EJCTS Click here to go to Edwards website
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Eur J Cardiothorac Surg 2008;34:1075-1080. doi:10.1016/j.ejcts.2008.08.004
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Aguiló, R.
Right arrow Articles by Novoa, A. M.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Aguiló, R.
Right arrow Articles by Novoa, A. M.
Related Collections
Right arrow Lung - cancer

Multiple independent primary cancers do not adversely affect survival of the lung cancer patient

Rafael Aguilóa,b,*, Francesc Maciàc,d,f, Miquel Portab,d,f, Montserrat Casamitjanac,d,f, Joan Minguellaa,b, Ana Maria Novoac,e

a Servei de Cirurgia General, Abdominal i Toràcica, Hospital Universitari del Mar, Institut Municipal d’Assistència Sanitària (IMAS), Barcelona, Spain
b School of Medicine, Universitat Autònoma de Barcelona, Spain
c Servei d’Avaluació i Epidemiologia Clínica, Hospital Universitari del Mar, Institut Municipal d’Assistència Sanitària (IMAS), Barcelona, Spain
d Unitat de Recerca en Epidemiologia Clínica i Molecular del Càncer, Institut Municipal d’Investigació Mèdica (IMIM, IMAS), Spain
e Unitat Docent de Medicina Preventiva i Salut Pública (IMAS-UPF-ASPB), Barcelona, Spain
f CIBER de Epidemiología y Salud Pública (CIBERESP), Spain

Received 6 June 2008; received in revised form 30 July 2008; accepted 4 August 2008.

* Corresponding author. Address: Servei de Cirurgia General, Abdominal i Toràcica, Hospital Universitari del Mar (IMAS), Passeig Marítim, 25-29, E-08003 Barcelona, Spain. Tel.: +34 93 248 3209; fax: +34 93 248 3433. (Email: 95183{at}imas.imim.es).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objective: Diagnosis of multiple independent primary cancers is increasing in many settings. Objectives of this study were to analyze clinical characteristics, organ location, and prognosis associated with the presentation of multiple independent primaries when a lung cancer is involved. Methods: We analyzed all patients with a histology-proven diagnosis of lung cancer registered from January 1990 to December 2004 at the Tumor Registry of the Hospital del Mar, Barcelona. We compared 1686 patients presenting a lung cancer as unique primary versus 228 patients presenting a lung cancer and another independent primary. Cofactors included age, sex, smoking habit, lung cancer histology and stage, type and intention of treatment, organ location of the other cancer, and survival from the date of lung cancer diagnosis. Results: Seventy percent of the other cancers were tobacco-related. Independent risk factors of cancer multiplicity were smoking (OR: 3.99; 95% CI: 1.4–11.2), lung cancer stages I (OR: 1.84; 95% CI: 1.2–2.9) and II (OR: 3.25; 95% CI: 1.7–6.3), and older age (OR: 3.11; 95% CI: 1.9–5.1). Once adjusted by age and sex, the main determinant of survival was lung cancer stage rather than cancer multiplicity. However, patients with multiple cancers presented a slightly better survival than patients with a lung cancer as unique primary. When analyzed by subgroups, survival was higher in patients with the lung cancer first (HR: 0.44; 95% CI: 0.24–0.80), and in patients with the other cancer first (HR: 0.80; 95% CI: 0.65–0.99), but it was not different in the patients with a lung cancer and a synchronous other cancer (HR: 0.80; 95% CI: 0.52–1.15). Conclusions: The risk of developing a second independent cancer was strongly associated with tobacco smoking. Cancer multiplicity was not associated with a worse prognosis. As a consequence, when a first primary tobacco-related cancer is treated with curative intention, patients should be closely followed up for an early diagnosis of a possible new independent cancer; and if diagnosed, treatment to cure should be considered as the first option.

Key Words: Lung neoplasms • Second primary neoplasms • Smoking • Survival • Prognosis


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
The arising of multiple primary cancers in a same patient was already addressed in 1932 by Warren and Gates, who proposed as diagnostic criteria that each tumor must be histologically distinct, and that the possibility of a tumor being a metastasis of the other must be ruled out [1]. Interest on multiple independent primary cancers is currently renewed as the incidence of second primaries continues to increase in many settings [2–5]. In 2002 the American College of Surgeons defined multiple independent primaries (MIP) as ‘two or more tumors arising at different sites or at the same site when histologic characteristics differ’ [6].

