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Eur J Cardiothorac Surg 2000;18:524-528
© 2000 Elsevier Science NL

Lung cancer following previous extrapulmonary malignancy

Gilbert Massard, Xavier Ducrocq, Marc Beaufigeau, Stefano Elia, Romain Kessler, Jean-François Hervé, Jean-Marie Wihlm

Service de Chirurgie Thoracique, Hôpitaux Universitaires de Strasbourg, F-67091 Strasbourg, France

Received 5 May 2000; received in revised form 11 August 2000; accepted 5 September 2000.

Corresponding author. Tel.:+33-3-8811-6202; fax: +33-3-8811-6077
e-mail: gilbert.massard{at}chru-strasbourg.fr


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Objective: Having demonstrated a poor prognosis of operable lung cancer in patients with previous head and neck malignancies, we intended to evaluate prognosis of lung cancer in patients with a history of extrapulmonary and extracervical malignancies. Methods: The population of this study included 55 patients; these were 40 males and 15 females, with a mean age 64.4±8.6 years. The previous malignancy was considered tobacco-induced in 15 patients (kidney, two; bladder, ten; esophagus, three), hormone-dependant in 18 (breast, six; female genital, eight; prostate, four), and miscellaneous in 22 (leukemia, four; skin, seven; colon, 11). Following complete resection, 25 patients were classified stage I, 13 were stage II, and 17 were stage IIIA. Results: There were two early perioperative deaths (3.6%), and three during the second month owing to cardiovascular complications. At the conclusion of the study (July 1st, 1997), 32 further patients had died (58.2%): 25 had progression of lung cancer, one had progression of previous malignancy, and six were without evidence of disease. Five-year survival (Kaplan–Meier) was estimated 47±10.2% in stage I (median 44 months), 30.8±15.6% in stage II (median 26 months), and 16.7±9.9% in stage IIIA (median 17 months). When excluding five early perioperative deaths, 5-year survival was 51.1±10.6% in stage I (median 93 months), 33.3±16.7% in stage II (median 36.5 months), and 19.0±11.2% in stage IIIA (median 20.5 months). Comparing the three groups defined according to location of previous malignancy, there was no significant difference neither in stage distribution ({chi}2=1.326; P=0.857), nor in 5-year survival estimates: 38.9±12.9% (median 27 months) after tobacco-induced malignancies, 38.9±11.5% (median 24 months) following hormone-dependant malignancies, and 28.4±10.2% (median 28 months) following miscellaneous cancers ({chi}2=0.059; P=0.9707). Conclusions: In opposition to data collected in patients with previous head and neck cancer, survival estimates according to stage were contained within the universally accepted range no high risk group has been identified. Resection of lung cancer with curative intent is a fair option in patients with previous extrapulmonary malignancy.

Key Words: Multiple cancers • Bronchogenic cancer • Surgery


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 References
 
In previous publications, we have demonstrated that a past medical history of head and neck cancer heralds a poor prognosis for subsequent primary bronchial cancer [1,2]. Global survival at 5 years following curative resection was estimated as low as 19.7%, and survival curves were skewed down by one stage. In particular, 5-year survival following resection of stage I lung cancer was only 33.3% [2]. Potential explanation for these poor results were advanced age, and combined alcohol and tobacco abuse. Besides its deleterious influence on comorbidity, this combined chronic intoxication may lead to diffuse histogenetic abnormalities of squamous cell epithelia. The unfavorable prognosis differed from the relatively acceptable survival rates observed following resection of second primary lung cancers [3,4]. Medline research failed to identify any publication which specifically analyses prognosis of lung cancer occurring after a first extrathoracic and extracervical primary cancer. Two recent studies dealing with the problems of surgery for lung cancer in the elderly have marginally stated that a history of malignant disease does not influence overall prognosis; however, the subsets subjected to survival analysis were small [5,6]. Intuitively, one would expect a less favorable prognosis because association of several diseases should increase the operative risk; some of these patients could integrate a multiple neoplasia syndrome.

This study has been designed to estimate operative risk and long-term survival in a cohort of lung cancer patients whose medical history revealed a first extrapulmonary and extracervical primary cancer. Patients with previous head and neck cancers were excluded since they had been subjected to two dedicated reports [1,2]. We also checked whether the location of the first primary cancer could have any influence on prognosis.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 References
 
2.1. Patients
Patient charts were identified by screening of a database into which data were entered prospectively for any patient undergoing surgery for lung malignancy at our department. The definition of previous malignancy excluded previous head and neck cancers, which have been extensively investigated by our group [1,2].

