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Second Cancers Occurring in Patients With Early Stage Non–Small-Cell Lung Cancer Treated With Chest Radiation Therapy Alone

Departments of Oncology and Surgery, University Hospital, Kragujevac; Institute for Lung Diseases and TB, Clinical Center, Belgrade, Yugoslavia; and Department of Oncology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.

Address reprint to Branislav Jeremic, MD, PhD, Department of Radiation Oncology, University Hospital, Hoppe-Seyler-Strasse 3, D-72076 Tuebingen, Germany; email: bjeremic{at}med.uni-tuebingen.de

	ABSTRACT

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PURPOSE: To investigate the incidence of second cancers occurring in patients with early stage (I/II) non–small-cell lung cancer (NSCLC) treated with radiation therapy (RT) alone.

PATIENTS AND METHODS: Seventy-eight patients had been treated with conventionally fractionated (CF) RT (1982 to 1987), and 116 patients had been treated with hyperfractionated (Hfx) RT (1988 to 1993). Tumor doses were 60 Gy for CF and 69.6 Gy (1.2 Gy bid) for Hfx.

RESULTS: A total of 26 patients developed second cancers. The cumulative incidence of second cancer was 21.8% (SE, 4.7%) at 5 years and 34.8% (SE, 6.7%) at 10 years. For second lung cancers, it was 6.0% (SE, 2.8%) at 5 years and 14.2% (SE, 5.2%) at 10 years, and for second nonlung cancers, it was 16.3% (SE, 4.2%) at 5 years and 22.2% (SE, 5.7%) at 10 years. The rate of developing second cancer per patient per year was 4.3% (95% confidence intervals [CI], 2.7% to 5.9%), with the rates being 1.4% (CI, 0.5% to 2.3%) for the second lung cancers and 2.8% (CI, 1.5% to 4.1%) for second nonlung cancers. The rate of developing second cancers during the first and second 5-year period after RT (0 to 5 and 5 to 10 years) was 4.3% (CI, 2.4% to 6.2%) and 4.2% (CI, 0.6% to 7.8%), respectively, for all cancers. These rates were 1.0% (CI, 0.1% to 1.9%) and 2.2% (CI, 0% to 4.6%), respectively, for second lung cancers, and 3.2% (CI, 1.6% to 4.8%) and 1.5% (CI, 0% to 3.6%), respectively, for second nonlung cancers.

CONCLUSION: Long-term survivors after RT alone for early stage NSCLC carry the same risk of developing second cancer, either lung or nonlung, as their counterparts treated surgically when the results of this study are compared with those of the published literature.

	INTRODUCTION

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THE TREATMENT OF choice for patients with early stage (I and II) non–small-cell lung cancer (NSCLC) is surgery. However, a proportion of these patients never undergoes surgery because of their advanced age, medical inoperability, or simple refusal. These patients are usually treated with radiation therapy (RT) alone. Patients treated with standard fractionation RT have 5-year survival rates ranging 15% to 20%,^1-5 which may go up to 25% to 30% with the use of hyperfractionation (Hfx).^6,7 This means that a proportion of such patients become long-term survivors and, as such, they are candidates for experiencing the occurrence of second cancer. Various surgical series showed that second cancers, of either lung or nonlung origin, occur in long-term survivors.^8-11 The rate of developing second lung cancer was about 1% to 2% per patient per year,^12-18 with the cumulative risk of developing second primary lung or other smoking-related cancers ranging from 10% to 20% after 5 years after resection.

Although there are a number of studies reporting occurrences of second cancer in surgically treated patients with early stage NSCLC, virtually no such report exists on the occurrence of second cancer in patients treated with RT alone. To investigate the incidence of second cancer in patients with early stage NSCLC treated with RT alone, we retrospectively analyzed our database regarding this subset of patients treated at a single institution over the period of 12 years.

