Eur J Cardiothorac Surg 2007;32:653-658. doi:10.1016/j.ejcts.2007.06.024
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
Primary lung cancer and extrapulmonary malignancy
Hans-Stefan Hofmanna,*,
Heinz Neefa,
Peter Schmidtb
a Department of Cardio-Thoracic Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Street 40, 06096 Halle, Germany
b Cancer Center Halle of the Martin Luther University Halle-Wittenberg, Ernst-Grube-Street 40, 06096 Halle, Germany
Received 7 March 2007;
received in revised form 6 June 2007;
accepted 11 June 2007.
* Corresponding author. Tel.: +49 345 557 2719; fax: +49 345 557 2782. (Email: stefan.hofmann{at}medizin.uni-halle.de).
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Abstract
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Objective: The incidence of second primary malignancies seems to be increasing. The aim of this study was to investigate the incidence, treatment and outcome for patients with second primary lung cancer (SPLC). Methods: Between January 1996 and December 2005, 163 patients with SPLC, occurring after an extrapulmonary malignancy, were recruited by the Tumor Center of Halle (Saale), which represents a region of nearly 1.0 million inhabitants in Germany. The SPLCs were treated under curative aim (n
= 59), with palliative intend (n
= 76) or best supportive care (n
= 28). Results: The incidence of SPLC was 1.6 per 100,000 inhabitants. The localization of the first tumor differed depending on the sex of the patients. The actuarial 5-year survival rate of all patients was 12.7% (median survival time 11.4 months). Univariate analysis revealed treatment strategy as a prognostic factor (p
= 0.0001). Patients with SPLC having undergone curative treatment turned out to have the best prognosis (median survival: 31.0 months). The Cox proportional hazards model demonstrated that only TNM-staging system was a multivariate and significant independent prognostic predictor for overall survival. The method of surgery, standard lung resection (e.g. lobectomy) versus limited resection had no considerable influence on overall survival (p
= 0.22), respectively recurrence-free survival (p
= 0.55). Conclusions: In cases of operability, standard resection must be the method of choice, because of its best survival rates. The results support the demand of an exact and short-term oncological care system to detect early stages of SPLC for patients operated upon for tumors at different sites.
Key Words: Lung cancer • Extrapulmonary malignancy • Surgery • Survival
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1. Introduction
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The proportion of second or higher order invasive cancers reported to the US International Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program has continuously increased over the past 25 years, from approximately 6% in 1973 to 15.1% in 1998. Because of improved survival rates of cancer patients and the higher ages of the human population, the incidence of second malignancies is increasing. Additionally the tumor therapy itself (radiotherapy or chemotherapy) can induce second neoplasms. We are, in a sense, the ‘unfortunate victims of our own success’ [1]. A few anatomic sites are at risk for second malignancies within the same organ—breast, colon, head/neck and lung. Another aspect of cancer is the increased risk of a second malignancy in other organs. The incidence of second cancer is reported by nearly 1–2% [2–4].
The purpose of this population-based study was to investigate the incidence and treatment of patients with second primary lung cancer (SPLC) after extrapulmonary malignancy, within a region of 1 million inhabitants. Additionally we examined the survival of these patients including the results of treatment.
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2. Patients and methods
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In this retrospective study, we reviewed patients with SPLC after extrapulmonary malignancy to evaluate the incidence, kind of treatment and survival for this tumor type in a well-defined region between January 1996 and December 2005. All newly diagnosed SPLC patients in the District of Halle and Dessau—a region of about 1 million inhabitants were recruited. One hundred and sixty-three patients were evaluated with SPLC after extrapulmonary malignancy in contrast to 5284 primary bronchogenic carcinoma cases. In 7 patients, the diagnosis of SPLC was determined by autopsy and 2 patients died from their cancer during the time of diagnostics. Treatment strategies were planned according to the interdisciplinary guidelines of the Cancer Center Halle [5] following the recommendations on the therapy of bronchial carcinoma of the German Association of Thoracic Surgery [6]. The treatment of the patients depended on the tumor staging, histology and functional status. Tumor as well as nodal and distant metastasis status was determined by computer tomography. N2 disease was not confirmed by mediastinoscopy. In all resectable cancers, surgery was the first choice of treatment. Because of multiple therapeutic concepts and strategies we divided our patients in three categories: curative treatment (surgery with resection, chemotherapy up to stage IIIA and radiotherapy stage I–II), treatment in palliative aim (palliative surgery, chemotherapy stage IIIB and V, radiotherapy Stage IIIA, IIIB and IV), and best supportive care.