Several questions arise when MIP involve a lung cancer. Multiplicity may be related to sharing a common etiologic factor such as tobacco smoking or asbestos exposure, to genetically related individual susceptibility, or to improvements in survival due to earlier diagnosis and better medical care [7–9]. Besides, identification of any clinical characteristics as related to cancer multiplicity would possibly be useful as a sign of alarm. Finally, interest is justified in assessing if cancer multiplicity carries differences in prognosis.

Our study was aimed at analyzing the clinical characteristics, organ location, and prognosis of MIP involving a lung cancer.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
The study was based on the clinical information recorded by the Tumor Registry of Hospital del Mar (RTHMar), Barcelona, Spain [10]. Any cancer of any patient visited in our hospital at any time during the disease process is registered, even if the patient has been diagnosed or treated in another center. The clinical information is collected through an exhaustive revision of the medical records, pathology reports, and minutes of cancer committees. Skin basocellular carcinomas are not registered.

We first identified all patients with a diagnosis of lung cancer registered between January 1990 and December 2004, which yielded 2030 patients (12.4% of all cancer patients registered in the period). Of them, we excluded 116 patients (5.7%) without histological proof of lung cancer (which was not obtained due to advanced age, advanced disease or poor general status). The resulting 1914 patients (94.3%) with a diagnosis of lung cancer confirmed by cytology or biopsy entered the analysis. The following variables were used: patients’ age at the date of lung cancer diagnosis, sex, date of lung cancer diagnosis, lung cancer histology and stage, type of lung cancer treatment (surgery, chemotherapy, radiotherapy), treatment intention (curative, palliative), and tobacco smoking (registered since January 1993). All additional information available in the RTHMar for patients included in the study regarding any other independent primary cancer was next merged into the database. MIP are registered according to the standard criteria of the International Agency for Research on Cancer [11]. Extension of the lung cancer was staged using the tumor-node-metastasis international system [12]. Based on scientific consensus [7], the following cancers were considered potentially tobacco-related: mouth, pharynx, larynx, lung, esophagus, stomach, liver, pancreas, kidney, urinary bladder, colon-rectum, and uterine cervix.

Patients were grouped as follows: group I included patients presenting a lung cancer as unique primary; group II included patients presenting a lung cancer and another independent cancer. For the analysis of survival, patients in group II were divided as ‘synchronous’ (when less than two months had elapsed between the diagnosis of the two primaries), and ‘metachronous’ [13]. Patients with metachronous MIP were further subdivided into those presenting their lung cancer first (group II-lung cancer first), and those presenting their other cancer(s) first (group II-other cancer first). Patients with three or more cancers were included in the group II-lung cancer first, except when the lung cancer was the last one, in which case they were included in the group II-other cancer first. Patients with two primary lung cancers were included in group II-lung cancer first, and the second lung cancer was counted as other cancer.

Univariate statistics were computed as customary. Differences between groups were tested by Fischer's exact test for categorical variables, and by Student's t test and ANOVA for continuous variables. Clinical variables significantly associated with the presentation of MIP in the univariate model were tested by stepwise multivariate logistic regression analysis. The response variable was neoplasia multiplicity (dichotomous: 1 representing multiplicity, and 0 its absence). Observed survival was calculated from the date of lung cancer diagnosis to death, loss of follow-up, or end of the study period by the method described by Kaplan and Meier. Differences between groups were tested by the log-rank test. Multivariate survival analyses were performed by Cox proportional hazards regression. Throughout, the level of statistical significance was set at 0.05, and all tests were two-tailed. Analyses were performed using SPSS® version 13.5 for Windows (SPSS Inc, Chicago, IL).


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
The 1914 patients included in the study presented 2167 cancers. Group I included 1686 (88.1%) patients with a lung cancer as unique primary, while group II comprised 228 (11.9%) patients presenting a lung cancer and some other cancer(s). The percentage of patients in the latter group increased from 7.4% in 1990–1995, to 9.6% in 1995–1999, and to 17.6% in 2000–2004. Organ location of the other cancers is shown in Table 1 . From the date of lung cancer diagnosis, 86 out of 253 (34%) other cancers were diagnosed within 1 year, and 171 of 253 (67.6%) within 5 years, with no significant differences between tobacco-related and tobacco unrelated cancers.