From January 1986 to December 1995, we thus identified 55 patients. These were 40 males and 15 females, with a mean age 64.4±8.6 years (range: 36–84 years; median age 66 years). The median delay between the two malignancies was 48 months, whereas the range extended from 3 to 300 months. According to their location, previous malignancies were classified into three groups tobacco-induced cancers, 15; hormone dependant cancers, 18; miscellaneous, 22 (Table 1). There was no proven or suspected multiple neoplasia syndrome. None of these 55 patients underwent induction chemotherapy prior to surgery.


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  		Table 1. Location of previous malignancy

 
2.2. Methods
Indication of surgical resection was validated by the usual oncologic and functional requirements. Besides, we verified that complete remission of the previous malignancy was maintained. The latter information was requested from the team in charge of the follow-up of the previous malignancy. In case of any doubt, patients were referred for further evaluation to the concerned organ specialist of our institution.

Loco-regional lung cancer staging was made with computed tomography (CT) scan and fiberoptic bronchoscopy. Abdominal ultrasound and CT scan of adrenal glands was obtained routinely, whereas brain CT scan and nuclear bone scan were electively performed in patients presenting symptoms. Functional evaluation included spirometry, blood gas analysis during rest and exercise, carbon monoxide diffusion capacity and split perfusion nuclear scan as a routine.

Lobectomy, bilobectomy or pneumonectomy was performed according to the local extent of disease. Routine lymph node sampling was performed at the hilar and mediastinal level.

Operative mortality included any death during the first 30 days, or during the initial hospital stay as well.

Survival analysis took into account any event of both the previous extrathoracic cancer and the current lung malignancy. Locoregional recurrence, metastatic progression, and third primary malignancies were indexed separately. Cause of death was identified by clinical means, since autopsy could not be performed on a routine basis.

2.3. Statistics
Quantitative data were reported as mean±SE, or median and range. Qualitative data were compared with the chi-squared test. Survival data were updated for July 1st 1997, by contact with the patient or his referring physician. Survival estimates were made with the Kaplan–Meier model and compared with the log-rank test. Statistical significance was admitted for any value of P below 0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 References
 
3.1. Presentation, surgery and pathology
Preoperative chest films disclosed a rounded peripheral opacity in 38 patients, a hilar mass in nine and atelectasis in seven. A single patient presented with a normal chest film; following recent onset of hemoptysis, he underwent fiberoptic bronchoscopy which disclosed an endobronchial tumor. The tumor was located on the right side in 24 patients (upper lobe, 14 middle, three; lower lobe, seven), and on the left side in 31 (upper lobe, 19; lower lobe, 12). Resection was performed with standard lobectomy in 34 patients, bilobectomy in four, pneumonectomy in 16, and with segmentectomy in one patient. Tissue diagnosis was squamous cell carcinoma in 38 patients, adenocarcinoma in 13, large cell carcinoma in two, and neuroendocrine carcinoma in two. Fourteen patients were staged T1, 33 were T2 and eight were T3. Nodal status was N0 in 27 patients, N1 in 13 and N2 in 15. According to the revisions of 1997 [7], 25 patients were classified stage I, 13 were stage II, and 17 were stage IIIA.

3.2. Post-operative complications
There were two operative deaths (4%): one patient suffered major pulmonary embolism, and one patient died from metabolic complications of acute renal failure. Non-lethal morbidity included one empyema following pneumonectomy, one bronchial fistula following lobectomy, one pneumonia with respiratory failure, two deep vein thromboses (one of whom originated pulmonary embolism), one myocardial infarction, and one duodenal ulcer bleeding. Three patients experienced sudden death at home during the second post-operative month; if we include the latter to estimation of post-operative mortality, the rate reaches 10%.

Adjuvant radiotherapy was administrated to 15 patients. Adjuvant chemotherapy was given to two patients.

3.3. Long-term follow-up
At the conclusion of the study (July 1st, 1997), 18 patients were alive and 37 had deceased. Cause of death was related to surgery in five patients. Six patients died free of disease. Twenty-six deaths were related to recurrence of cancer: first cancer (colorectal adenocarcinoma) in one patient, bronchial cancer in 24, and second primary lung cancer in one patient.

Metastatic recurrence of the first cancer was observed in a single patient (1.8%), presenting with hepatic metastases of a colorectal adenocarcinoma during follow-up. Patterns of recurrence of bronchial cancer included metastatic spread in 21 patients (38.2%), isolated local recurrence in one patient (1.8%), and combination of local recurrence and metastases in two patients (3.6%).

Seven patients developed a third primary cancer (12.7%): these were three metachronous bronchogenic cancers, two head and neck cancers, one renal clear cell adenocarcinoma, and one bladder carcinoma.