	PATIENTS AND METHODS

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Hospital records of all patients with NSCLC at early stages (I and II) according to the International Staging System¹⁹ treated with RT alone at the Department of Oncology, University Hospital, Kragujevac, Yugoslavia were reviewed. It is a regional referral center that does all of the radiotherapy for a defined population of approximately 1.5 million. Patients treated with either conventional fractionated (CF) RT or Hfx RT were deemed suitable for this analysis. In all cases, patients were, although technically operable, deemed unsuitable for surgery because of their concomitant medical problems (cardiovascular or pulmonary diseases) (CF RT, n = 59; Hfx RT, n = 72) or because they refused surgery (CF RT, n = 19; Hfx RT, n = 44). Because the institutional policy on the treatment of these patients changed only regarding the choice of radiation fractionation pattern, they were all suitable for the analysis. No patients underwent surgery and no patients received any form of adjuvant (chemo- or immunotherapy) therapy. Patients treated with Hfx RT (1988 to 1993) all underwent pretreatment staging with thoracic and upper abdominal computed tomography (CT) scanning; whereas of those treated with CF (1981 to 1987), pretreatment staging with thoracic and upper abdominal CT scanning was performed in 55 (70%) out of 78 patients, being performed in 22 patients (69%) with stage I and in 33 patients (71%) with stage II disease. No patient underwent mediastinoscopy. Between 1981 and 1987, our policy was to treat both clinical stage I and II disease with CF with tumor doses of 60 Gy in 30 daily fractions in 30 treatment days over 6 weeks. From January 1988, an Hfx RT regimen was introduced in both clinical stage I and II NSCLC with tumor doses of 69.6 Gy in 58 fractions in 29 treatment days (bid fractionation) over 6 weeks. Two daily fractions of 1.2 Gy were used with an interfraction interval of 4.5 to 6 hours. Details of the Hfx RT regimens were published previously.^6,7 For CF, initial treatments were given up to 45 Gy in 24 daily fractions using anteroposterior-posteroranterior fields, after which a multifield technique was used to spare spinal cord while giving additional 15 Gy in eight daily fractions in 1.5 weeks. All fields were treated daily. The target volume for all stage I patients included the primary tumor and ipsilateral hilum with a 2-cm margin up to 45 Gy (CF) or 50.4 Gy (Hfx), followed by the treatment of primary tumor only up to either 60 Gy (CF) or 69.6 Gy (Hfx). For all stage II patients, the target volume included the primary tumor and ipsilateral hilum with a 2-cm margin and the ipsilateral mediastinum from the suprasternal notch to a level 6 cm below the carina (upper- or middle-lobe lesions) or to the diaphragm (lower-lobe lesions), followed by the treatment of primary tumor and ipsilateral hilum up to either 60 Gy (CF) or 69.6 Gy (Hfx). Doses were specified at mid-depth at the central axis for parallel-opposed fields and at the intersection of central axes for other techniques.

During the follow-up period after RT was administered for their initial (early) NSCLC, all patients returned regularly to our institution. The follow-up procedures included laboratory and clinical tests including thoracic and upper abdominal CT scanning, accompanied with other tests, if needed. Local physicians were also included in the follow-up of these patients in-between regular visits, as appropriate. Patients were observed at 2- to 3-month intervals during the first 2 years, at 4- to 6-month intervals during years 3 and 4, and at 6- to 12-month intervals thereafter. Deaths that occurred outside our institution were documented by contacting local physicians and hospital specialists and obtaining death records/certificates, if necessary.

Second cancers were documented clinically, and all patients also had cytologic and/or pathologic verification of their second cancer. After the diagnosis and treatment of their second cancer, patients were generally followed up using the following institutional policy at the following intervals: first year, 2 to 3 months; second year, 4 months; 3 to 5 years, 6 months; and once a year thereafter. Owing to the different tumor types (locations/histologies) encountered, different diagnostic tools were used during the follow-up, including a thoracic and upper abdominal CT scan as mandatory, accompanied with conventional radiographs (with contrast radiographs if needed), endoscopy, ultrasound, and radionuclide scans. Full blood counts and biochemistry analyses were performed on each follow-up visit.

