median survival time was 3 months (mean 13 months). The 5-year overall survival rates were 51% for patients who underwent surgical treatment, 11% for patients treated with radiotherapy alone, and only 5% for patients who received neither surgery nor radiotherapy. In the latter group, there were no differences in survival between patients treated with chemotherapy, laser therapy, or who received no treatment. Ten years after diagnosis, only three of the 260 patients who were not treated surgically were alive. The 10-year overall survival rate for patients treated surgically, with or without radiotherapy, is 33% (Fig. 2Go).


Figure 2
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  		FIG. 2. Survival in tracheal cancer according to type of treatment.

 
Except for ACC, there were no significant differences in survival between the different histological types. The survival of patients with ACC was significantly better than that for all other histological types (P < 0.0001, Table 4Go and Fig. 3Go). Eleven (52.4%) of 21 cases of ACC underwent surgery, which was combined with radiotherapy in eight. These 11 cases made up 32.4% of all surgically treated patients. Other histological types in this group included eighteen patients with SCC (52.9%), two epithelial large cell carcinomas (5.9%), one carcinoid (2.9%), one epithelial-myoepithelial carcinoma (2.9%), and one malignant melanoma (2.9%).


Figure 3
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  		FIG. 3. Survival in tracheal cancer according to histological type. SCC = squamous cell carcinoma; ACC = adenoid cystic carcinoma.

 
The differences in survival following different methods of treatment were also investigated in the histologically homogeneous group of patients with SCC who were alive at diagnosis (n = 156). The survival time within this group in relation to method of treatment showed nearly the same outcome per treatment modality as the overall outcome (P < 0.0001, Table 5Go and Fig. 4Go). Survival of patients treated with surgery only (n = 5) and patients treated with surgery and radiotherapy (n = 13) did not differ significantly (median 49 months and median 23 months, respectively).


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  		TABLE 5. Survival in tracheal Squamous Cell Carcinoma according to type of treatment (P < 0.0001)
 

Figure 4
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  		FIG. 4. Survival in tracheal Squamous Cell Carcinoma (n = 156) according to type of treatment.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
In this study, data from the Netherlands Cancer Registry (NCR) were used and reviewed retrospectively. Data collection and data management were carried out on a nationwide basis and related to the histological diagnosis.14 We included all cases of tracheal cancer reported in the files of the NCR and found that four of 312 reported cases were misclassified (1.3%). In two other epidemiological studies, the frequency of misclassification of tracheal tumors (16–29%) led to the conclusion that the incidence may be overestimated.1,5

According to the study of Licht et al., tracheal cancer in Denmark makes up 0.02% of all reported malignancies; in our study, this proportion was higher (0.034%). This might indicate that some of the 308 cases of tracheal cancer that we found were misclassified. However, the data on all cases were extracted from the patients’ medical records and checked individually by trained registration employees of the Comprehensive Cancer Centers before being entered into the NCR.14 For the coding of the data, national and international standards are used. Although registration errors will occur, it is unlikely that the difference between the results of Licht et al. and ours can be explained by misclassification.

Only a few other epidemiological studies on tracheal cancer have been performed. In Finland, the annual incidence of tracheal cancer is 0.104 per 100,000 inhabitants, and the proportion of all malignancies accounted for by tracheal cancer is 0.038%.1 This is in accordance with the figures in the Netherlands, which are 0.142 per 100,000 inhabitants and a proportion of 0.034% of all malignancies.

Licht et al. in Denmark found that 17% of all cases of tracheal carcinoma were found incidentally at autopsy,5 whereas in our study this was only 4.9%. This is probably due to the difference in the total number of autopsies per year: in Denmark, autopsy is performed in 27% of all deaths,5 while in the Netherlands it is only performed in 7%.15