View this table:
[in this window]
[in a new window]

  		Table 1 Location of other cancers preceding or following the lung cancer
 
Clinical characteristics of patients are summarized in Table 2 . The male-to-female ratio was 9:1, similar in the two groups. Univariate differences between the groups were significant for age, smoking, lung cancer histology, lung cancer stage, and surgical treatment with curative intention. In group I (lung cancer as unique primary), patients diagnosed at earlier lung cancer stages (I and II) comprised 13.8%, while this percentage was 30% in group II (patients with a lung cancer and another primary). As expected, these figures closely match the percentage of patients undergoing surgical treatment with curative intention, 11.1% and 21.5%, respectively. Adjuvant or neoadjuvant chemotherapy were administered to 70 of 214 (32.7%) surgical patients in group I, and to 15 of 50 (30.0%) patients in group II (p = 0.87).


View this table:
[in this window]
[in a new window]

  		Table 2 Clinical characteristics
 
Table 3 summarizes multivariate analyses assessing the probability of presenting MIP involving lung cancer against the probability of presenting lung cancer as unique primary. Clinical characteristics related to a significantly higher probability of cancer multiplicity were tobacco smoking (odds ratio: 3.99), age older than 60 years, and lung cancer stages I and II (Table 3, model A). When the previous three factors were taken into account, the squamous-cell carcinoma histology was also a significant risk factor, while surgery with a curative intent was not (Table 3, model B).


View this table:
[in this window]
[in a new window]

  		Table 3 Multivariate analysis of the risk of presenting multiple independent primaries involving lung cancer
 
Clinical characteristics of patients with MIP differed by subgroup as shown in Table 4 . The only significant difference among subgroups was that the percentage of patients with earlier lung cancer stages (I and II), which are potentially amenable to curative surgery, was higher in group II-lung cancer first (18 of 32, 69.2%), than in group II-synchronous (13 of 43, 37.1%), and in group II-other cancer first (26 of 153, 20.2%). Differences in sex, age, smoking, and histology were not significant.


View this table:
[in this window]
[in a new window]

  		Table 4 Clinical characteristics of MIP involving lung cancer (group II)
 
Differences in observed survival were clinically and statistically significant (log-rank test: 42.4, p < 0.01) (Fig. 1 ). Multivariate Cox analyses showed that patients in group II-lung cancer first presented an almost fourfold higher survival than patients in group I (lung cancer as unique primary) (hazard ratio (HR): 0.28, p < 0.001), while for patients with a synchronous or a previous other cancer, survival was not any worse than for group I (indeed, it was slightly better and almost statistically significant) (Table 5 , Model A). Results were similar when adjusted by age and sex (Model B). When lung cancer stage (the most important known prognostic factor) was taken into account (Model C), survival in group II-lung cancer first was still higher (more than twofold, HR: 0.44; p < 0.001); in group II-other cancer first it was more than 20% higher (HR: 0.80; p = 0.024), and in the group of patients with a synchronous other cancer it did not differ significantly (always, with respect to group I). Model C also showed that females and younger patients, as well as patients with tumors in earlier stages had higher chances of survival.


Figure 1
View larger version (24K):
[in this window]
[in a new window]

  		Fig. 1. Survival curves of patient groups with observed survival time calculated from the date of lung cancer diagnosis.

Median (95% CI) observed survival in months (mo), and observed 5-year survival (5-ys)—Group I: 7 (6–8) mo; 5-ys: 7.3%. Group II-synchronous: 10 (6–14) mo; 5-ys: 6.4%. Group II-lung cancer first: 78 (39–117) mo; 5-ys: 51.5%. Group II-other cancer first: 9 (7–11) mo; 5-ys: 9.4%. Log-rank test: 42.4; p < 0.001.

 

View this table:
[in this window]
[in a new window]

  		Table 5 Relative risk of death by group and selected variables
 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
The main findings of our study were that the percentage of patients with MIP involving a lung cancer has increased substantially in recent years; that independent risk factors of cancer multiplicity were smoking, lung cancer diagnosed at stages I and II, and age older than 60 years; and that prognosis was not worse for patients with multiple cancers, as the main determinant of survival was not cancer multiplicity but lung cancer stage. These findings imply that any patient treated for a first primary cancer with curative intention should be closely followed-up. Furthermore, if a second independent cancer is diagnosed, treatment with curative intention should again be considered the first option.

In our series, the 228 patients with MIP represented 11.9% of the total 1914 lung cancer patients analyzed. Similar percentages were reported by other studies that also used hospital cancer registries [14–17]. To our knowledge, this is the first study based on a hospital tumor registry that compares a consecutive series of patients with lung cancer as unique primary and patients with lung cancer plus any another independent primary cancer, the survival of the latter analyzed by three subgroups: lung cancer first, lung cancer plus a synchronous other cancer, and other cancer first. While a study based on a hospital tumor registry cannot be assumed to be fully representative of the general population, it often can analyze a spectrum of clinical information (e.g., stage, histology) that is clinically more relevant than data included in most population-based cancer registries [18]. Using population registries, Buiatti et al. reported that 2.4% second primary cancers occurred among 19,252 cancer patients [2], and Levi et al. reported a significant excess of second lung cancers and other tobacco-related cancers in lung cancer patients [3], whereas Teppo et al. concluded that the relative risk of new primary cancers among patients diagnosed of lung cancer was higher in recent times [5].