The criteria for a second primary lung cancer were those as originally described by Martini and Malamed²⁰; a tumor was considered a second primary if it was with different histology or with the same histology as initial NSCLC but if (1) the free interval between the occurrence of cancers was at least 2 years, (2) second cancer originated from a carcinoma-in-situ, or (3) second cancer was in different lobe or lung, but neither cancer in lymphatics common to both cancers nor extrapulmonary metastases were found at the time of diagnosis.

The cutoff date for data collection was August 1, 1999. Survival rates and cumulative risks of developing second cancer were both calculated according to the Kaplan-Meier method, and the differences between the survival curves were analyzed using the log-rank test. Data for patients who were alive at last follow-up or dead without second cancer development were used as censored data in calculating the cumulative risks, and data for patients who were alive at last follow-up or died of any causes unrelated to the second cancer were used as censored data in calculating cause-specific survival (CSS). The rate of secondary cancer development was calculated as the ratio of second primary cancer cases over 100 patient-years of follow-up.^14,21 Differences between pairs of groups were analyzed using the ² test, Fisher’s exact test (when there was a numerator of 5 of less), Student’s t test, or Welch’s t test. All these statistical analyses were carried out using the computer program HALBAU 4 (Gendaisuugakusha, Kyoto, Japan).

	RESULTS

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During the 12-year period (November 1981 to June 1993), a total of 194 patients underwent RT alone for early stage NSCLC. There were 78 patients treated with CF, and 116 patients treated with Hfx. None of the patients were lost to follow-up. With the median follow-up period for living patients of 89 months (range, 55 to 171 months), the overall survival for all 194 patients was 23.7% (SE, 3.1%) at 5 years and 16.5% (SE, 2.9%) at 10 years. Deaths from intercurrent disease were observed in 21 patients (eight in the CF group and 13 in the Hfx group, P = .83). Characteristics of these 194 patients are listed in Table 1. There was no difference in any of these pretreatment patient characteristics between the four subgroups of patients.

View larger version (10K): [in this window] [in a new window]   Fig 1. Cumulative incidence of second cancer: any cancer (_____), second lung cancer (_ _ _ _), second nonlung cancer (..........).

There was no difference in the incidence of second cancer between stage I and II patients and between CF and Hfx groups. The rate of developing second cancer per patient per year during the first 5 years was 4.4% (CI, 1.2% to 7.5%) in the CF group and 4.3% (CI, 2.9% to 6.5%) in the Hfx group (P = .90). For second lung cancers, this rate was 1.2% (CI, 0% to 2.9%) in the CF group and 1.0% (CI, 0% to 2.0%) in the Hfx group (P = 1.0). There was no influence of sex, age, weight loss, T stage, or location on the occurrence of second cancer. Patients having lower Karnofsky performance status (KPS) had significantly lower cumulative incidence of second cancer than those with higher KPS because of a longer survival in higher KPS patients who, therefore, had more chance to develop second cancers. Histology had the most profound effect on the development of second cancer. Patients with squamous cell carcinomas had lower incidence of second cancer than those with adenocarcinoma (P = .00004) and those with large-cell carcinoma (P < .00001) The difference between patients with adenocarcinoma and those with large-cell carcinoma was not significant (P = .066) ( Table 2). There were 16 intercurrent deaths in the squamous cell carcinoma group and five in the nonsquamous cell carcinoma or nonspecific histology group. Among them, 10 in the former and three in the latter group were caused by cardiovascular events. The proportion of all intercurrent deaths is, therefore, 13 out of 119 patients with squamous histology versus eight out of 75 patients with nonsquamous histology. The proportion of death from cardiovascular event is 10 out of 119 (squamous) versus three out of 75 (nonsquamous).

