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Three Part Question

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

Clinical Scenario

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.

Search Strategy

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.

Search Outcome

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

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Law et al, 1982, UK	64 patients with positive resection margins from a total of 1000 pts undergoing lobectomy or pneumectomy from 1966-1975	Retrospective Cohort study (level 3b)	5 year survival	No evidence of recurrence or residual tumour survival 40% 9/29 (27%) with Mucosal spread 0/18 survivors with peri-bronchial spread (no 3 yr survivors) 1/8 (13%) Lymphatic permeation 6/9 (67%) for CIS	It was found that residual tumour did not adversely affect survival Only 7/26 with residual tumour suffered macroscopic bronchial stump recurrence
			Incidence of residual tumour	64/1000 patients (6.4%)
Liewald et al, 1992, Germany	21 patients with positive resection margins from 805pts undergoing lung resection from 1978-1988 mediastinal lymphadenectomy performed in 15 and Intraoperative frozen section performed in 8 of these 21 patients	Retrospective cohort study (level 3b)	Survival	Extramucosal microscopic residual disease median 10.3mth survival Mucosal microscopic residual disease median 26mth survival Eighteen of 21 pts received radiation therapy Two pts had completion pneumonectomy	Re-operation for pts with Stage I and II with N0 and N1 recommended, together with intraoperative frozen section of bronchial resection margin for all patients
			Incidence of residual tumour	21/805 Patients (2.6%)
			Intraoperative frozen section	4 of 8 patients with frozen section had residual tumour overlooked on first assessment.
Gebitekin et al, 1994, UK	40 patients with positive resection margins from 735 patients undergoing lung resection between 1980-1989 37.5% of patients received radiotherapy	Retrospective cohort study (level 3b)	5 year Survival	Positive bronchial resection margin 21.6% , median survival 15 mths. This was not improved with radiotherapy (18% RT versus 23% no RT) negative resection margin 32% (52% stage I, 37% stage II) p=NS	No statistically significant impact on survival with microscopic residual disease. No benefit with Radiotherapy
			Incidence of residual tumour	40/735 patients (5.4%)
			Recurrence	29/40 (72.5%) recurrence after median 17mths.
Snijder et al, 1998, Netherlands	23 patients who had positive resection margins from a total of 834 pts with resected stage I non small cell carcinoma from 1977-1993 13 patients had intraoperative frozen section 5 of 23 patients had re-resection	Retrospective Cohort study (level 3b)	5 year Survival	survival in resection group 54% In re-operation group survival was 40%	Residual disease significantly affects survival and further resection is recommended. Radiotherapy did not improve survival.
			Intraoperative frozen section	Of 8 studies CIS was found in 4 and invasive carcinoma in 3
			Radiotherapy	25mth median survival in radiotherapy group, 50mths in no RT group
			Incidence of residual tumour	23/834 patients (2.8%)
Lacasse et al, 1998, USA	25 patients with positive resection margins from 399 patients who had lung resection for tumour included in a prospective CT versus mediastinoscopy study from 1987-1990 199 patients suffered any recurrence	Retrospective analysis from a Prospective Cohort Study (level 3b)	3 year Survival	Positive resection margin 16/28(57%) recurrence. Negative resection margin184/374 (49%) recurrence p=NS	Concluded that positive resection margin did not impact survival Patients with positive resection margins received higher levels of adjuvant therapy
			Predictors of survival	Tumour size (OR 1.2) Nodal status (OR 1.6) but not positive resection margin
			Incidence of residual tumour	25/399 patients (6.2%)
Ghiribelli et al, 1999, Italy	47 patients with positive resection margins from 1384 patients from 1983-1998 All patients underwent complete mediastinal lymphadenectomy 2 completion pneumonectomy and 17 pts had radiotherapy.	Retrospective Cohort Study (level 3b)	5 year Survival	Stage I: no residual disease 68%, residual disease 50% Stage II : No residual 42%, residual 39% Stage III; Residual or no residual 16%. Median survival of 47pts was 22 months	Authors suggest frozen section for all patients undergoing lung resection. Pts with stage I-II and positive margins should have re-operation. Pts with N2 disease should not have reoperation
Hofman et al, 2002, Germany	26 patients with microscopic residual disease after 596 underwent lung resection from 1992-1997 frozen section and extended lymph node excision carried out in all patients 15/26 had post-operative radiation.	Retrospective Cohort study (level 3b)	Five yr survival	14% 5 year survival for patients with positive margins Post RT, median survival 14months, without RT, 6 months (p=NS) Extrabronchial residual tumor better survival	Poor survival for patients with positive margins but no significant benefit for radiotherapy.
			Detection with frozen section	9/15 patients who had frozen section but subsequent positive margins had this missed by the frozen section.
Lequalglie et al, 2003, Italy	56 patients who had residual disease at the bronchial resection margin from 4530 patients from 1988-1998 No patient with in situ Carcinoma was included. 18 pts received Radiotherapy, 2 received chemotherapy	Retrospective Cohort Study (Level 3b)	Survival in patients with residual tumour	Stage I untreated 1/8 had recurrence Stage I radiation 7/11 relapses	They recommend no additional resection or radiotherapy for patients with involved resection margins
			Survival compared to patients without incomplete resection	Stage I-II complete resection 64.5%-62.5% Stage I-II incomplete resection 66.1%-63.5%
			Incidence of residual tumour	56/4530 patients (1.2%)
Shields, 1974, USA	221 patients with microscopically incomplete resection from 2371 patients in the Veterans Administration adjuvant trials. 67 patients had incomplete resection from bronchial resection margin	Retrospective Cohort Study (Level 3b)	1 year survival	24 of 67 patients with incomplete bronchial resection margin survived 1 year 50% survival if residual tumour was microscopic only (25% 4 yr survival)	Very heterogeneous groups of patients reported. No recommendations for patients with microscopic residual tumour given
			Incidence of residual tumour at bronchial resection margin	67/2371 patients (2.8%)
Kaiser et al, 1989, USA	45 patients with microscopic extramucosal residual disease from 2890 patients undergoing lung resection from 1975-1985 All patients underwent complete mediastinal lymphadenectomy	Retrospective Cohort Study (Level 3b)	Survival	15 month median survival 20% 3 year survival 30% 3 year survival for patients with N2 disease with no residual tumour	Most patients had stage III disease when residual tumour was detected. Re-operation is recommended in patients with stage I-II tumours, but this is not supported by the evidence presented.
			Recurrence	81% had recurrence , 32% were local recurrence 81% had recurrence , 32% were local recurrence median survival after recurrence detection was 5 months
			Incidence of residual tumour	45/2890 patients (1.6%)
Heikkila et al, 1986, Finland	44 patients with microscopic residual tumour out of 1044 patients undergoing lung resection from 1961-1970 Most patients received post-operative radiotherapy.	Retrospective Cohort Study (Level 3b)	5 year Survival	34% for all patients, 48% for stage I tumour.	Post-operative radiotherapy recommended for residual tumour. No comparison group with no residual tumour given or a group without post-operative radiotherapy.
			Incidence of residual tumour	44/1044 patients (4%)
Jeffrey RM, 1972, UK	18 patients with bronchial residual tumour from 663 patients undergoing lung resection from 1952-1963.	Retrospective Cohort Study (Level 3b)	5 year Survival	6/18 (33%) patients with residual bronchial tumour 183/663 (27%) of all resections P=NS	No difference in mortality demonstrated
			Incidence of Residual tumour	18/663 patients (2.7%)
Sooare et al, 1979, Northern Ireland	64 patients with microscopic residual tumour from 434 patients undergoing lung resection from 1968-1972	Retrospective Cohort Study (Level 3b)	Survival	50% 1-year and 23% 5-year survival.	Non control group survival is reported. Survival was deemed to be similar to complete resection patients
			Incidence of Residual tumour	64/434 patients (14.7%)