Several mechanisms may underlie the growing incidence of MIP involving lung cancer, including better results in recent decades in the treatment of cancer and other diseases, the effect of common carcinogens, and genetically related susceptibility to carcinogens [2–5,7–9]. Among characteristics analyzed in our study, smoking emerged as the most important independent risk factor of cancer multiplicity. We also identified age, and lung cancer stages I and II as independent risk factors of presenting MIP. This result links survival and multiplicity, as lung cancer stages I and II are well established survival factors [19]. Certainly, as already noted by Rheingold, the probability of developing a second cancer depends on surviving a first cancer [4]. So, our patients with a prior lung cancer and a second other cancer (group II-lung cancer first) probably represent a select subgroup of lung cancer patients: they showed a much higher chance of survival than all the other groups, as 69% had their diagnosis of lung cancer at stage I or II. Interestingly, curative surgery lost its statistical significance in multivariate analyses, probably because it largely covariates with stage.

The incidence of MIP involving a lung cancer may continue to increase in the future, aided by improved diagnostic tools (high-resolution scan, positron emission tomography, endoscopic ultrasonography), and by molecular biology techniques for the differential diagnosis of tumors [20]. Establishing the prognostic significance of cancer multiplicity is especially important in terms of treatment, as in most cases, the clinical management of a second primary must be decided without being certain whether the first primary is cured (in our series, 67.6% second cancers were diagnosed within 5 year from the diagnosis of the first primary). Importantly, then, results showed that cancer multiplicity does not carry a worse prognosis. The observation that lung cancer survival is associated with lung cancer stage rather than to cancer multiplicity has previously been reported [15,17,21–23]. In their studies on patients with a lung cancer as second primary, Massard et al. reported that lung cancer survival varied according to lung cancer stage, and that no higher risk of death was related to multiplicity [22]. Koppe et al. observed that a history of previous malignancy was a favorable prognostic factor in the univariate analysis, although not so in the multivariate analysis [23]. Particularly outstanding is our group of patients with a lung cancer and a synchronous other cancer (group II-synchronous), which showed no significant difference in survival compared to patients with a unique lung cancer. Thus, it seems that both cancers barely interact, and that it is the cancer with worst prognosis that is the one which ultimately determines the outcome.

Along with other available evidence, results strongly suggest that a second independent cancer should be approached as a separate entity in terms of prognosis and treatment: if the first primary was treated with curative intention, a thorough surveillance addressed to diagnose as early as possible the second cancer should be a part of the follow-up [24,25]. Results also emphasize the importance of distinguishing a recurrence from a second primary, in order to offer the patient the most appropriate management option.


   Acknowledgments
 
We gratefully acknowledge technical assistance by David J. MacFarlane, Tomàs López and Eduard Molins.


   Footnotes
 
{star} Supported in part by research grants from ‘Red temática de investigación cooperativa de centros en Cáncer’ (C03/10), ‘Red temática de investigación cooperativa de centros en Epidemiología y salud pública’ (C03/09), and CIBER de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Ministry of Health, Madrid.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

