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Ann Thorac Surg 2006;81:434-439
© 2006 The Society of Thoracic Surgeons
a Department of Cardiothoracic Surgery, Allegheny General Hospital, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
b Department of Radiation Oncology, Allegheny General Hospital, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
c Division of Thoracic and Foregut Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
Accepted for publication August 25, 2005.
* Address correspondence to Dr Birdas, The West Penn Center For Lung and Thoracic Disease, 4815 Liberty Ave, Ste 158, Pittsburgh, PA 15224 (Email: tbirdas1{at}aol.com).
Presented at the Forty-first Annual Meeting of The Society of Thoracic Surgeons, Tampa, FL, Jan 24–26, 2005.
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Abstract |
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METHODS: We retrospectively reviewed 167 stage Ib NSCLC patients: 126 underwent lobectomy and 41 sublobar resection with 125 I brachytherapy over the resection staple line. Endpoints were perioperative outcomes, incidence of recurrence, and disease-free and overall survival.
RESULTS: Patients undergoing sublobar resections had significantly worse preoperative pulmonary function. Hospital mortality, nonfatal complications, and median length of stay were similar in the two groups. Median follow-up was 25.1 months. Local recurrence in sublobar resection patients was 2 of 41 (4.8%), similar to the lobectomy group: 4 of 126 (3.2%; p = 0.6). At 4 years, both groups had equivalent disease-free survival (sublobar group, 43.0%; median, 37.7 months; and lobectomy group, 42.8%; median 41.8 months, p = 0.57) and overall survival (sublobar group, 54.1%; median, 50.2 months; and lobectomy group, 51.8%; median, 56.9 months; p = 0.38).
CONCLUSIONS: Sublobar resection with brachytherapy reduced local recurrence rates to the equivalent of lobectomy in patients with stage Ib NSCLC, and resulted in similar perioperative outcomes and disease-free and overall survival, despite being used in patients with compromised lung function. We recommend the addition of intraoperative brachytherapy to sublobar resections in stage Ib patients who cannot tolerate a lobectomy.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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All patients underwent preoperative clinical and radiologic staging with computed chest tomography. We do not perform routine surgical staging of the mediastinum, but rather use it selectively [10]. All procedures were performed by one of three surgeons (R.H.M., R.J.K., or R.J.L.). The decision to perform a lobectomy or a lesser resection was undertaken preoperatively, based on the patient's overall medical condition and, particularly, preoperative pulmonary function [11], represented by the forced expiratory volume in one second and the carbon monoxide diffusion capacity. For patients who had no available preoperative diagnosis of malignancy, intraoperative confirmation by surgical biopsy was obtained before the definitive treatment. The mediastinal lymph nodes were sampled intraoperatively in a systematic fashion.
The technique of I125 brachytherapy has been previously described in detail [8]. Briefly, the implant consists of a polyglyconate mesh (Ethicon, Somerville, New Jersey) on which polyglyconate sutures with embedded 125 I seeds were sewn at 1-cm spacing to achieve a prescribed dose of 10,000 to 12,000 cGy to a 0.5 cm depth. The implant was then applied on the resection line, after frozen section examination confirmed the absence of microscopically positive margin. The application was performed thoracoscopically or through the thoracotomy incision. The postoperative management was similar to that of other patients with lung resections. No isolation or special precautions were required.
All patients were followed up at 3 weeks and at 3, 6, 12, 18, and 24 months postoperatively and yearly thereafter. Chest radiographs were obtained on every clinic visit. Computed tomography scans were obtained at 3 months and at all yearly visits. We defined recurrence patterns according to previous reports [2]. Local recurrence was defined as evidence of tumor within the same lobe, the hilum, or the mediastinal nodes; and distant recurrence wa defined as evidence of tumor in any other lobe or outside the hemithorax. In addition to information from our database, mortality data were obtained from the Social Security Death Index. Endpoints for this report were incidence of perioperative outcomes, recurrence rates, and disease-free and overall survival.
The Institutional Review Board at Allegheny General Hospital approved the study in August 2004. The need for individual informed consent was waived. Statistical analysis was performed with the use of StatView 5.0 (SAS Institute, Carey, North Carolina). The 
2 test was used for dichotomous variables and Student's t test for continuous variables. Survival analysis was performed using the Kaplan-Meier method and the log-rank test. Adjusted survival analyses were obtained with the Cox proportional hazards model. The level of statistical significance was set at p less than 0.05.