All data were collected in the Clinical Cancer Registry Halle (Saale), applying a modified version of the Gießen Tumor Documentation System (GTS). The statistical analysis was performed using the Statistical Package for the Social Sciences version 12.0 software package (SPSS Inc, Chicago, IL, U.S.A.). Quantitative variables were expressed as mean ± standard deviation. Differences in the frequency of subgroups of SPLC patients versus PLC patients were analyzed by Pearson's 
2-test. For all patients, survival was calculated from the date of surgery until the date of last follow-up or the date of death. 1st September 2006 was the last term to update survival. Survivorship was calculated according to the Kaplan–Meier method. Differences in survival were tested for significance by the log-rank test. A Cox proportional hazards model was used to examine and adjust for any explanatory variables. Forward stepwise procedure was used to select the variables with the greatest prognostic value (p
< 0.05).
Pulmonary tumors were classified as SPLC according to the criteria of Martini et al. [7]. In cases of same histology, additional investigations (immunohistochemistry) were made to decide whether these lesions are metastases or SPLC. Cases lacking unambiguous classification data were not included in the analyses. The time interval between primary extrapulmonary tumors and SPLC was defined as starting from the day of diagnosis of the extrapulmonary malignancy and the day of diagnosing the SPLC. The mean time of this interval was 7.3 months (within a range of 0–100 months). Time intervals of 
2 years were determined as synchronous, >2 years as metachronous tumors. In a case with the presumption diagnosis of a second primary lung cancer, a complete metastatic work-up focusing on the control of the primary extrapulmonary tumor localization was performed.
Survival time of patients with SPLC was defined as starting from the day of diagnosis of the SPLC. The recurrence-free interval of resected SPLC was described as time between the operation and the first occurrence of local recurrence or distant metastasis.
To discuss survival prognoses of patients having SPLC compared with patients with primary bronchial carcinoma, a comparison group of patients (n
= 1696) with primary bronchial carcinoma was used, being investigated by a study (HALLUCA), between 1 April 1996 and 30 September 1999. This study was in correlation to our present investigation; a population-based study of the same region with high accuracy in data management. All data were created by the same Cancer Registry of the Cancer Center Halle. The clinical and pathological characteristics of this group were demonstrated in Table 2.
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3. Results
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3.1 Incidence of second primary lung cancer after extrapulmonary malignancy
Within ten years (1996–2005), 163 patients (141 men, 22 women) having SPLC were found altogether. This corresponds to a SPLC incidence rate of 1.6 per 100,000 inhabitants.
For the same period and within the same region, 5284 primary bronchial carcinomas were recorded, corresponding to an incidence rate of 52.8 per 100,000 inhabitants. This reveals a ratio of 1:33 between SPLC and primary bronchial carcinoma.
The SPLCs were diagnosed at a mean age of 65.3 (±9.9) years.
3.2 Previous and synchronous extrapulmonary malignancy
One hundred and seven patients had SPLC at the same time as the extrapulmonary malignancy (synchronous tumors). For 56 patients with metachronous tumors the mean interval between first extrapulmonary malignancy and the SPLC was 46.6 (±21.5) months.