	DISCUSSION

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Cumulative incidence of second cancer was clearly documented in surgical series. Pastorino et al³³ reported on patients with resected stage I NSCLC who entered into retinol chemoprevention trial. Similar proportions of second lung and nonlung cancers occurred in the two treatment groups. At 5 years, the estimated proportion of patients with a new primary was 14% and 24% for the retinol and control groups, respectively (P = .09). However, when new primaries in the field of prevention (lung, head and neck, and bladder) were considered separately, the estimated proportions were 11% and 20% at 5 years for the retinol and control groups, respectively (P = .045). In a report by Martini et al¹⁵ on patients resected for stage I NSCLC, second primary cancers developed in 34% of patients, which confirmed previous observations of the same group.³⁴ The ratio of second lung versus nonlung cancer was 1:2. New cancers developed in 9% patients who survived 5 or more years after operation. Of these, 5% were second lung cancers and 4% second nonlung cancers. In the study of Walsh et al,¹⁸ there were 9.8% new malignancies, of which second nonlung primaries occurred in 8% of patients. The cumulative incidence of second cancer in the current study was 21.8% at 5 years and 34.8% at 10 years. For second lung cancer, it was 6% at 5 years and 14.2% at 10 years, similar to percentages observed by Pastorino et al³³ and Saito et al³⁵ (11% at 5 years and 12.8% at 7 years).

Another issue reported on second cancer was occurrence rates with the passage of the time. Thomas and Rubinstein¹⁰ reported on 973 patients operated for T1N0 NSCLC. The occurrence rates for second nonpulmonary cancer were similar during the first and the second 5-year periods after surgery, but they doubled from 0.009 to 0.020 for second pulmonary cancer. All other studies reported the rate of developing second primary lung cancer of 1% to 2% per patient per year,^12-15,17,35 except the studies of Van Meerbeck et al²¹ (based on a hospital registry) and Woolner et al³⁶ (4%). In our series, the rate of development of second lung cancer was 1.4% per patient per year, which is in agreement with the rates in most surgical series. Second nonlung primaries developed at a rate of 2.8% per patient per year. The difference in rates between nonlung cancers and lung cancers also reflects the rate of all other cancers expected in the general population of this relatively advanced age. The rate of developing second cancer in the current study remained unchanged with the passage of the time after RT for primary lung cancer. It was 4.3% for the initial 5 years and 4.2% for the second 5-year period. Opposite trends were seen for second lung primaries and second nonlung primaries, an increase for the former (from 1.0% to 2.2%) and a decrease for the latter (from 3.2% to 1.5%). The former finding is consistent with that of Thomas and Rubinstein¹⁴ and Razzuk et al,¹² who observed an increase in the rate from 1% to 2% for the first and second 5-year period, and Van Meerbeck et al.²¹ Only Pairolero et al¹³ reported on the decrease in the rate of development of second lung cancer from 2.5% during the first 5 years to 1% after 6 years after surgery, probably a result of only two out of 35 patients having second lung cancers after 6 years. An overall rate of developing second lung cancer was 2.2% per 100 patient-years

In previous studies,^{12,21,32,35,37} more than 50% of metachronous lung tumors were in the opposite lung. This is in sharp contrast with the findings of the current study in which of nine lung cancers, only three (33%) were in the opposite lung. No rational explanation exists for this finding, except that surgery removed completely or partially remaining (uninvolved) ipsilateral lung that initially contained tumor. Contrary to that, our patients had both lungs available for the development of the second lung primary. Although RT may have itself contributed to the occurrence of second cancer and not just a volume depletion by surgery, of all nine second lung cancers, only one (11%) arose in RT treatment field used to treat initial lung cancer, within 1.5 cm from the field edge after a latency period of 88 months (patient no. 18, Table 3).

