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Second Primary Tumors Involving Non-small Cell Lung Cancer^*

Prevalence and Its Influence on Survival

^* From the Department of Nuclear Medicine, Leiden University Medical Center, Leiden, the Netherlands.

Correspondence to: M.P.M. Stokkel, PhD, Department of Radiology, Division of Nuclear Medicine, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, the Netherlands; e-mail: m.p.m.stokkel{at}lumc.nl

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Objectives: Patients with lung cancer have a relative high risk for second primary cancers. We studied the prevalence of second primary tumors in patients with a diagnosis of non-small cell lung cancer (NSCLC) in their history or at follow-up. Furthermore, we studied survival in subgroups of those patients.

Methods and patients: Retrospectively, 860 patients with NSCLC that had been diagnosed in the period from January 1, 1990, to December 31, 1999, were evaluated for second primary cancers either in their history or in the follow-up period. The patients were divided into the following four groups: group I, patients with another primary tumor detected in the follow-up period (n = 44); group II, patients with another primary tumor in their history (n = 148); group III, patients with no other primary tumor found in their history or at follow-up (n = 634); and group IV, patients with more than one other primary tumor in found in their history or at follow-up (n = 34).

Results: The most frequently diagnosed double tumors were located in the lungs, the head and neck region, and the urinary tract. The interval between another malignancy as the first tumor (group II, 83 months) and NSCLC as the second malignancy was significantly longer than vice versa (group I, 14.5 months; p < 0.05). In > 80% of patients, the second primary tumors were diagnosed within 1 year after NSCLC was diagnosed. The 5-year survival rate is significantly better for patients with more than two primary malignancies compared to patients without two primary malignancies and patients with one other tumor in their history (p = 0.004 and 0.012, respectively). The 5-year survival rate in patients with a second tumor in the follow-up period was better than in patients without any other second tumor (p = 0.029). As the TNM stage and therapy were comparable in all subgroups, it could not be used as explanation for the difference in survival rates.

Conclusion: In 25% of patients, additional tumors that were NSCLC were diagnosed either in their history or in the follow-up period. The majority of second tumors following NSCLC are diagnosed within 1 year. Nevertheless, patients with a second tumor tend to have an overall better survival rate than patients without second primaries, suggesting different growth habits.

Key Words: follow-up • non-small cell lung cancer • prognosis • second primary tumors

	Introduction

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Lung cancer is, after coronary heart disease, the second leading cause of death in men in the Netherlands. Due to advanced diagnostic tools for detecting a malignancy in an earlier stage and to better treatment of other diseases, more than one primary tumor in one single person is becoming more and more prominent. An increased use of cytostatic drugs may increase the overall risk for a new primary malignancy.¹ However, Rheingold et al² have suggested that when cancer is not associated with mortality and is equally distributed throughout the population, approximately 33% of the population (one in three persons) will develop a malignancy, 11% (one in nine persons) will develop a second primary tumor, and so on. In this respect, there are several cancers with the same etiology that are known to occur more frequently than may be expected from cancer statistics (eg, breast cancer with ovarian cancer, and head and neck cancer with lung malignancies). From this point of view, it is interesting to know whether prognosis and survival are different in subgroups of patients with a second tumor either preceding or following a non-small cell lung carcinoma (NSCLC) compared with patients with a NSCLC as a solitary tumor.

In the literature, only a few studies³⁴ have been published on patients with an NSCLC as a secondary or tertiary primary tumor and the influence on survival in these patient groups. However, as far as we know, no study has been published that compares the clinical outcomes among patients with another primary malignancy in their history, patients with another tumor found in the follow-up period, patients with more than one other tumor in their history, and patients without any other tumor. The aim of the present study was to describe the patient and tumor characteristics of patients with second primary malignancies in association with NSCLC and to investigate whether NSCLC patients with another primary tumor, either in their history or in the follow-up period, have a comparable survival rate to patients without another primary tumor. In addition, we wanted to study the intervals between the primary and second primary tumors to assess the effect on follow-up strategies.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Retrospectively, we reviewed all NSCLC patients who received their diagnoses at the Leiden University Medical Center in the period between January 1, 1990, and December 31, 1999. We used the hospital information system and medical records to collect data about these patients and their tumors. The database we used was tumor related, and if more than one tumor was diagnosed in one single patient, each tumor was registered separately. In the database, the following parameters were registered: (1) patient characteristics (ie, date of birth and gender); (2) NSCLC characteristics (ie, date of diagnosing the NSCLC, TNM classification, histology, therapy [surgery, radiation therapy, or chemotherapy]), and follow-up; (3) other malignancies with their characteristics (ie, date of diagnosis, histology, TNM classification, site of the tumor, and therapy). The TNM classification that was used for staging the NSCLC was according to the revised criteria from the International System for Staging Lung Cancer described by Mountain⁵⁶ in 1997. The nonmelanoma skin cancers (ie, squamous cell carcinoma and basocellular carcinoma) were not registered as a second primary tumor as these were not supposed to have influence on prognosis and survival.