The localization of the first tumor differed depending on the sex of the patients. In women, genital (36.4%), breast (22.7%) and gastro-intestinal cancers (18.2%) were observed as index tumors (Table 1
). Among men we often saw first cancer in the pharyngolaryngeal tract (24.1%), gastro-intestinum (19.9%) and prostate (14.9%).
The extrapulmonary index tumors were treated with curative intention in 122 (75%) patients, with 106 surgical resections. Fifteen (9%) patients received palliative treatment of the first extrapulmonary tumor and 26 (16%) best supportive care. The reason for the last two treatment strategies was (with the exception of three cases) the synchronous occurrence of the extrapulmonary index tumor and the SPLC. Three patients received palliative hormonal therapy because of prostate carcinoma.
3.3 Second primary lung cancer
85.9% of the second primary lung cancers were NSCLC and 14.1% of SCLC histology respectively. There were 21.4% stage I, 6.8% stage II, 31.9% stage III and 35.6% of stage IV tumors. In seven (4%) people, the stage of the tumor was not reported.
Because of a large number of stage III and IV tumors, nearly half of patients (n
= 76) could only treated under palliative aim. Fifty nine patients received curative treatment. The most frequent therapy with curative intention was surgery (n
= 51). In 21 cases, only best supportive care was given. The patients’ clinical data are summarized in Table 2
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Table 2 Clinical and pathological characteristics of patients with second primary lung cancer and extrapulmonary malignancy
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3.4 Survival rates
The 1-, 3- and 5-year overall survival rate in all registered patients with SPLC simultaneous or after extrapulmonary malignancy (n
= 163) was 47.5, 22.0 and 12.7%, respectively. Median survival time amounted to 11.4 months.
Causes of death of patients with SPLC were 11 local recurrences/pulmonary metastases, 11 diffuse metastatic spreads, 9 brain, 8 bone, 5 liver and 3 adrenal metastases. Sixty eight patients with unknown causes of death died shortly after diagnosis, their median survival was 3.1 (±12.4) month and only 16 of them could be treated with curative aim.
A univariate analysis revealed treatment strategy as a prognostic factor (p
= 0.0001). Patients having undergone curative treatment of pulmonary index tumor as well as SPLC, turned out to have the best prognosis in our study, showing median survival of 31.0 months and a 1-year survival rate of 80% (Fig. 1
). Also, the median survival and 1-year survival rate of patients with non curative treatment of the index tumor, but curative treatment of the SPLC were significantly better than the survival of patients with noncurative treatment of the SPLC. Within the group of patients with noncurative treatments, the survival rate did not differ considerably, i.e. patients treated palliatively had a median survival of 6.9 month (5-year survival rate—4%), respectively 1.6 month (5-year survival rate—0%) for patients with best supportive care therapy (Fig. 2
).
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Fig. 1. Survival of patients with SPLC after extrapulmonary index tumor depending on treatment intention (curative vs non-curative).
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The Cox proportional hazards model demonstrated that only TNM-staging system was a significant independent prognostic predictor for overall survival (Table 3
). Patients with palliative or best supportive care therapy had a 1.6, respectively 1.7, higher relative risk for overall survival in correlation to patients with treatment in curative aim, but these differences were not significant (p
= 0.3).
The comparison group of patients with primary bronchogenic carcinoma had 1-, 3- and 5- year survival rates of 40.2, 14.3 and 8.0% and median survival of 9.2 months respectively. This group of primary lung cancers without extra malignancy had a significantly (p
= 0.03) worse survival prognosis than the patients with SPLC and extrapulmonary malignancy (Fig. 3
). It has to be mentioned that the groups of SPLC and primary bronchial carcinoma differ significantly in some clinical parameters: the proportion of patients with SCLC is higher in the comparison group with primary bronchogenic carcinoma, being 21.3% in contrast to 14.1% for SPLC. Only 13.6% of the patients with primary lung cancer were at stage I compared to 21.4% for SPLC. Therefore, a lower rate of curative treated patients was found in primary bronchial carcinoma (30.1%) versus SPLC (36%) group.