In patients who had undergone successful resection for NSCLC and developed second cancer, 70% to 95% of the new tumors were also histologically NSCLC.^32,37-40 This is in contrast with our study in which all nine patients who developed second lung cancer had different histology, although none of our patients developed small-cell lung cancer after initial NSCLC. Because of follow-up at regular intervals in surgical series, the vast majority of patients with second lung cancer were diagnosed as having either stage I or II disease.^12,37,38,40 Similarly, all our patients with second lung cancer were either at stage I or II. Because of initial medical inoperability that requested initial RT alone, the same approach was used after diagnosis of second lung cancer. All but one patient underwent radical RT that encompassed area of tumor plus a 2-cm margin. Survival of these nine patients (30% at 5 years) is similar to that of similarly staged patients with primary NSCLC treated with either CF or Hfx RT.^6,7,23,24,26 It seems at least comparable with those of surgical series^12,37,41-43 of second lung cancer, with a resectability rate of approximately 50%, median survival times of 1 to 2 years, and 5 year survivals ranging from 4% to 32%, as recently summarized by Johnson⁴⁴ in the most comprehensive review on this topic published to date. Furthermore, an excellent 5-year CSS of 53% was obtained in these patients. The same applies to the patients having second nonlung primaries who had 5-year CSS of 86%, owing to the favorable distribution of location and stage of second tumors, such as early head and neck cancer and skin cancer for which the patients were more likely to be cured by radical RT alone (survival for 17 such patients at 5 years = 35%). These results reemphasize the necessity for close surveillance of the patients initially treated for early stage NSCLC because this approach is highly rewarding. It may also provide useful information for the efficacy of the follow-up procedures.⁴⁴

A disadvantage of this study is that smoking habits of the patients before and after treatment of both initial early NSCLC and second cancers were systematically collected only during recent years. Although no study reported on the relative rates of the development of second metachronous cancers in patients regarding smoking habits, one study disclosed a greater exposure to cigarette smoke in patients who developed multiple primary lung cancers than in those developing a single lung cancer.⁴⁵ Another disadvantage of our study is that we did not compare the rate of second cancer with that in patients treated surgically in our own institution because of unavailability of such data. Doing this may have enabled better comparison than only using published reports from the literature.

This study showed a higher incidence of second cancer in patients with squamous cell carcinoma than in those with other NSCLC, but the reason for this observation is not clear. Squamous cell lung cancer is generally more smoking-related than the other NSCLC, and smoking is also associated with more cardiovascular disease. If patients die from cardiovascular disease, they do not survive to develop second cancer. Indeed, 10 out of 119 patients with squamous histology but only three out of the 75 patients with nonsquamous or nonspecific histology died of a cardiovascular event. However, the proportion of overall intercurrent deaths were similar (13 of 119 patients with squamous v eight of 75 patients with nonsquamous histology), so intercurrent deaths may not be a good reason for the lower incidence of second cancer in patients with squamous cell lung cancer. Another reason may be the small number of patients, especially with large-cell histology, and the comparison might just reflect random variance. This issue should be investigated in future studies.

In conclusion, this study showed that patients treated for early stage NSCLC by RT alone were at risk for developing second cancer and this risk increased with time. According to our results, which represent the first systematic approach in this issue on RT for early stage NSCLC, there seem to be no major differences between surgery-treated and radiation-treated patients with early stage NSCLC regarding the occurrence of second cancer, both lung and nonlung. Close follow-up after curative RT for initial lung cancer is necessary because patients with second cancer may be identified in early stages, treated appropriately, and have similar outcome as their initial lung or nonlung cancer counterparts.

	ACKNOWLEDGMENTS

 
Supported in part by the grant-in-aid for Scientific Research from the Japanese Ministry of Education, Science and Culture (grant nos. 11470190, 11877152, and 10557087).

We thank Bruce E. Johnson, MD, for his comments and suggestions.

	NOTES

 
Presented during the Ninth International Association for the Study of Lung Cancer Meeting held in Tokyo, Japan, September 11-15, 2000.

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Submitted April 19, 2000; accepted October 23, 2000.

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