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Results |
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The overall survival curves and disease-free survival curves are shown in Figures 1 and 2,
respectively. At 4 years, both groups had equivalent disease-free survival (sublobar group, 43%; median, 37.7 months; and lobectomy group, 42.8%; median, 41.8 months; p = 0.57) and overall survival (sublobar group, 54.1%; median, 50.2 months; and lobectomy group, 51.8%; median, 56.9 months; p = 0.38). Risk factors were examined in a univariate model; those with a p value less than 0.2 were included in a multivariate proportional hazards survival analysis. Only older age was found to be an independent negative prognostic factor for overall survival (p < 0.015). These results are shown in Table 3.
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Comment |
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In the years after publication of the LCSG study, several reports, primarily from Japan, suggested that segmental resections may be equivalent to lobar resection for small peripheral stage I tumors. In recent years, an increasing number of high-risk patients who cannot tolerate a formal lobar resection are referred for surgical treatment. Sublobar resections, which are associated with lower perioperative mortality and morbidity rates [16, 17] and preserve lung function compared with lobectomy [18], may be the only surgical options in these patients. Other modalities, primarily local external beam radiation at the staple line ("postage stamp" therapy) have been tested as adjunct therapies [19], in an attempt to decrease the local recurrences. Although effective, such treatments usually necessitate wide radiotherapy fields and are unavoidably associated with significant compliance problems.
These concerns led us [7] and others [9] to explore an alternative route of administering radiotherapy to patients undergoing sublobar resections, namely, the use of intraoperative brachytherapy over the resection line. We have previously reported a significant reduction of local recurrences in a group of stage I patients (23% with stage Ib) compared with a historical group of patients undergoing sublobar resection alone [8]. Fernando and coworkers [20] recently reported a comparison between high-risk patients with stage Ia tumors undergoing SR/B and a contemporary group of patients undergoing lobectomy. Again, the addition of intraoperative brachytherapy reduced the local recurrence rates to levels equivalent of the lobectomy patients. Of interest, no survival difference was seen among patients with tumors less than 2 cm in size, whereas lobectomy patients with tumors between 2 and 3 cm experienced a survival benefit—although the number of cancer deaths was similar in the two groups.
In the current report, we examined the effects of intraoperative brachytherapy when applied to high-risk patients with stage Ib NSCLC, comparing that group with a contemporary group of patients of similar stage undergoing lobectomy. Our results are in concordance with previous findings. In this high-risk group of patients, perioperative outcomes were similar to those of lobectomy patients. Local recurrence was 4.8%, not significantly different from that of the lobectomy group (3.2%). One of the two recurrences occurred in a patient with positive resection margins on permanent pathology. This finding emphasizes the importance of reliable frozen pathologic examination when sublobar resections are undertaken. Distant recurrences, as well as disease-free and overall survival, were equivalent in the two groups. Although lobectomy patients had larger tumors on average, tumor size within this group of T2N0 patients was not a significant negative predictor for disease-free or overall survival. This finding is not unexpected, as there are generally no reported differences in survival between T2 tumors with visceral invasion only compared with T2 tumors larger than 3 cm, regardless of the method of treatment. From the different factors examined, only age was shown to have a negative effect. In addition, within the SR/B group, no survival differences were seen between thoracoscopic and open resections or between wedge and segmental resections. Although both local recurrences occurred in patients who underwent a thoracoscopic wedge resection, the small number of events precludes any meaningful analysis.
The main limitation of the study lies in its retrospective nature. As a result, the two groups contained patients with different baseline characteristics; high-risk patients were considered unfit for a more extensive resection. We used preoperative pulmonary function tests as a surrogate of the high operative risk. Undoubtedly, several other criteria are important; they differ between surgeons and cannot always be quantified and studied. Additionally, a sublobar resection would not be technically feasible in all patients who underwent a lobectomy, for example, in patients with more centrally located T2 tumors. As we were not able to compare the number of lymph nodes sampled, and therefore the adequacy of intraoperative evaluation of the mediastinum, in the different groups, it is possible that some of our patients in the thoracoscopic SR/B group were understaged. In that case, the true SR/B long-term outcomes would be even better than the ones reported. Although a recent study of thoracoscopic wedge resections showed that thoracoscopic sampling was feasible in only half of the patients [19], there have been several other reports of thoracoscopic anatomic resections that showed no difference in the efficacy of mediastinal nodal evaluation between open and thoracoscopic approaches [21, 22]. Similar considerations apply to the only histologic difference between the two groups: many more bronchioloalveolar tumors, generally considered more favorable prognostically, were seen in the lobectomy group. Even though this was not a significant factor in univariate analysis, the effect, if any, would reinforce our findings.