When one looks at the available literature on the distribution of the histological types of tracheal cancer (Table 6Go), it is striking that in all epidemiological studies, including ours, SCC accounts for 46–72% of all cancers while ACC makes up only 3–11%.2,5–7,16 In contrast, in studies performed in surgical clinics, ACC is seen in 30–50% of all cases.11,17–20 In a study by Bhattacharyya, based on the U.S. SEER database, 19 of 92 cases of tracheal cancer consisted of ACC (20.7%). However, patients with distant metastasis were excluded in this study.21 Gaissert suggests that this disparity in the distribution of histological types of tracheal cancer could be explained by the absence of radiological and pathological review of cases in epidemiological studies.17 However, this is the third national epidemiological study in which a lower percentage of ACC was found. All our cases were registered nationally only on the basis of a histological diagnosis. Still, in all three of the national epidemiological studies mentioned above, 47–80% of patients with ACC underwent surgical resection, while overall, only 6–18% received surgery. In a Danish national study, small cell and large cell carcinoma accounted for 7.3% and 1.8% of all cases, respectively,5 while in our study these portions were 11.0% and 7.5%, respectively. An explanation for these relatively high incidences could not be found, as pathology slides were not reviewed in this retrospective chart review. Gelder and Hetzel also observed an unexpected high incidence of small cell carcinoma (6%).7


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  		TABLE 6. Treatment modalities and distribution of histological types in 5 epidemiological studies
 
In our patients, more than 50% of those with ACC received surgical treatment, compared to only 8.1% of the patients with other histological types of primary tracheal carcinoma. More than 30% of all surgically treated patients had ACC. Moreover, it seems that patients with ACC are more often operable than patients with other histological types.22 These results are suggestive of a selection bias in studies from surgical clinics, as a result of which ACC appears to be a common histological type.

It was already known that most patients with tracheal cancer are male.1,23 ACC is associated with a more equal distribution between the sexes or may even be found predominantly in females.24 Another characteristic of ACC is that it is found in younger patients. Gelder and Hetzel found a mean age of 50 years in 34 patients with ACC.7 The 135 patients with ACC in the study of Gaissert et al. had a mean age of 49 years.9 In our study, this difference in age was less clear and in fact not significant (P = 0.054). The mean age of patients with ACC was almost 60 years (with an equal distribution between males and females). Patients with ACC have by far the best prognosis of all histological types, regardless of treatment modality,6,16,19 which is also confirmed by our series (Table 4Go). In our study, patients with ACC had a 10-year survival rate of 61%.

We also analyzed the impact of other primary tumors, prior to or after the diagnosis of tracheal cancer, on survival. However, no significant effect on survival was found. León et al. found that 16% of patients with malignancies of the head and neck developed other primary tumors, which led to a significant decrease in survival.25 The high incidence of other primary tumors is closely related to the abuse of tobacco and alcohol.26 It is known that the vast majority of patients with tracheal cancer are smokers. Of all patients with primary tracheal cancer, 77–86% smoke or have a history of smoking.1,5,7 This predominance is even more explicit in patients with SCC, of which 89–92% are smokers, whereas ACC is distributed more equally between non-smokers and smokers, the latter group making up 45–60% of all patients with ACC.7,9,27

According to the studies listed in Table 6Go, 6–18% of all patients with tracheal cancer underwent surgery as their primary treatment, 27–73% were treated with radiotherapy, and 9–66% had other types of treatment or best supportive care. These figures correspond to those for patients with tracheal cancer in the Netherlands during the period 1989–2002. When we look at the survival following different methods of treatment, it is clear that patients who underwent surgical resection of their tracheal cancer survived longer than patients who were treated otherwise (P < 0.0001). One of the reasons for this difference is that ACC makes up 32.4% (n = 11) of the group of operated patients (n = 34). Nevertheless, when we looked at the patients with SCC separately, we found that in this histologically homogeneous group, patients treated with surgery had a 5-year survival of 41% compared to 11% in patients treated with radiotherapy (P < 0.0001, Table 5Go). This indicates that, irrespective of histological type, surgical treatment yields the best survival. The differences in outcome between surgery with and without adjuvant radiotherapy were not analyzed separately since radiotherapy was used in patients selected by staging information and surgical margins. In a French multicenter study including 208 cases of tracheal tumors, Regnard et al. found that the 5-year survival rate after surgery was 62%.11 However, this may be too optimistic, since 11% of the included tumors were benign. Gaissert et al. included 270 cases of tracheal cancer, half SCC and half ACC, and achieved a 5-year survival rate of 56% in operated cases.9 A Japanese study even showed a 5-year survival rate of 72% in surgically treated patients, although this group consisted of only 16 patients, of which nine had SCC and seven had ACC.19 Given these good results, the available literature on tracheal cancer shows consensus regarding treatment: surgery is the only realistic treatment with curative intent and leads to the best survival rates.18,28 However, not all tumors in patients presenting with tracheal carcinoma are resectable due to locally advanced disease, meta-static disease, or contraindicating co-morbidity.12,29