  1. Warren S, Gates O. Multiple primary malignant tumors: a survey of the literature and a statistical study. Am J Cancer 1932;16:1358-1414.
  2. Buiatti E, Crocetti E, Acciai S, Gafà L, Falcini F, Milandri C, la Rosa M. Incidence of second primary cancers in three Italian population-based cancer registries. Eur J Cancer 1997;33:1829-1834.[CrossRef][Medline]
  3. Levi F, Randimbison L, Te VC, la Vecchia C. Second primary cancers in patients with lung carcinoma. Cancer 1999;86:186-190.[CrossRef][Medline]
  4. Rheingold SR, Neugut AI, Meadows AT. Second cancers: incidence, risk factors, and management. In: Bast BC, Kufe DW, Pollock RE, editors. Cancer medicine. Hamilton, ON, Canada: B.C. Decker; 2000. pp. 2399-2406.
  5. Teppo L, Salminen E, Pukkala E. Risk of a new primary cancer among patients with lung cancer of different histological types. Eur J Cancer 2001;37:613-619.[CrossRef][Medline]
  6. The Facility Oncology Registry Data Standards (FORDS). Chicago: Commission on Cancer, American College of Surgeons; 2002.
  7. In: Boyle P, Gray N, Henningfield J, Seffrin J, Zatonski W, editors. Tobacco. Science, policy and public health. Oxford: Oxford University Press; 2004.
  8. Miller YE. Pathogenesis of lung cancer, 100 year report. Am J Respir Cell Mol Biol 2005;33:216-222.[Abstract/Free Full Text]
  9. Haiman CA, Stram DO, Wilkens LR, Pike MC, Kolonel LN, Henderson BE, Le Marchand L. Ethnic and racial differences in the smoking-related risk of lung cancer. N Engl J Med 2006;354:333-342.[Abstract/Free Full Text]
  10. Porta M, Malats N, Morell E, Gómez G, Gallén M, Macià F, Casamitjana M, Fabregat X. Decreased survival of patients with lung cancer admitted to a teaching hospital through the emergency department in Barcelona, Spain. J Epidemiol Community Health 1998;52(2):137-138.[Medline]
  11. Muir CS, Percy C. Classification and coding of neoplasms. In: Jensen OM, Parkin DM, Maclennan R, Muir CS, Skeet RG (Eds.), Cancer registration: principles and methods. IARC Scientific Publications: 95. Lyon: International Agency for Research on Cancer; 1991.
  12. Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997;111:1710-1717.[CrossRef][Medline]
  13. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg 1975;70:606-612.[Abstract]
  14. Utsumi T, Fujii Y, Takeda S, Minami M, Yoon HE, Okumura M, Matsuda H. Clinical study on lung cancer as second primary cancer. Surg Today 1998;28:487-491.[CrossRef][Medline]
  15. Liu YY, Chen YM, Yen SH, Tsai ChM, Perng RP. Multiple primary malignancies involving lung cancer—clinical characteristics and prognosis. Lung Cancer 2002;35:189-194.[CrossRef][Medline]
  16. Brock MV, Alberg AJ, Hooker CM, Kammer AL, Xu L, Roig CM, Yang SC. Risk of subsequent primary neoplasms developing in lung cancer patients with prior malignancies. J Thorac Cardiovasc Surg 2004;127:1119-1125.[Abstract/Free Full Text]
  17. Duchateau CS, Stokkel M. Second primary tumors involving non-small cell lung cancer. Prevalence and its influence on survival. Chest 2005;127:1152-1158.[CrossRef][Medline]
  18. Young JL. The hospital-based cancer registry: In: Jensen OM, Parkin DM, Maclennan R, Muir CS, Skeet RG, editors. Cancer registration: principles and methods. IARC Scientific Publications: 95. Lyon: International Agency for Research on Cancer; 1991.
  19. Mountain CF. Staging and prognosis in lung cancer. In: Franco K, Putnam J, editors. Advanced therapy in thoracic surgery. London: BC Decker Inc; 1998. pp. 75-82.
  20. Jett JR, Miller YE. Update in lung cancer 2005. Am J Respir Crit Care Med 2006;173:695-697.[Free Full Text]
  21. Johnson BE. Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 1998;90:1335-1345.[Abstract/Free Full Text]
  22. Massard G, Ducrocq X, Beaufigeau M, Elia S, Kessler R, Hervé JF, Wihlm JM. Lung cancer following previous extrapulmonary malignancy. Eur J Cardiothorac Surg 2000;18:524-528.[Abstract/Free Full Text]
  23. Koppe MJ, Zoetmulder FAN, van Zandwijk N, Hart AAM, Baas P, Rutgers EJTk. The prognostic significance of a previous malignancy in operable non-small cell lung cancer. Lung Cancer 2001;32:47-53.[CrossRef][Medline]
  24. Egermann U, Jaeggi K, Habitcht JM, Perruchoud AP, Dalquen P, Solèr M. Regular follow-up after curative resection of non-small cell lung cancer: a real benefit for patients?. Eur Respir J 2002;19:464-468.[Abstract/Free Full Text]
  25. Colice GL, Rubins J, Unger M. Follow-up and surveillance of the lung cancer patient following curative-intent therapy. Chest 2003;123(1 Suppl.):272S-283S.[CrossRef][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Aguiló, R.
Right arrow Articles by Novoa, A. M.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Aguiló, R.
Right arrow Articles by Novoa, A. M.
Related Collections
Right arrow Lung - cancer

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS