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Ann Thorac Surg 1998;65:212-216
© 1998 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Survival in Resected Stage I Lung Cancer With Residual Tumor at the Bronchial Resection Margin

Department of Pulmonology, Sint Antonius Hospital, Nieuwegein, the Netherlands
Department of Thoracic Surgery, Sint Antonius Hospital, Nieuwegein, the Netherlands
Department of Pathology, Sint Antonius Hospital, Nieuwegein, the Netherlands

Accepted for publication July 23, 1997.

Dr Snijder, Department of Pulmonology, Sint Antonius Hospital, PO Box 2500, 3430 EM Nieuwegein, the Netherlands.

	Abstract

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Background. Sometimes microscopic residual tumor is found at the bronchial resection margin despite an apparently complete resection of lung cancer. This may adversely affect the patient’s prognosis. Its impact on survival is unclear.

Methods. The records of 834 patients with resected stage I non–small cell lung cancer were studied. Patients with complete resection were assigned to the complete resection group (n = 802); patients with microscopic residual tumor at the bronchial resection margin that was accepted were assigned to the residual tumor group (n = 23). Residual tumor was classified as carcinoma in situ, mucosal residual disease, or peribronchial residual disease.

Results. The 5-year survival in the patients in the complete resection group was 54%; it was 58% in the residual tumor group with carcinoma in situ and 27.3% in the residual tumor group with invasive tumor (mucosal residual disease or peribronchial residual disease). The difference in survival between patients in the complete resection group and patients in the residual tumor group with invasive tumor was significant (p = 0.03).

Conclusions. The presence of mucosal or peribronchial residual disease, but not carcinoma in situ, at the bronchial resection margin in patients with stage I non–small cell lung cancer has an adverse effect on survival.

	Introduction

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The treatment of choice in patients with stage I non–small cell lung cancer (NSCLC) is surgical resection. Excellent 5-year survival rates have been noted in patients who undergo complete resection [1][2]. During the operation, however, the surgeon can be confronted with a more advanced tumor than was expected preoperatively, and it may be impossible to remove all macroscopic disease. If complete resection is impossible, surgical therapy should be abandoned, in view of the high mortality and poor survival [2]. However, in some patients, microscopic residual tumor is found at the bronchial resection margin after the operation. Despite the incomplete resection, long-term survivors have been described [2][3][4][5][6][7][8][9][10]. Gebitekin and colleagues [3] reported that residual tumor at the bronchial resection margin did not influence survival in their patients with stage I or stage II disease. However, other investigators have found that the pattern of microscopic residual tumor affects survival [2][4][5][8][10]. In most of these reports, however, the lung cancer stage was not mentioned, which impedes proper evaluation of the influence of a positive resection margin on long-term outcome.

We investigated retrospectively the importance of microscopic residual tumor at the bronchial resection margin in patients with resected NSCLC and restricted the study to patients with stage I disease. Patients with completely resected stage I NSCLC have better survival rates than patients with more advanced stages of lung cancer. If a positive resection margin has an adverse effect on survival, it should become obvious in this group of patients.

	Material and Methods

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The records of all patients who underwent pulmonary resection because of lung cancer between 1977 and 1993 at the Sint Antonius Hospital, Nieuwegein, the Netherlands, were reviewed. Of the 2,009 consecutive patients, 834 had stage I NSCLC. Cervical mediastinoscopy was performed in 791 patients, biopsy samples were taken of stations 2, 4 (both left and right), and 7 according to Naruke and associates’ map [11]. During thoracotomy biopsy samples were obtained from the N₁ nodes draining from the tumor, because the previous samples had been negative. In lower lobe operations, biopsy samples from stations 8 and 9 were also taken. Staging was postsurgical and done according to the New International Staging System For Lung Cancer [12].

Of the 834 patients with stage I NSCLC, 4 had gross residual disease and were excluded from the study. Of the remaining 830 patients, 802 underwent complete resection (the complete resection group). Twenty-eight patients had microscopic residual disease at the resection margin, which was accepted in 23 patients (the residual tumor group). The other 5 patients with residual tumor underwent a second thoracotomy right after the first operation (3 to 34 days) (the revision operation group).

During the operation in 13 patients in the residual tumor group (56.5%), frozen section microscopic studies of the bronchial resection margin were assessed. They revealed carcinoma in situ (CIS) in 4 and invasive tumor in 3 patients. This was accepted, and no further resection was done. We could not determine from the records why this decision was made at that time.

The pattern of microscopic residual disease at the resection margin was classified as CIS, mucosal residual disease (MRD), peribronchial residual disease (PRD), or lymphatic infiltration. Mucosal residual disease and PRD were defined as invasive tumor.

Recurrent disease was described as local or distant. Local recurrence was defined as tumor recurring within the thorax; distant recurrences were those occurring outside the thorax.