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Fig. 3. Kaplan–Meier plots of overall survival for patients with second primary lung cancer (SPLC) and primary lung cancer (PLC).
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3.5 Method of surgery and survival in SPLC
The survival rates of SPLC patients treated with surgery under curative aim (n
= 51) were 81, 56 and 36% after 1, 3 and 5 years, with a median survival of 39.7 months. Because surgical strategy is determined by the patients’ history, sometimes (n
= 11) only atypical resection was performed under the presumption diagnosis of pulmonary metastasis of the extrapulmonary index tumor. For these patients with limited resection, the 3-year survival rate after RO-resection was 29% (median survival: 25.0 months). The overall 3-year survival of patients with standard (anatomic) resection (n
= 37) of 61% (median survival 43.2 months) was relatively better (Fig. 4
). The same trend in favor of standard resection could be observed for recurrence free survival. But both differences were not significant—p
= 0.22 for overall survival, respectively p
= 0.55 for recurrence free survival.
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Fig. 4. Kaplan–Meier plots of surgically treated SPLC patients (R0-resection) depending on surgical procedure. (A) Overall survival, (B) recurrence free survival.
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4. Discussion
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In our study there was an incidence of 1.2 per 100,000 inhabitants for SPLC after extrapulmonary primary tumors. This was calculated for the first time in a population group by the way of a clinical epidemiologic study. Previous studies about SPLC have been performed in selected patient populations [8] or focused on a special clinical aspect [9]. As already shown, the Tumor Center Halle (Saale) reported an incidence of primary bronchial carcinoma of 53.8 for the same population, which corresponds to the national data recorded for this region [10].
The large proportion of patients with synchronous SPLC (nearly two-thirds) proves that the occurrence of two primary malignancies in the same individual represents not only the consequence of adverse effects of previous tumor therapies (radiotherapy/chemotherapy), but may be of multifactorial origin. The determinants include lifestyle, e.g. tobacco, alcohol and diet, environmental causes; but also host factors such as genetic susceptibility, immune functions, and hormonal status [11].
The present study identifies malignant tumors of the larynx and pharynx as the most frequent extrapulmonary primary tumors registered in men. SPLC in patients with pharyngolaryngeal tumors is not unusual, especially in male patients younger than 60 years. In the cases of second primary tumors in patients with head and neck squamous cell carcinoma, the lung was the next frequent location (34%) after tumors of the pharyngolaryngeal region [12]. In 1986, De Vries and Snow [13] noted that 14% of the patients with laryngeal cancer developed a second primary tumor, 10% of which occurred in the lung. Stopping the major causes for these tumors, e.g. smoking and drinking alcohol, did not prevent the development of second primary tumors [14], because irreversible genetic modifications in the tissue had occurred. Interestingly, Hong et al. [15] demonstrated that 13-cis-retinoic acid prevents the appearance of second primary tumors in patients previously treated for squamous cell carcinoma of the oral cavity and upper respiratory tract. This so-called chemoprevention may be perhaps one way to stop or slow down carcinogenic processes in high-risk patients.
In women, tumors of the reproduction system were the most frequent location of primary tumor. Genetic analyses of normal tissues [16] proved that the lung is very similar to the normal tissues of the female reproduction system, with regard to its gene expression, which could lead to the conclusion that the same genetic modifications might occur in their tumorigenesis. Kapp et al. [17] described a significant increase of lung cancer in women with invasive carcinoma of the cervix, treated by radiation therapy. Werner et al. [18] also suggest an abnormal genetic background and/or common etiology for the initial and second tumors, because most second neoplasms were distant from the radiation field.
