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Ann Thorac Surg 1996;62:830-834
© 1996 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Postresection Irradiation for T2 N0 M0 Non–Small Cell Carcinoma: A Prospective, Randomized Study

Department of Pneumology, , Unit of Thoracic Surgery, Unit of Radiotherapy (Centre Oscar Lambret), and Laboratory of Pathology, Hôpital Calmette, Centre Hospitalier Régional Universitaire, Lille, France

Accepted for publication April 20, 1996.

	Abstract

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Background. Stage I nonirradiated T2 N0 non–small cell lung carcinoma has a postoperative prognosis not very different from stage II irradiated T1 N1 carcinoma. The hypothesis was that more locoregional malignant sites are overlooked in T2 N0 M0 than in T1 N0 M0 tumors, considering the better prognosis of this last group, and that T2 N0 cancer might benefit from postresection irradiation.

Methods. From 1985 to 1991, 163 non–small cell lung carcinomas were classified T2 N0 M0 and randomized for irradiation or nonirradiation after operation. After revision of all the cases, 132 were included in this study: 60 were irradiated and 72 were not irradiated. All were followed up. The study was closed in October 1995. Statistical analysis was then performed considering volume, location, cell type, survival, and recurrence in the two groups.

Results. One hundred thirteen patients were followed up during a minimum of 5 years: the survival was 44.2%. There was no significant difference considering cell type or irradiation. There was no recurrence-free survivor beyond 5 years with a tumor invading the visceral pleura. At the close of the study (follow up, 4 years 3 months to 10 years 1 month), 49 of 132 patients were alive. The median survival was 3 years 11 months. Fifty-nine patients had died of local (21) or distant (40) recurrences (2 patients had both local and distant recurrence). There was again no significant difference considering cell type or irradiation, either in the survival or in the mode of recurrence.

Conclusions. Stage I T2 N0 M0 non–small cell lung carcinoma tends to manifest distant metastasis. Prospective studies of stratified systemic adjuvant therapy should improve the present moderate result of radical resection in this group of tumors.

	Introduction

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
In 1985, a retrospective survey of our clinical records of 204 patients with resected non–small cell lung carcinoma showed that the postoperative actuarial 5-year survival was 74.2% for T1 N0 M0, 35.6% for T2 N0 M0, and 32.1% for T1 N1 M0 tumors. In the first two groups, no postoperative radiotherapy had been administered. The last one had been irradiated after resection. The similarity of survivals between T2 N0 M0 and T1 N1 M0 staged patients led us to hypothesize that more locoregional malignant sites might have been left in T2 N0 than in T1 N0 cancers and that T2 N0 tumors might benefit from postresection irradiation.

	Patients and Methods

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
From September 1985 to July 1991, 163 non–small cell lung carcinomas were classified T2 N0 M0 after pulmonary resection and lymph node dissection including scissural, hilar, and homolateral paratracheal, subcarinal, and paraesophageal nodes. They were in 156 men and 7 women who had a mean age of 58.5 ± 8.02 years. After the preoperative work-up, they were informed of the possibility, advantages, and disadvantages of being irradiated or not after operation, and their consent to either decision was obtained. At reception of the pathology report, they were randomized with a table of randomization according to Snedecor and Cochran [1]. Thirty-one patients were excluded from the study. Three died in the hospital (1.8%): 1 of pneumonia, 1 of pulmonary embolism, and 1 of hemoptysis associated with a bronchial fistula. Two died at home (1.2%) within 3 months, 1 of a circulatory arrest of unknown origin and 1 of hemoptysis. Radiotherapy was refused by 3 patients who had accepted it or by their doctors. Finally, a review of all the cases was made by two pathologists: 9 tumors were reclassified as being T1 N0 M0 and 2 as being T3 N0 M0; 2 were eliminated because of a small cell component and 10 because of a microscopic lymph node metastasis.

The studied population comprised 126 men and 6 women. Seventy-six tumors were squamous: 53 were well differentiated and 23 were moderately or poorly differentiated. Forty-seven tumors were adenocarcinomas, 2 were adenosquamous, 4 were bronchioloalveolar, 2 were undifferentiated, and 1 was composite (adenocarcinoma and squamous carcinoma).

The resections were 4 segmentectomies, 99 lobectomies including 7 sleeve resections, 4 bilobectomies, and 25 pneumonectomies. The pneumonectomies were necessitated by 10 bronchial tumoral extensions, 9 pulmonary artery invasions, 1 hilar infiltration, and 3 fissural crossings. The cause for pneumonectomy was not established in 2 operative records.

Postoperative irradiation was administered to 60 patients, 56 men and 4 women, aged 58.15 ± 8.15 years (range, 38 to 72 years). The resections had consisted of 3 segmentectomies, 44 lobectomies, 3 bilobectomies, and 10 pneumonectomies. The tumors were 36 squamous, 23 nonsquamous, and 1 composite. The mean diameter was 4.7 cm. The total irradiation dose varied between 45 and 60 Gy and was centered on the hilum and upper mediastinum.