The patients were divided into four groups. The first group (I) included patients with NSCLC as the first tumor and with a second primary tumor in the follow-up period. The second group (II) included patients with another primary tumor in their history in whom the second primary tumor was NSCLC. The third group (III) contained patients with the NSCLC as the only tumor, and the fourth group (IV) contained patients with more than two primary tumors in their history and/or in the follow-up period. Patients with another tumor detected at the same time as the NSCLC (simultaneous tumors) were added to group 2. To be sure that two tumors were second primaries and not a primary tumor with a metastasis, the tumors must have fulfilled the criteria described in the next section.

We used May 1, 2002, as the census date, revealing a minimum period of follow-up of at least 29 months for each patient. As end points, we used death irrespective of cause or survival at the census date.

Definition of a Second Primary Lung Tumor
To divide the tumors between synchronous tumors and metachronous tumors, we used the criteria defined by Martini and Melamed,⁷ which are in agreement with most of the studies in the literature describing second primary lung cancers. If tumors are present at the same time, they must be separated and the histology must be different. If both tumors have the same histology, they are located in different lungs, lobes, or segments, they have no common lymphatics, and there are no distant metastases present, they are considered to be two independent primary tumors. If these criteria are not met, the two tumors are considered to be a primary tumor with a metastasis (stage IV tumor). Tumors with the same histology must have an interval of at least 2 years, originating from carcinoma in situ (CIS) or without common lymphatics to be considered as metachronous.

Statistical Analysis
Quantitative variables were summarized with their mean or median and SD. One-way analysis of variance and the ² test were performed where appropriate. Multivariate analysis with respect to survival was performed with the Cox regression model. Finally, survival curves of the different subgroups are presented according to the Kaplan-Meier method. Throughout, a p value of 0.05 was considered to be statistically significant.

	Results

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During the previously described period, 860 new NSCLCs were diagnosed at the Leiden University Medical Center. A total of 316 patients had a history of another malignancy or developed a secondary primary in the follow-up period. In 90 patients, the malignancy concerned a nonmelanoma skin cancer, and, as described before, these tumors were not registered as a secondary primary tumor. As a result, a second primary tumor developed in 44 patients (5.1%) during the follow-up period (group 1), 148 patients (17.2%) had another malignancy in their history (group 2), and 634 patients (73.7%) had NSCLC as their only malignancy (group 3). In 34 patients (4.0%), more than one other primary tumor was found (group 4); 30 patients had three primary tumors, and four patients had four primary tumors.

Five patients moved to another country 1,991, 822, 594, 18, and 348 days after the diagnosis of NSCLC, and one patient was lost to follow-up 17 days before the census date. The patient characteristics of each group are summarized in Table 1 . In groups I and II, the second primary tumors were most frequently located in the lungs, the head and neck region, and the urinary tract (Table 2 ). In 64% and 56%, respectively, the second tumor was located in the organ systems mentioned above. In 10% of the patients (n = 15) with another malignancy preceding NSCLC, the malignancy concerned a lymphoma, leukemia, or myeloma.

View larger version (79K): [in this window] [in a new window] [Download PPT slide]   Figure 1. TNM classification of NSCLC presenting as a first or second primary tumor, demonstrating no significant differences between both groups (p = 0.41).

With respect to NSCLC treatment, we found no statistically significant differences among the four subgroups (p = 0.179). In this study, 29% of the patients were not treated anymore, but the prevalence of nontreatment was equal in the subgroups (Table 1).

Figure 2 shows the Kaplan Meier curves for survival after the diagnosis of NSCLC in the four different groups. Patients with NSCLC as the first malignancy and another in the follow-up period (group I) had a significantly (p = 0.011) better survival rate than patients without any other tumor (group III). We also found a significantly better survival rate for patients with more than one tumor in their history (group IV), compared to patients with no other tumors (group III) [p = 0.012]. In addition, patients with another malignancy in their history were found to have a significantly better 5-year survival rate than patients without another tumor (p = 0.029), whereas patients with more than two primary tumors had a significantly better 5-year survival rate compared with patients with another tumor in their history (p = 0.004). In conclusion, patients with a primary NSCLC as the solitary tumor and no other tumors had the worst survival rate of those in the groups studied.

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Survival curves of patients with NSCLC as a solitary tumor, as the first or second primary tumor or patients with multiple tumors, demonstrating significant differences between subgroups (p = 0.011).

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

The prevalence of two or more malignancies in one patient has increased over the past decades. Several explanations can be given for the fact that multiple primary tumors are being diagnosed more and more, and are nowadays not an exception anymore. Due to better treatment options for other diseases, such as heart and vessel diseases, the life expectancy in men has increased, which definitely affects the prevalence of malignancies in general. In addition, the increased use of radiation therapy and/or chemotherapy for the first tumor also seems to increase the number of secondary cancers. Finally, an important theory often used to explain multiple malignancies is the "field cancerization theory," which states that organ systems exposed to the same carcinogenic agents have a greater chance of transforming into a malignancy.⁸ For example, the coincidence of lung cancer with head and neck cancer and/or cancer of the bladder has been well-described. In this respect, smoking plays an important role as a carcinogenic agent in the etiology of malignancies at these sites.⁹¹⁰ Another example is alcohol, a well-known risk factor for cancer of the oral cavity and stomach.⁹ Beside the environmental factors, hereditary factors also play an important role in the genesis of cancer. More than 30 genes are currently known to have potential roles in the development of a malignancy. The genes that are related to an increased risk of (multiple) cancer are tumor suppressor genes and DNA-repair genes.¹¹

With respect to the prevalence of secondary cancers, percentages ranging from 1 to 4.6% are found in the literature.^1121314 The high prevalence in the present study can be explained by the fact that NSCLC was used as a primary selection criterion. In the studies by Aydiner et al¹² and Kaneko and Yamaguchi,¹³ the prevalence of multiple cancers in general was reported, whereas Teppo et al¹ and Levi et al¹⁴ described the prevalence of second primary tumors during the follow-up of patients with NSCLC as being the first tumor. In the present study, the percentage of secondary tumors diagnosed after NSCLC was 5.1%, and this is more in agreement with the percentages (range, 3 to 13.4%) cited in the literature.¹⁵

In our data, > 50% of the second primary tumors either preceding NSCLC (group II) or following NSCLC (group I) were located in the lungs (27.6%), the head and neck area (20.3%), or the urinary tract (10.4%). These are all smoking-related tumors, and the combination of these tumor sites is described earlier in the scope of the field-cancerization theory. Regarding all patients studied (n = 860 [groups I, II, III, IV]), a second primary tumor was found in the lungs in only 6.1% of the patients, either preceding or following NSCLC, which is more in agreement with previously published data.¹⁶¹⁷¹⁸

The Kaplan-Meier curves show a significantly better survival rate for patients with another tumor in the follow-up period (group II) compared to patients without any other secondary primary tumor (group III) [p = 0.011]. Also, patients with more than two primary tumors (group IV) were found to have a significantly better survival rate than patients with NSCLC as the single tumor (group III) [p = 0.012]. Our results are in contrast to those of Koppe et al,¹⁹ who did not find any difference in survival between patients with NSCLC and another tumor in their history, and patients with a second primary tumor found in follow-up period after NSCLC, measured from the date of the thoracotomy. However, in that study, only patients were selected who had undergone surgery for NSCLC. One of the limitations of the present study is that we were not able to register the cause of death in the subgroups. Due to its retrospective character, risk factors such as smoking, alcohol intake, and cardiovascular disease were not consistently recorded or available. Nevertheless, as the number of resected cancers is comparable in all groups, our results suggest that patients with two or more cancers have a predisposition to have tumors with a rather slow progression.