Follow-up data on survival were obtained until December 31, 1994. Follow-up data on recurrence were available in 97.5% of the patients in the complete resection group, 95.6% of the patients in the residual tumor group, and 100% of the patients in the revision operation group. Survival was estimated from the date of the operation using the Kaplan-Meier survival analysis method [13]. Patients dying within 30 days of operation were excluded from survival analyses. Differences in the observed survival between groups were tested for statistical significance using the log-rank test and were considered statistically significant if the p value was less than 0.05 [14].

	Results

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Microscopic residual tumor at the bronchial resection margin that was accepted postoperatively (residual tumor group) was found in 2.8% (23/834) of the patients (Table 1). This group consisted of 22 men and 1 woman, aged 52.4 to 76.5 years (mean, 65.8 years). The tumor was located in the right lung in 15 (65%) and in the left lung in 8 (35%) patients. Pneumonectomy had been performed in 5 (21.7%), sleeve lobectomy in 3 (13%), lobectomy in 13 (56.5%), and segmentectomy in 2 (8.7%) patients.

The revision operation group consisted of 4 men and 1 woman (5/834), aged 40.2 to 75.3 years (mean, 65 years). The tumor was located on the right side in 2 and on the left side in 3 patients. One sleeve lobectomy and three lobectomies were converted to pneumonectomy. In 1 patient the segmentectomy was converted to a lobectomy. Histologically there was squamous cell carcinoma in 4 and adenocarcinoma in 1 patient. The breakdown according to the pattern of residual disease was as follows: MRD in 3, CIS in 1, and MRD plus PRD in 1 patient. During the second thoracotomy the residual tumor was completely resected in all patients. Histologic examination of this material confirmed MRD in 2 patients and MRD plus PRD in 1 patient. In 1 patient the originally diagnosed MRD appeared to be CIS, and in another patient the presumed CIS turned out to be metaplasia at the revision procedure.

Mortality and Morbidity
The 30-day postoperative mortality in the 802 patients in the complete resection group was 3.5% (n = 28). There were no deaths within 30 days of operation and no bronchopleural fistulas in the residual tumor group. Neither did any of the patients in the revision operation group die within 30 days of the second thoracotomy, although 1 patient eventually died after 90 days because of intractable sepsis attributed to a bronchopleural fistula.

Postoperative Treatment
Four patients in the residual tumor group received adjuvant radiotherapy after recovery from the operation; this consisted of 40 Gray on the bronchial stump, hilum, and mediastinum administered in 20 sessions, with a surdosage of up to 60 Gray on the stump. One of these patients had CIS; 3 had MRD. No chemotherapy was given. No patients in the revision operation group received adjuvant therapy.

Survival
The overall 5-year survival in the complete resection group was 54% (n = 802). Patients in the residual tumor group (n = 23) had a 5-year survival rate of 43% (p = 0.09).

Survival was affected by the pattern of microscopic residual disease (Fig 1). The patients in the residual tumor group with invasive tumor (MRD or PRD) at the resection margin had a 5-year survival rate of 27.3% (p = 0.03), whereas the patients with CIS had survival rates equivalent to those in the complete resection group (58% versus 54%; p = 0.74).

View larger version (13K): [in this window] [in a new window]   Cumulative survival in patients in complete resection group (solid line), those with carcinoma in situ (dotted line), and those with invasive tumor (mucosal or peribronchial residual disease) (dashed line). Complete resection versus carcinoma in situ, p = 0.74; carcinoma in situ versus invasive tumor, p = 0.16; complete resection versus invasive tumor, p = 0.03.

Adjuvant radiotherapy did not improve survival in the patients in the residual tumor group. The median survival time in patients in this group receiving radiotherapy was 25.5 months, compared with 50 months in the remaining patients in the residual tumor group. None of the 4 patients who received adjuvant radiotherapy survived 5 years. If the patients with CIS are excluded from the groups with and without adjuvant radiotherapy, the median survival time becomes 27 months in the former and 38 months in the latter group.

The 5 patients in the revision operation group had a 5-year survival rate of 40%, with a median survival time of 38.4 months.

Recurrences
Disease recurred in 48.5% of the patients in the complete resection group, as compared with 72.7% of the patients in the residual tumor group. There were more local recurrences in the residual tumor group than in the complete resection group (Table 2). Of the 12 patients with local recurrence in the residual tumor group, 7 cases were detected by routine bronchoscopy, of which 6 were located at the bronchial stump.

View larger version (15K): [in this window] [in a new window]   Recurrence data broken down according to pattern of residual disease. (CIS = carcinoma in situ; CR = complete resection; MRD = mucosal residual disease; PRD = peribronchial residual disease; white bars = local recurrent disease; hatched bars = distant recurrent disease; black bars = local + distant recurrent disease.)

In the residual tumor group, adjuvant radiotherapy administered right after the original thoracotomy did not prevent local recurrences, which were all located in the ipsilateral hemithorax. Recurrent disease developed in all 4 of these patients after a median time of 18.5 months. Disease recurred after a median time of 34 months in 12 of the 19 patients who were not irradiated.

Comparison of the outcomes from surgical procedures in the residual tumor group showed that there were fewer local recurrences in the patients who underwent a pneumonectomy.