No adjuvant therapy was used for 72 patients, 70 men and 2 women, aged 59.29 ± 8.37 years (range, 40 to 78 years). The resections had consisted of 1 segmentectomy, 55 lobectomies, 1 bilobectomy, and 15 pneumonectomies. The tumors were 40 squamous, 30 nonsquamous, and 2 adenosquamous. Their mean diameter was 4.5 cm.

The 132 patients were followed up every 6 months for the first 2 years and every year from then on. The recorded information was clinical history, symptoms, and general status; physical examination; standard posteroanterior and lateral chest radiographs; bronchoscopy; computed tomograms; and total body scintigram in case of suspicion of recurrence. Recurrences in bronchial stump, hilum, and mediastinum were defined as local. In all other sites they were considered distant.

The follow-up study of the patients was closed on October 10, 1995. The minimum period of follow-up was 4 years 3 months, and the maximum period was 10 years 1 month. The survival curves were made according to Kaplan-Meier. Comparisons of survival in each group were made according to the log rank test. Statistical analysis was performed with the SAS logitial (Statistical Analysis Software, SAS Institute Inc, Cary, NC) by the Centre d'Etudes Statistiques, CHRU, Lille, France.

	Results

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
A group of 113 patients was followed up for more than 5 years; 50 of them (44.2%) survived beyond that period of time (Fig 1). Three of them had a mediastinal recurrence at 60.6, 61.3, and 67.8 months and 1 of them had a bone metastasis at 65.9 months. Table 1 shows no differences in 5-year survival correlated with either postoperative irradiation or cell type. The mean diameter of the tumors in the 5-year survivors was 4.79 cm, compared with 4.5 cm for the group (p = 0.83). There were 15 survivors for 43 central locations (34.8%), 20 survivors for 34 midzone locations (58.8%), and 15 survivors for 36 peripheral locations (41.6%). These differences were not significant (p = 0.83). There was 1 survivor in 5 cases of peripheral tumors with invaded visceral pleura (4 recurrences) and there were 15 survivors in 31 cases of peripheral tumors with intact visceral pleura (10 recurrences). The difference is significant for recurrences (p = 0.01), but the figures are too small for a definite conclusion.

View larger version (12K): [in this window] [in a new window]   Fig 1. . Overall survival of 113 patients followed up during a minimum of 5 years.

View larger version (10K): [in this window] [in a new window]   Fig 2. . Overall survival of the whole population of 132 patients.

View larger version (14K): [in this window] [in a new window]   Fig 3. . Disease-free survival of irradiated and nonirradiated patients.

View larger version (15K): [in this window] [in a new window]   Fig 4. . Overall survival of patients, correlated with irradiation.

View larger version (15K): [in this window] [in a new window]   Fig 5. . Survival of patients with squamous cell carcinomas, correlated with irradiation.

View larger version (15K): [in this window] [in a new window]   Fig 6. . Survival of patients with nonsquamous cell carcinomas, correlated with irradiation.

The median survival after pneumonectomy was shorter than after partial resection of the lung, but the difference was not significant (p = 0.39). Irradiation after pneumonectomy did not affect the prognosis (p = 0.51).

Fifty-nine patients had died of recurrence. The median delay of emergence of a sign of recurrence was 1,388 days (45.5 months). There were 22 local recurrences, and distant recurrences concerned one or several sites: lung (11), pleura (2), skeleton (10), liver (13), brain (8), adrenal glands (3), and extrathoracic lymph nodes (4). Two patients had associated local and distant recurrences. Among the 11 pulmonary locations, one could be discussed as a metachronous primitive cancer. Radiotherapy had no effect on recurrence (p = 0.21). There was no significant difference between the incidences and dates of discovery of the recurrences between squamous and nonsquamous cancers (p = 0.307). There was no difference according to irradiation and cell type (p = 0.34). Irradiation did not influence the ratio of local recurrence/distal recurrence whatever the cell type (p = 0.20 and 0.52). The delay of recurrence was not influenced either (p = 0.54 and 0.79).

Twenty-four patients had died with no sign of recurrence of lung cancer. However, 7 of them had died of another cancer: upper respiratory tract carcinoma (5), eye melanoma (1), and small intestinal sarcoma (1). In fact, 11 (8.3%) of 132 patients who underwent operation had 12 extrapulmonary primitive malignancies: 6 in the upper respiratory tract, 2 in the esophagus (1 of them associated with a laryngeal location), 2 in the intestine, 1 in the uterus, and 1 in the eye.

One patient died of an irradiated lung and 1 of a hemorrhage during the dilation of a bronchial stenotic anastomosis after irradiation. The cause of death remained unknown for 15 patients, but a recent control had shown no sign of recurrence of the bronchial tumor in 3 of them.