Several other treatment modalities have been described. Endoscopic resection can be used to relieve airway obstruction but does not provide complete resection and the chances of a cure are therefore minimal.17 Radiotherapy can also be used as palliation or as adjuvant treatment after surgery.30,31 Webb et al. recommend adjuvant radiotherapy in patients treated with surgical excision.27 Very poor survival rates in patients treated with radiotherapy alone are seen in most studies. A French study by Mornex et al. reported a 5-year survival rate of 8% in 82 patients treated with radiotherapy,8 and Makarewicz reported a 5-year survival rate of 9% in 23 cases in 1998.32 Our data show a 5-year survival rate of 11% in patients treated by primary radiotherapy. The application of endotracheal brachytherapy after external-beam irradiation has shown to improve local tumor control. This relatively new treatment modality is subject of future research to further optimize the management of tracheal tumors. Cisplatinum based chemotherapy is the treatment of choice for selected patients with disseminated and locally advanced disease. The intent of chemotherapy is usually palliative and chemotherapy can only be advised in patients with a good performance status. Small cell cancer of the trachea is very rare and is often part of a disseminated disease where chemotherapy can be successful, but no large trials have been published.33 There is very little data available on the effect of adjuvant or neoadjuvant chemotherapy or concurrent chemoradiotherapy of non small cell tracheal carcinomas.34

It can be expected that only patients in the best clinical condition and with the most favorable tumor stage are offered surgery, thus affecting the survival rate. Still, Gaissert17 and Macchiarini12 state that, unless technically impossible, surgery should be the treatment of choice in patients with tracheal cancer. The implementation of this recommendation is impeded by the lack of a uniform staging system for tracheal cancer because the classic TNM-staging cannot be applied. New staging systems for tracheal carcinomas have been suggested by Bhattacharyya21 and Macchiarini.12 The value of these systems should be subject of future research projects.

Hazama et al. and Gaissert concluded that resection is indicated in even more than 50% of all patients with tracheal cancer.18,20 This is in contrast to all the studies listed in Table 6Go, including our study, in which only 10% were treated surgically. The reason why surgery is considered in only a few cases may be that only few centers have gained experience in the management of tracheal malignancies because of their rarity.17 This is also supported by Gelder and Hetzel.7 Licht et al. also report a nihilistic attitude towards the management of tracheal cancer in Denmark.5 Based on our findings, this also seems to be the case in the Netherlands, although future research is needed to determine to what extent contra-indications to surgery play a role in the small number of patients treated with surgical resection of their tracheal cancer.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
Looking at the survival rates in our study, we can conclude that overall, the prognosis of patients with tracheal cancer is dismal. Surgery of patients with a tracheal carcinoma can lead to a significantly better survival, compared to radiotherapy. In our patients and in other epidemiological studies, however, surgery was offered to only 10% of all patients. Several studies indicate that surgery would be applicable in at least 50% of all cases of tracheal cancer. Whether this discrepancy is based on a difference in patient population or unawareness among physicians about developing treatment possibilities needs to be investigated.

Research should be conducted to develop a standard classification that can be used to determine resectability. Given the infrequent incidence of this disease, the management and treatment of these patients should be performed by multidisciplinary teams in centers equipped and experienced with the full range of treatment modalities (surgery, radiotherapy, chemotherapy, and endobronchial treatment) in order to achieve more experience with this rare tumor within these teams. We believe that this centralization could optimize palliative care and may improve survival in selected patients. Further studies are needed to evaluate the role of adjuvant chemotherapy and concurrent or sequential chemoradiotherapy to further improve survival.

Received for publication September 4, 2006. Accepted for publication September 5, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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