3.4. Survival estimates
Global survival at 5 years was estimated 47±10.2% in stage I (median 44 months), 30.8±15.6% in stage II (median 26 months), and 16.7±9.9% in stage III (median: 17 months) (Fig. 1) . When excluding the five early deaths not related to disease from survival analysis, the 5-year survival rates were 51.1±10.6% for stage I (median 93 months), 33.3±16.7% for stage II (median 36.5 months), and 19.0±11.2% for stage IIIA (median 20.5 months). When comparing the three subgroups defined by location of the first cancer, stage distribution appeared to be similar ({chi}2=1.326; P=0.857). Respective 5-year survival rates were 38.9±12.9% (median 27 months) for malignancies depending on tobacco abuse, 38.9±11.5% (median 24 months) for hormone-dependent cancers, and 28.4±10.2% (median 28 months) for miscellaneous cancers (Fig. 2) . The latter survival curves were statistically similar ({chi}2=0.059; P=0.9707).



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  		Fig. 1. Survival (Kaplan–Meier) according to stage. Any death has been considered as event.

 


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  		Fig. 2. Survival (Kaplan–Meyer) according to location of first malignancy.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
References
 
4.1. Operative risk
Although operative mortality during the first 30 days was at an acceptable range of 4%, there were three further early deaths occurring during the second post-operative month, and which were due to acute cardiovascular events. We speculate that these deaths might have been favored by the recent lung resection; if we include them into the operative mortality, the rate raises to almost 10%. This is considerably higher than the universally accepted reference values [8,9], and still overrides the known increase of operative mortality observed in elderly patients [5,6]. Several possible causes may be hypothesized. The present cohort distincts itself by a relatively advanced age, with a median age of 66 years. Most probably, there has been an increased prevalence of comorbidities, and more particularly of latent coronary disease. Advanced age is a validated risk factor for cardiac adverse events [10]. Deep venous thrombosis is favored in patients with malignant disease; its prevalence of 7.2% observed in this cohort was sensibly higher than generally reported [8]. Previous chemotherapy or irradiation may also alter immune defense mechanisms against infection. Chronic pyelonephritis in patients with transileal urinary diversion may generate metabolic complications.

4.2. Primary cancer or solitary metastasis?
Aggressive surgical management of second primary lung cancers, as defined by the criteria of Martini and Melamed, is meaningful [11]. Surgical treatment implicates however an obvious increase of operative risk. In case of a homolateral second cancer, completion pneumonectomy is required. This operation carries an operative mortality close to 10% [12]. In case of a contralateral second cancer, the operation concerning the functionally predominant lung is credited an increased morbidity, although this has not yet been reported as such. Long-term results justify the operative risk: the estimated global 5-year survival rates range from 35 to 45%; rates for stage I vary from 40 to 60% [3,4,12]. These survival figures cannot be reached with non-surgical management.

In patients with a history of an extrapulmonary primary cancer, the tissue diagnosis of a solitary lung mass may respond either to a primary lung cancer, or to a single metastasis.

In patients with preceding squamous cell carcinoma of the head and neck, the usual working hypothesis is to interpret the new lung lesion as a second primary cancer [1,2]. Although this sillogism is debatable from a theoretical point of view, it has proven to be useful for pragmatic patient care. In previous publications, we have positively argumented this position in patients with a history of head and neck cancer [1,2].

Malignancies located both outside of the chest and outside of the head and neck are most often adenocarcinomas. A subsequent bronchial squamous cell carcinoma certainly is a primary cancer. On the opposite, when the lung lesion proves to be an adenocarcinoma, the debate about its primary or secondary nature is open. Our data confirm that the optimal treatment for primary bronchial adenocarcinoma as second cancer is still surgical resection. However, surgical resection is also a reasonable option in case of a solitary metastasis. According to the data drawn from the International Registry, one may expect rough survival rates of 36% at 5 years following complete resection [13]. Five-year survival for single metastases was 43%: 5-year survival was 45% when the disease free interval was 3 years or more. Resection of single metastases occurring after a disease free interval of 3 years or more achieved a 5-year survival rate of 50% [13]. When breaking down to the precise tissue diagnosis, the 5-year survival rates range from 35 to 45%; patients with colorectal cancer or renal cancer have the greatest chances for long-term survival [14,15]. Although there has not been any randomized study, it is likely that similar survival rates cannot be obtained by any other oncologic treatment modality.

4.3. Prognostic risk factors
The survival rates by stage reported in this study are located in the lower range of classic references [16]. In opposition to our former conclusions in patients with a history of head and neck cancer, the previous malignancy did not adversely influence long-term survival. We have failed to identify any prognostic indicator in relation with the location of the first cancer.

We should stress the fact that 13% of this cohort developed a third primary cancer. None of the patients of this cohort fulfilled clinical criteria of a hereditary multiple neoplasia syndrome, such as the Lynch syndrome or the Muir–Torre syndrome. None of the patients with preceeding breast cancer met the criteria of the BRCA2 syndrome. There was no single patient with a history of sarcoma as observed with the Li–Fraumeni syndrome. In fact, such syndromes have a very low prevalence, and may be discussed in less than 5% of patients with ‘frequent’ cancers [17]. We did not further investigate our patients with expensive molecular biology techniques, because we had no clinical arguments to do so.

Diffuse abnormalities of the mucosa induced by tobacco abuse certainly increase the risk for multiple cancers. Patients surviving following resection of stage I disease have a global risk of 11.7% to develop a second primary cancer [18]. Approximately 7% of patients with lung cancer have a history of head and neck malignancy [1]. Multiple bronchial cancers are heralded by mucosal changes such as dysplasia and carcinoma in situ. We have recently reported a series of patients with R1 resection. Almost 50% of those who had residual carcinoma in situ at the bronchial resection margin experienced multiple primary cancers [19].

We conclude that despite a high operative mortality, surgical management of lung cancer following previous extrathoracic malignancies provides the patient with fair chances for long-term survival. We did not observe an adverse prognostic effect as previously mentioned with head and neck cancers. We failed to identify any prognostic indicator, but raise admonitions against the substantial risk for third primary cancer.


   Footnotes
 
Presented at the 13th Annual Meeting of the European Association for Cardio-thoracic Surgery, Glasgow, Scotland, UK, September 5–8, 1999.


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

  1. Massard G., Roeslin N., Jung G.M., Dumont P., Wihlm J.M., Morand G. Bronchogenic cancer associated with head and neck tumors. Survival analysis of 194 patients. J Thorac Cardiovasc Surg 1993;106:218-227.[Abstract]
  2. Massard G., Wihlm J.M., Ameur S., Jung G.M., Rouge C., Dumont P., Roeslin N., Morand G. Association of bonchial and pharyngo-laryngeal malignancies. A reappraisal. Eur J Cardio-thorac Surg 1996;10:397-402.[Abstract]
  3. Deschamps C., Pairolero P.C., Trastek V.F., Payne W.S. Multiple primary lung cancers. Results of surgical treatment. J Thorac Cardiovasc Surg 1990;99:769-777.[Abstract]
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  5. Massard G., Moog R., Wihlm J.M., Kessler R., Dabbagh A., Lesage A., Roeslin N., Morand G. Bronchogenic cancer in the elderly: operative risk and long-term prognosis. Thorac Cardiovasc Surg 1996;44:40-45.[Medline]
  6. Thomas P., Piraux M., Jacques L.F., Gregoire J., Bedard P., Deslauriers J. Clinical patterns and trends of outcome of elderly patients with bronchogenic carcinoma. Eur J Cardio-thorac Surg 1998;13:266-274.
  7. Mountain C.F. Revisions in the international system for staging lung cancer. Chest 1997;111:1710-1717.[Abstract/Free Full Text]
  8. Roeslin N., Morand G. Complications et mortalité de la chirurgie du cancer bronchique. Rev Pneumol Clin 1992(48):231-236.
  9. Ginsberg U., Hill L.D., Eagan R.T., Thomas P., Mountain C.F., Deslauriers J. Modern 30-day operative mortality for surgical resection in lung cancer. J Thorac Cardiovasc Surg 1983;86:654-658.[Abstract]
  10. Fleisher L.A., Eagle K.A. Screening for cardiac disease in patients having noncardiac surgery. Ann Int Med 1996;124:767-772.[Abstract/Free Full Text]
  11. Martini N., Melamed M.R. Multiple primary lung cancers. J Thorac Cardiovasc Surg 1975;70:606-612.[Abstract]
  12. Massard G., Lyons G., Wihlm J.M., Fernoux P., Dumont P., Kessler R., Roeslin N., Morand G. Early and long-term results after completion pneumonectomy. Ann Thorac Surg 1995;59:196-200.[Abstract/Free Full Text]
  13. The International Registry of Lung Metastases. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. J Thorac Cardiovasc Surg 1997;113:37-49.[Abstract/Free Full Text]
  14. Cerfolio U., Allen M.S., Deschamps C., Daly R.C., Wallrichs S.L., Trastek V.F., Pairolero P.C. Pulmonary resection of metastatic renal cell carcinoma. Ann Thorac Surg 1994;57:339-344.[Abstract]
  15. McAfee M.K., Allen M.S., Trastek V.F., Ilstrup D.M., Deschamps C., Pairolero P.C. Colorectal lung metastases: results of surgical excision. Ann Thorac Surg 1992;53:780-786.[Abstract]
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  18. Martini N., Bains M.S., Burt M.E., Zakowski M.F., McCormack P., Rusch V.W., Ginsberg R.J. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 1995;109:120-129.[Abstract/Free Full Text]
  19. Massard G., Doddoli C., Gasser B., Ducrocq X., Kessler R., Schumacher C., Jung G.M., Wihlm J.M. Prognostic implications of a positive bronchial resection margin. Eur J Cardio-thorac Surg 2000;17:557-565.[Abstract/Free Full Text]



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