Should Lobectomy or pneumonectomy patients with microscopic involvement of the bronchial resection margin undergo re-operation to improve their long-term survival?

December 7, 2005

December 8, 2005

Balasubramanian S, Au J., Cardiothoracic Registrars (Department of Cardiothoracic Surgery, Blackpool Victoria Infirmary, Department of Cardiothoracic Surgery, James Cook University Hospital)

Joel Dunning, Department of Cardiothoracic Surgery, Blackpool Victoria Infirmary, Department of Cardiothoracic Surgery, James Cook University Hospital

In [patients post lung resection with microscopic bronchial residual tumour] is [re-operation] of any benefit for [long-term survival].

You performed a right lower lobectomy on a 67-year-old gentleman who had a 4-cm squamous cell carcinoma of the right lower lobe. He is a life long smoker and his tumour was staged as T2 N0 pre-operatively. You are now due to see him in your clinic but you discover that the histologist found a tumour involving the bronchial resection margin. You wonder whether to offer this patient completion pneumonectomy or whether to send him to an oncologist for post-operative radiotherapy and spare him this additional operation. Thus, you resolve to search the literature before seeing him that afternoon.

Medline 1966–May 2005 using the OVID interface

[exp Pneumonectomy/OR Pneumonectomy.mp OR lung resection.mp] AND [exp Neoplasm, Residual/OR exp Neoplasm Recurrence, Local/OR incomplete resection.mp OR bronchial resection margin.mp] AND [exp Survival/OR Survival.mp OR exp Mortality/OR mortality.mp] limit to humans.

A total of 427 papers were found of which 14 papers were relevant

Thirteen studies were found, all of which were cohort studies reporting the survival of patients with histologically identified residual tumour at the bronchial resection margin.
Law et al. in 1982 reported 64 patients who had microscopic involvement of the bronchial resection margin. They found the patients with mucosal bronchial involvement had better survival than other forms of residual tumour and almost as good as when no spread had been apparent at surgery. Of the 26 patients with mucosal bronchial margin involvement, only seven subsequently developed a macroscopic recurrence of tumour. The 5-year survival for patients with full resection was 40%, and for patients with mucosal involvement was 27%. Survival analysis showed this difference to be non-significant.

Liewald et al. described 21 patients with microscopic involvement. They found that the median survival was only 12.1 months, which was a poor survival rate. Of the 21 patients, 18 had radiotherapy and two had completion pneumonectomy. They suggested that re-operation should be performed for patients with Stage I and II disease with N0 and N1 spread and intraoperative frozen section should be performed in all patients undergoing lung resection to confirm full excision. They also found that patients with squamous cell carcinoma had better prognosis than adenocarcinoma.

Gebitekin et al. studied 40 patients with microscopic involvement of bronchial margin of the 735 patients who underwent pulmonary resection. Of the 40 cases with positive bronchial stump, 29 developed recurrence at a median of 17 months. Median recurrence for stage I was 30.5 months and stage II was 15 months, stage IIIa was 8.5 months and stage IIIb was 10.5 months. Overall five-year survival rate with patients with positive margin was 21.6% in contrast to the negative margin of 32%. This was not a statistically significant difference. They found no significant survival advantage for patients with stage I and II disease. They also found no advantage for these patients with adjuvant radiotherapy.

Snijder et al. reported 23 patients with residual bronchial margin out of 834 patients who underwent resections. Five of the group underwent second thoracotomy for residual tumour. Five-year survival for patients with complete resection was 54% and in patients with residual tumour group it was 27%. They found that adjuvant radiotherapy did not improve survival in the patients with residual tumour. The median survival for patients receiving radiotherapy was 25.5 months and for revision operation it was 38.4 months. Disease recurred in 48.5% of the patients in the complete resection group as compared to 72.7% of the patients in the residual tumour group. Thus, patients with positive resection margins had a significantly poorer outcome and further resection was recommended if possible.

Lacasse et al. reported 25 patients with positive bronchial margin. Sixteen of the 25 patients had recurrence and 10 of the 25 received adjuvant radiotherapy. They compared their survival to the total study population of 399 patients. Fifty-seven percent of patients with positive margins had recurrence compared to a 49% recurrence rate in the overall resection group which was not a significant difference. They concluded that positive resection margins did not significantly impact on survival.

Ghiribelli et al. described 47 patients with positive bronchial resection margins. Thirty patients had extramucosal and 17 had mucosal involvement. Survival was lower for patients with positive resection margins. The authors reported four false negative intra-operative frozen sections as the extrabronchial tissue was not fully assessed. Bronchial stump recurrence was 55% but there were no stump recurrences in patients who underwent completion pneumonectomy. They recommend intraoperative frozen section for all patients. They recommend re-operation for Stage I and II patients.

Hofmann et al. reported 26 patients with microscopic spread out of 596 patients who underwent pulmonary resection. Twenty patients of the microscopic residual tumour were Stage IIIa. They reported 11 patients with false negative frozen section, the majority of them involving the peribronchial group. Fifteen patients received radiotherapy. Five year survival was 14% for all recurrence patients. They found no significant difference in survival between patients who did and did not receive post-operative radiotherapy in the N2 group (14 vs. 6 months).

Lequaglie et al. reported on 56 patients out of a cohort of 4530 patients with positive margins. 25/56 patients (44.6%) developed disease relapse. Sixteen patients had loco-regional and nine had distant metastases. Overall 5-year survival was 44%. They found a similar prognosis for patients with stage I and II patients with microscopic residual disease to that of completely resected tumour, with a 5-year survival around 65%. They concluded that neither re-operation nor radiation therapy impacted survival.

Five further studies are tabulated, reporting cohorts from 1955 to 1985 (Shields, Kaiser, Heikkila, Jeffrey, Soorae).

In summary in these 13 papers, the incidence of residual tumour ranged from 1.2% to 14% with most reporting incidences around 2–4%. Two studies recommend intra-operative frozen section for all patients to minimise the possibility of residual tumour being missed although 4 papers reported patients missed using this strategy. Only 4 studies recommend re-operation with the remaining papers reporting no significant difference in survival for patients with residual tumour. Of the 4 studies recommending re-operation, all recommend this only for stage I or II tumours. In addition there was no good evidence that radiotherapy improved survival for these patients and only one paper recommended radiotherapy as a treatment option.

For patients with stage I–II tumours who could easily tolerate re-operation, further resection is an acceptable treatment option and may improve survival. However, only 4 of the 13 studies that we identified recommend this strategy. In addition, there is no convincing evidence that radiotherapy significantly improves survival for patients not selected for re-operation.

1. Law MR, Hodson ME, Lennox SC.. Implications of histologically reported residual tumour on bronchial margin after resection for bronchial carcinoma.
2. Liewald F, Hatz RA, Dienemann H, Sunder-Plassmann L.. Importance of microscopic residual disease at the bronchial margin after resection for non-small-cell carcinoma of the lung.
3. Gebitekin C, Gupta NK, Satur MR, Martin PG, Saunders NR, Walker DR.. Fate of patients with residual tumour at the bronchial resection margin.
4. Snijder RJ, Riviere AB, Elbers HJJ, Van den Bosch J.. Survival in resected stage I lung cancer with residual tumour at the bronchial resection margin.
5. Lacasse Y, Bucher HC, Wong E, Griffith L, Walter S, Ginsberg RJ, Guyatt GH.. Incomplete resection' in non-small cell lung cancer: Need for a new definition.
6. Ghiribelli C, Voltolini L, Paladini P, Luzzi L, DiBisceglie M, Gotti G.. Treatment and survival after lung resection for non-small cell lung cancer in patients with microscopic residual disease at the bronchial stump.
7. Hofman HS, Taege C, Lautenschlager C, Neef H, Silber RE.. Microscopic (R1) and macroscopic (R2) residual disease in patients with resected non-small cell lung cancer.
8. Lequalglie C, Conti B, Brega Massone P, Giudice G.. Unsuspected residual disease at the resection margin after surgery for lung cancer: fate of patients after long term follow up.
9. Shields TW.. The fate of patients after incomplete resection of bronchial carcinoma.
10. Kaiser LR, Fleshener P, Keller S, Martini N.. Significance of extramucosal residualtumor at the bronchial resection margin.
11. Heikkila I, Harjula A, Suomalainen RJ, Mattila P, Mattila S.. Residual carcinoma in bronchial resection line.
12. Jeffrey RM.. Tumour remaining in the bronchial stump following resection.
13. Soorae AS, Stevenson HM.. Survival with residual tumour on the bronchial margin after resection for bronchogenic carcinoma.