Despite these limitations, we believe our findings merit further consideration. We believe that these results should be confirmed in a prospective trial. Although the American College of Surgeons Oncology Group (ACOSOG) has designed a prospective multi-institutional study comparing adjuvant brachytherapy with sublobar resection versus sublobar resection alone in high-risk patients with stage Ia NSCLC (ACOSOG 4032), patients with tumors larger than 3 cm are not included in the current trial scheme (T2 tumors less than 3 cm with visceral pleural invasion are included). Based on our findings, it would appear reasonable to broaden the inclusion criteria to involve all patients with stage I tumors for whom a sublobar resection is technically feasible.
In conclusion, the addition of intraoperative brachytherapy to sublobar resection in high-risk patients with stage Ib NSCLC resulted in similar recurrence rates and long-term survival compared with lobectomy. Adjuvant brachytherapy should be considered for all patients with stage Ib who cannot tolerate a lobectomy.
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Discussion |
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DR BIRDAS: We did not get routine postoperative pulmonary function tests, definitely not in the lobectomy group. We did get some in the sublobar group. I don't have any concrete data to show. We do have data, however, that show that segmental resections alone without brachytherapy are associated with preserved PFTs.
DR ARA A. VAPORCIYAN (Houston, TX): I enjoyed your presentation very much. I have a couple of questions. What was the extent of the nodal dissection that was performed for the sublobar resections? I noticed that most of the wedge resections were done by VATS, and I was interested in hearing if those patients also received a complete nodal dissection or a similar nodal assessment as the lobectomy patients did?
The second question has to do with the fact that this was a retrospective study. Based on that, I would assume that the decision to proceed with a sublobar resection was based on poor pulmonary function. Since these patients wouldn't be offered a lobectomy anyway, wouldn't another comparison group be external beam radiotherapy for those patients and see how the outcome of a sublobar resection compares with external beam definitive radiotherapy?
DR BIRDAS: I'll start by addressing the second question first. I think that is obviously an excellent idea. As I said, there was a recent CALGB trial 4 or 5 years ago that looked at that. It didn't compare with brachytherapy, of course. I think that would be a good idea to do in the future. There were some problems associated with that study, though, with regard to compliance. I think probably less than 60% or so of patients were able to complete their external beam postage stamp radiation. So that is something we can improve in the future.
Regarding the first question, our database did not differentiate between the extent of dissection with regard to a sampling or complete dissection. I do have a comment about the VATS. These patients, who actually happen to be even older and higher risk than the rest of the population, did not have a full nodal sampling, so it is possible that some of them could have been understaged—but their results were still not worse.
DR STEPHEN R. HAZELRIGG (Springfield, IL): I guess one of the comments I was going to make is based on a comparison of these two groups, which I think is a little bit awkward, but instead I will emphasize that I do think this technique may hold some promise. We have begun to use this I-125, although very strictly, for patients who we previously would have done a wedge resection and added the postage stamp, as we've referred to it, radiation for local control, which required numerous trips back and forth to the hospital over a period of several weeks and did encompass usually a little wider field. This allows it to be done at the same setting, and for locations like ours where we treat patients in a large rural area, it has some big advantages. It's all done at the same time. And it really doesn't cook the lung because it delivers the brachytherapy over a very short, about 1 mm, 2 mm depth of penetration. So we have followed our pulmonary functions, and it really has seemed to be a pretty good way to spare the lung. Although I don't think we should liberalize our indications for resection, I would emphasize that just for those patients who you truly previously would have done a wedge and added postoperative radiation, this seems to potentially be a good alternative, although it needs more study.