Lung cancer is one of the most common tumors, following Hodgkin's disease, having a strict correlation to radiotherapy/chemotherapy [19]. The risk for SPLC increases with time from treatment (20–25 years) and is the highest in patients treated at age 45 years or older [8]. In our study, all patients with Hodgkin's lymphoma developed a synchronous appearance of both tumors, thus a risk caused by a completed radiotherapy/chemotherapy is uncertain. These patients’ average age of 76 years was clearly higher than that of the other patients with SPLC, but typical for lymphoma [20]. Older patients might perhaps have accumulated more genetic damage and be more susceptible to mutagenic effects. Age is probably also a surrogate for the duration of long cigarette smoking, an important contributor to increased risk.
There is little knowledge about the survival of patients with second pulmonary neoplasms after an extrapulmonary first tumor. Our 5-year survival rate of 12.5% for all SPLC is clearly above the survival data, which other authors [21,22] obtained in population-based studies for primary bronchial carcinoma. The fact that the survival prognosis of patients with SPLC significantly depends on the tumor stage corresponds to the data we know from primary bronchial carcinoma [22,23]. The prognosis for patients suffering from SPLC and having an initial extrapulmonary tumor is mainly determined by the SPLC and not by the initial extrapulmonary tumors. This hypothesis is based on two facts. First: patients who died showed the classical metastatic spread of the bronchial carcinoma (lung, adrenal, liver, bone and brain). Second: curatively treated patients had the best survival prognosis. Patients with non-curative treatment of the SPLC did not differ considerably in survival, depending on the treatment of their extrapulmonary index tumor (curative or non-curative). So, the extrapulmonary index tumor, especially the treatment, had only a small influence on the prognosis of patients with non-curatively treated SPLC. However, this seems not to be true if the index tumor is a bronchial carcinoma itself. The prognosis of metachronous SPLC after pulmonary index tumor is less poor than that of PLC in the same stage [24].
The survival rates of the patients with SPLC are slightly better than the survival of the primary bronchial cancer comparison group, which is determined by a shift towards lower tumor stages and fewer SCLCs. Patients with SPLC, having undergone curative treatment, turned out to have the best prognosis in our study, showing median survival of 31.0 months and a 1-year survival rate of 80.0% and a 5-year survival rate of 35%. Adebonojo et al. [24] reported an actuarial 5-year survival of 32% and a median survival of 43 months for 52 patients (51 of whom were surgically treated) with metachronous and synchronous multiple PLC. As histology of the pulmonary lesions is often unclear or under strong suspicion of pulmonary metastasis in the preoperative phase, limited resection is favored in these cases. Ginsberg and Rubinstein found that limited resection of T1NO NSCLC was to be associated with a 75% increase in recurrence rates and a 30% increase in overall death rates in comparison to lobectomy [25]. We could also show a considerable advantage in overall, as well as recurrence free, survival for patients with anatomical resection, but the differences to the survival rates of patients with limited resection were not significant. Iwasaki et al. were also not able to demonstrate a significant difference in survival rates between less vigorous therapy, including segmentectomy or VATS lobectomy or lobectomy with conventional thoracotomy, in patients with SPLC [9]. So, from our viewpoint, a second procedure after atypical resection does not have to be performed strictly after histologically proven SPLC, but should take place depending on the risks of the operation and the patient's wishes.
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5. Conclusions
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- 1. Most SPLC occur synchronously (<24 months) to the extrapulmonary index tumor. That's why short-term regular follow up of cancer patients must be performed to identify second neoplasms in curable stages, besides local recurrence and distant metastasis.
- 2. Cancer of the pharyngolaryngeal tract, gastrointestinal tract, female genitals and the breast can very often be found as index tumor in cases of SPLC.
- 3. The tumor stage of the SPLC has the highest prognostic value of all clinical data.
- 4. Patients with operable SPLC should be treated with anatomical (standard) resection, because this kind of treatment has the best prognosis.
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Acknowledgments
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The authors are grateful for the cooperation of departments and institutes co-working with the Cancer Center of Halle and the HALLUCA study.
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Abstract
1. Introduction