Comment(s)

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.

Clinical Bottom Line

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.

References

1. Law MR, Hodson ME, Lennox SC. Implications of histologically reported residual tumour on bronchial margin after resection for bronchial carcinoma. Thorax 1982;37:492–495.
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. J Thorac Cardiovasc Surg 1992;104:408–412.
3. Gebitekin C, Gupta NK, Satur MR, Martin PG, Saunders NR, Walker DR. Fate of patients with residual tumour at the bronchial resection margin. Eur J Cardiothorac Surg 1994;8:339–344.
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. Ann Thorac Surg 1998;65:212–216.
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. Ann Thorac Surg 1998;65:220–226.
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. Eur J Cardiothorac Surg 1999;16:555–559.
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. Eur J Cardiothorac Surg 2002;21:606–610.
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. Eur J Cardiothorac Surg 2003;23:229–232.
9. Shields TW. The fate of patients after incomplete resection of bronchial carcinoma. Surg Gynecol Obstet 1974;139:569–572.
10. Kaiser LR, Fleshener P, Keller S, Martini N. Significance of extramucosal residualtumor at the bronchial resection margin. Ann Thorac Surg 1989;47:265–269.
11. Heikkila I, Harjula A, Suomalainen RJ, Mattila P, Mattila S. Residual carcinoma in bronchial resection line. Ann Chir Gynaecol 1986;75:151–154.
12. Jeffrey RM. Tumour remaining in the bronchial stump following resection. Ann Roy Coll Surg 1972;51:55–59.
13. Soorae AS, Stevenson HM. Survival with residual tumour on the bronchial margin after resection for bronchogenic carcinoma. J Thoracic Cardiovasc Surg 1979;78:175–180.