DR JAMES D. LUKETICH (Pittsburgh, PA): I enjoyed the talk, Dr Birdas. How many of these patients had upper lobe predominant disease in the setting of emphysema, and did you do V/Q scans to assess the function or the perfusion to the lobe that you were attempting to save? We know from the NETT trial and other studies out there that some of these lobes, especially upper lobe predominant emphysema, have very little function. So doing a wedge or a segmental with brachytherapy to a lung that has very little perfusion, a lobe that has very little perfusion, to me would be maybe too much effort. Did you try to assess that before you made the decision to attempt to preserve part of that lobe?
DR BIRDAS: That's an excellent question. I do not have information, and our database did not differentiate between the different sides of the lobe, so I can't answer that, but that is definitely something to consider in the future prospective trials.
DR LEWIS WETSTEIN (Freehold, NJ): Thank you for an extremely interesting modality. I rise because you stated that no specific precautions have to be taken with this technique. Should the surgeon sewing this in be concerned? Obviously, his hands are being continuously radiated; should that not be cause for alarm?
DR BIRDAS: That's a good question. I should add that it's actually the radiation oncologist who prepares the implant, and then, of course, the surgeon who puts it in. I have always noticed that our radiation oncology colleagues seem to be a little more cautious than what they expect us to be, but they told me that there shouldn't be any problem with that.
DR RICARDO S. SANTOS (Pittsburgh, PA): I congratulate Dr Birdas and his colleagues in the reporting of this interesting investigation of adjuvant intraoperative brachytherapy after resection of stage I nonsmall cell lung cancer. I had an opportunity to work with these investigators in a recent study of this approach, but we did not focus upon the effect of tumor size on the recurrence pattern (Santos et al. Surgery 2003;134:691-7).
I have a comment regarding the question brought forward by Dr Cerfolio. I believe that the "oral tradition" proselytized regarding the lack of postoperative pulmonary functional change between lobectomy and sublobar resection is erroneous. This belief is based upon misinterpretation of the data from the previously reported results of the Lung Cancer Study Group trial of sublobar resection versus lobectomy for stage IA nonsmall cell lung cancer (Ginsberg RJ, Rubenstein LV. Ann Thorac Surg 1995;60:908-13). Although expounded otherwise, the final table of results reported from this study did demonstrate significant differences in postoperative pulmonary function between sublobar resection and lobectomy patient groups at intervals of follow-up measured out to a year postoperatively. These differences in postoperative function favoring sublobar resection has been corroborated by earlier work from this group at Allegheny General Hospital (Keenan, et al. Ann Thorac Surg 2004;78:228-33).
I also agree that use of a uniform definition of local/regional recurrence is a critically important issue as we move forward in the investigation of the utility of sublobar resection and other treatment modalities (ie, radiofrequency ablation or focused high-dose radiotherapy) for peripheral nonsmall-cell lung cancers. The intended investigation by ACOSOG of sublobar resection with or without adjuvant brachytherapy for physiologically compromised patients with peripheral nonsmall-cell lung cancer will utilize such a strict definition for local and regional recurrence. This definition will also be applied to a companion phase 1 trial proposed by ACOSOG investigating the role of radiofrequency ablation for similar patients.
Finally, the early results of the recently completed ACOSOG-30 trial, described earlier in this meeting by Dr Mark Allen, has assisted us in recognizing the present day perioperative morbidity associated with anatomic lung resection for stage I nonsmall-cell lung cancer. The maturation of the results of this trial will also help us to better understand the patterns of recurrence after anatomic resection by segmentectomy and lobectomy for stage 1 lung cancer. These results will help us to define the risk/benefit relationships for conventional surgical management of early-stage peripheral lung cancers.
DR DAVID W. JOHNSTONE (Lebanon, NH): How did you follow these patients for local recurrence, and did you see a difference in patterns of where the local recurrence—were recurrences in the parenchyma or the nodes?
DR BIRDAS: Both of the local recurrences in the sublobar group were indeed in the parenchyma. In the lobar group, 1 of 4 was at the stump and then the other 3 were in the mediastinum. As to the follow-up, the follow-up was the routine postoperative visits with radiographs and CT scans. We get CT scans usually at 3 months. These are stage I patients. Usually we get them at 3 months, a year, and then yearly thereafter, and radiographs are taken at every visit.
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