Skin metastasis occurred in 1 patient in the revision operation group 14 months after the second operation; she died 24 months later.

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This study shows that CIS at the bronchial resection margin does not affect the 5-year survival rate in patients with resected stage I NSCLC. The 5-year survival rate of 58% in this group is comparable to the 5-year survival rate of 54% in the complete resection group. Only small groups of patients with CIS at the bronchial resection margin have been described in the literature. Soorae and associates [5] found a 5-year survival rate of 70% in 10 patients with CIS, of which 4 had positive hilar nodes. Law and colleagues [4] found a 5-year survival rate of 66% in 9 patients with CIS but did not indicate the stage of disease. Tan and coworkers [10] found no difference in the survival rate between 6 patients with CIS in the resection line and patients with complete resection, but, again, the lung cancer stage was not mentioned.

We found that the survival rate in patients with invasive tumor at the resection margin (MRD or PRD) is significantly worse than that in patients who undergo complete resection. This differs from Gebitekin and associates’ [3] findings, who reported a 40.8% 5-year survival rate for 7 patients with resected stage I NSCLC with microscopic invasive tumor at the resection margin, compared with a 52% rate for patients with a complete resection. The difference was not statistically significant, which may be due to the small number of patients. Although others have not mentioned the survival of stage I patients explicitly, an adverse effect on survival when MRD or PRD is present has been noted [2][4][5][8][10].

In the present study the incidence of CIS was 1.4% and the incidence of invasive tumor was 1.3%, which is in line with data from other reports [2][3][4][5][6][7][9][10].

Recurrent disease, especially local recurrent disease, developed significantly more often in the residual tumor group than in the complete resection group. Surprisingly, it made no difference whether CIS or invasive tumor was found at the resection margin at the time of the thoracotomy. Why patients with CIS have the same percentage of recurrences but a better survival time than patients with invasive tumor at the resection margin could have to do with the higher number of resections of the recurrences in the patients with CIS (3/5 versus 1/7). A high incidence of local recurrences in patients with invasive tumor at the resection margin has been reported in the literature. Gebitekin and colleagues [3] found recurrences in 57% of their patients with stage I lung cancer with invasive tumor at the resection margin, which were all local. Kaiser and associates [8] noted recurrences in 56% of their patients with N0 disease and peribronchial tumor at the resection margin; 60% had local recurrent disease.

The bronchial stump was a frequent site of local recurrence in our patients in the residual tumor group. It was present in 6 patients, constituting 50% of all the cases of local recurrent disease. However, we found no stump recurrences in the revision operation group. Kaiser and coworkers [8] reported that 8 of their 45 patients with PRD had recurrence in the bronchial stump, constituting 72% of all their cases of locally recurrent disease. These high recurrence rates and the absence of stump recurrence in the revision operation group make us conclude that aggressive surgical therapy (ie, a revision operation, if possible) may prevent local recurrence and improve survival in patients with stage I NSCLC and microscopic invasive tumor at the resection margin. Furthermore, close follow-up with serial bronchoscopy is advisable in patients with a positive resection margin who cannot tolerate an extended surgical procedure shortly after thoracotomy. If recurrence develops, amputation of the stump or radiotherapy must be considered.

In the present study, patients with a positive resection margin derived no benefit from radiotherapy administered right after the original thoracotomy, in that there was neither a survival advantage nor a lower incidence of local recurrence. However, one has to be careful about drawing conclusions from this observation, because the number of patients is limited and because this is a retrospective study. In Gebitekin and colleagues’ study [3], patients with stage I lung cancer and a positive resection margin did not receive radiotherapy. The survival time in patients with stage II to IIIb lung cancer and a positive resection margin treated with adjuvant radiotherapy was not extended. Kaiser and associates [8] also reported that adjuvant radiotherapy had no effect on the development of recurrent disease in patients with PRD.

The patients in the revision operation group had a better survival rate and fewer recurrences than did the patients in the residual tumor group, although the difference was not statistically significant. Clearly this is a select group of patients who could tolerate a second thoracotomy immediately after the first one.

Despite the presence of invasive tumor or CIS at the bronchial resection margin, no bronchopleural fistulas developed in the residual tumor group. One patient in the revision operation group had a bronchopleural fistula. Except for Kaiser and colleagues’ results [8], an incidence of 9% to 22% was found in most studies [2][5][7][9].

In conclusion, the 5-year survival in patients after resection of stage I NSCLC with CIS at the resection margin is comparable to that in patients who undergo complete resection, although a high recurrence rate is to be expected. Survival in patients with MRD or PRD is shorter and recurrence more frequent than those in patients who undergo complete resection. The value of adjuvant radiotherapy is unclear. Aggressive surgical treatment (ie, a revision operation) should be considered in these patients. If the patient cannot tolerate an extended procedure, follow-up bronchoscopic evaluation of the stump is advisable.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We wish to thank Machteld van der Feltz, MD, and Hans C. Kelder, MD, for critically reviewing the manuscript.

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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