	Comment

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
If there is a general agreement on the favorable postresection prognosis of T1 N0 M0 tumors, there is still some wavering about the evolution and staging of T2 N0 M0 cancers: T2 N0 is considered as having an intermediate position between T1 N0 and T1 N1 [2], and several series show more similarities between T2 N0 and T1 N1 than between T2 N0 and T1 N0 tumors [3–7]. The risk of multifocal malignant sites in any cancer has logically been considered as increasing with time [8]. However, it has been shown in a multivariate prognostic factor analysis of 151 patients with stage I non–small cell lung cancers that T by itself was marginally significant [9]: other factors such as contact with the visceral pleura, local lymphatic invasion, grade of cell differentiation, and ploidy pattern appear as more important. Nevertheless, the time of recurrence is increasingly shorter with increasing TN status [10].

Although the cell type appears as an important factor in stage II [11], it has sometimes not been considered in the treatment of stage I lung cancer [12]. However, the relationship of disease extent and cell type to survival has been generally admitted [13]. Also, local recurrence has been considered as more frequent for squamous carcinoma and distant recurrence for adenocarcinoma [14]. Indeed, although the squamous tumors show a higher percentage of local-only recurrences, the difference is not significant, but the time to recurrence is shorter in the nonsquamous group [10]. In fact, in a study of 24 T1 N0 and 111 T2 N0 cancers, it was observed that two thirds of the first observed recurrences are in distant sites for tumors in stage I and for different cell types [15].

The site of the first recurrence is important to know as it is the cause of death of at least 70% of the patients, even with stage I and II tumors [15, 16]. This was confirmed in our series. The study by Feld and the Lung Cancer Study Group [10] showed, after a mean follow-up of 3.4 years, an incidence of relapse of 41% of T2 N0 cancers. The study included 196 T2 N0 tumors. The recurrence was local in 27% of cases. Similarly, Little and associates [4] observed, in 46 patients with resected T2 N0 cancers, a ratio of 18.2% local/81.8% distant recurrence and noted more frequent distant recurrence in T2 than in T1 tumors. After resection of an N0 cancer, the actuarial probability of recurrence at 5 years is 45% [17]. It is remarkable that for Yano and colleagues [18] there is no difference in the ratio of local/distant recurrence between N0 and N2 cancers.

There probably is a high (35%) prevalence of regional and distant residual malignant sites after resection considered as curative of early lung cancer [19]. The limited performance of a "radical operation" alone in stage I lung cancer accounts for the many tries at improvement by adjuvant therapy. Postoperative irradiation is usually administered after resection of N1 and N2 tumors, when resection was incomplete or when the cancer was adherent to adjacent structures (T3 and T4). Radiotherapy, although considered as efficient for small lesions, has generally not been used after resection of N0 cancers, especially in a prospective, randomized fashion. Vanhoutte and colleagues [20] randomized 175 patients with N0 tumors: the 5-year survival rate was lower in the irradiated population (24% versus 43%), as it was in our series. The study included 54 T2 cancers, 15 of them being irradiated with no significant benefit. The number was small, however, and no histopathologic information was given for this particular subgroup. Neverthless, the detrimental effect of radiation therapy was observed, which was particularly significant after pneumonectomy. The slight benefit from radiation therapy was a decrease in local relapse, with no effect on survival. More recently, Cangemi and associates [15] applied adjuvant radiotherapy in a small, nonrandomized number of patients with "adverse factors": adenocarcinoma and nodal involvement. They showed by statistical analysis that irradiation was a significant and independent predictor of poor outcome.

The prognosis of T2 N0 cancer lies not only in the completeness of its resection and of lymphadenectomy (essential at least for an accurate staging), but also in other factors that account for the importance of distant recurrences. Some of these factors concern pathology, and others concern biology. Many biologic factors have been studied, but the methodology of these studies is often unreliable [13]. So many variables are at stake that stratified studies of adjuvant therapy must be undertaken with sufficient numbers of patients. One type of adjuvant treatment, even if efficient, can control but one particular factor of spread of the malignancy and may have a deleterious effect by itself, and thus may fail to show an effect on survival. Systematic limited associations of treatments and elimination of powerless tools are the ways to improve prognosis if the studies include accurate staging and pathology, cellular activity, biology, and a 5-year minimum follow-up.

We conclude that T1 N0 M0 and T2 N0 M0 non–small cell lung cancers should not be put together into prospective therapeutic studies. There is a greater tendency for T2 N0 tumors to manifest distant metastases, which account for the lack of benefit from locoregional postresection irradiation. This particular group of bronchial carcinomas must be submitted to strict prospective studies of the effect of well-defined systemic adjuvant treatments to improve the present moderate result of radical resection.

	Acknowledgments

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
We are grateful to A. Duhamel, MD, for his statistical studies.

	Footnotes

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Lafitte, Hôpital Calmette, CHRU, 59037 Lille, France.

	References

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 

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