In the present study, in approximately 40% of the patients in group II NSCLC was diagnosed as a second primary tumor within 5 years after the diagnosis of the first tumor. In contrast, in patients in whom a new malignancy developed after the diagnosis of NSCLC, approximately 90% of malignancies were diagnosed within the first 5 years, and even 81.8% were diagnosed within the first year of the follow-up period. The different time intervals between the subgroups are probably related to different mechanisms inducing second primary tumors. Although the field-cancerization concept cannot be ruled out, it seems that the rather long mean interval between the diagnoses of the two primary tumors in subgroup II may be related to the cancer treatment for the first tumor. Indeed, many studies have pointed to a relation between lung cancer following chemotherapy and radiotherapy.^20212223 In these studies, a statistically significant increase in lung cancer was found, which appears 1 to 4 years after chemotherapy and 5 years after radiotherapy. An overall 27.3-fold increased risk of developing lung cancer was reported in patients treated with radiotherapy. In addition, the reported median time to the diagnosis of lung cancer in these series was approximately 26 years. The hypothesis of therapy-related NSCLC is supported by the increasing incidence of second tumors during the follow-up period, as shown in Table 1. As in group I, the incidence of second primary tumors per year is relatively constant during the follow-up period, so the field-cancerization concept may fit better. The continuous stimulation by tobacco and alcohol seems to induce an expanding preneoplastic field as the first and critical step in the epithelial carcinogenesis. It has been shown by Braakhuis and colleagues⁸²⁴ that clonal divergence in this field leads to the development of one or multiple tumors with a rather constant rate over years. In this respect, our results are in agreement with the data published by Liu et al.²⁵ They also found that the time interval in the group with NSCLC as the second tumor is significantly longer (46 months) compared to the group with NSCLC as the primary tumor (10 months; p < 0.001).

A parameter that was expected to be important for the prevalence of secondary primaries was the stage of the primary tumor, derived from the TNM criteria. However, we did not find a significant difference in distribution in the tumor stages between the groups. In our population, 52% of the patients with NSCLC as the first presenting tumor had a low-stage carcinoma (stage I or II), compared to 42% in group II. In the group of patients without any other tumor (group III), it was only 29%. In contrast to our results, Liu et al²⁵ found a significant difference in tumor stages, as 53% of the patients with NSCLC as the first primary tumor had a stage I/II tumor, and only 25% of the patients with NSCLC as the second primary tumor had a stage I/II tumor.

Finally, regarding the histologic data, we found a significant difference between the groups studied (p = 0.04). Regarding the data found in the literature, however, it is hard to draw any conclusion. In an article by Travis et al,²² describing lung cancer following treatment for Hodgkin disease, they found a prevalence of squamous cell carcinoma, adenocarcinoma, large cell tumors, and other carcinomas of 39.2%, 21.6%, 9%, and 14%, respectively. It was concluded that following therapy with alkylating agents, the risk of squamous cell lung cancer was only statistically elevated. Regarding radiation therapy, significantly increased risks for all designated morphologic groups occurred. With respect to the risk of new primary tumors following lung cancer, Teppo et al¹ found a larger excess of new primary tumors among patients with adenocarcinoma than those with squamous cell carcinoma. In contrast, however, Levi et al¹⁴ suggested that the increased risk was comparable for patients with both tumors. It has to be realized that in both studies, small cell lung cancer was included, whereas in the study by Teppo et al¹ a high percentage of patients was included with cytologic confirmation of malignancy but without histology (30%).

It can be concluded that second or multiple primary tumors are commonly seen in patients with NSCLC, either preceding or following its occurrence. As approximately 80% of the second primary tumors following NSCLC are diagnosed within the first year, a thorough workup protocol is recommended that should focus on both the staging of NSCLC as well as on the detection of other related tumors (eg, smoking-related tumors), such as head and neck tumors, lung tumors, and urinary tract tumors. Further studies are required to assess the role of more sophisticated imaging techniques, such as fluorodeoxyglucose positron emission tomography, in the early detection of second primary tumors in relation to the costs and consequences for treatment and survival. Moreover, as the present study suggests a difference in the growth habits of NSCLC between patients with and without second primary tumors, studies should focus on this aspect to get a better understanding of this possible prognostic feature.

	Footnotes

 
Abbreviations: NSCLC = non-small cell lung carcinoma

Received for publication February 5, 2004. Accepted for publication November 29, 2004.

	References

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via ISI Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Duchateau, C. S.J. Articles by Stokkel, M. P.M. Search for Related Content PubMed PubMed Citation Articles by Duchateau, C. S.J. Articles by Stokkel, M. P.M.