| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
a Division of Thoracic Surgery, Rush University Medical Center, Chicago, Illinois
b Section of Medical Oncology, Rush University Medical Center, Chicago, Illinois
Accepted for publication April 22, 2009.
* Address correspondence to Dr Liptay, University Thoracic Surgeons, 1725 W Harrison St, Ste 774, Chicago, IL 60612 (Email: michael_liptay{at}rush.edu).
Presented at the Forty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Jan 26–28, 2009.
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsCommentDiscussionReferences |
|---|
Methods: We reviewed medical records from patients undergoing concurrent chemoradiation therapy, followed by pneumonectomy (1983 to 2007). Clinical variables affecting Kaplan-Meier survival were analyzed.
Results: After chemoradiation therapy, 129 pneumonectomies (right, 65; left, 64) were performed. Postoperative pathologic stages were complete responders (CR), 21; I, 23; II, 19; III, 62; and IV, 4. The 90-day perioperative mortality was 20% (13 of 65) after right-sided pneumonectomy vs 9% (6 of 64) after left-sided pneumonectomy (p = 0.084). Complications occurred in 33% (43 of 129), including bronchopleural fistula in 12% (16 of 129) and acute respiratory distress syndrome in 2% (3 of 129). Overall 5-year survival was 33%. Survival was 32% for right-sided sections vs 34% for left-sided. CR patients had a 5-year survival of 48%. Survival of patients with postoperative N0, N1, and N2 nodes was 42%, 26%, and 28%, respectively. Multivariate analysis showed the development of major complications negatively affected 5-year survival for patients undergoing right-sided pneumonectomy (hazard ratio, 0.462; p = 0.0399).
Conclusions: Pneumonectomy after concurrent chemoradiation therapy achieved long-term survival. When neoadjuvant therapy resulted in complete response or nodal downstaging, survival was improved. The risk of early perioperative death and complications was higher for right-sided procedures, but long-term survival did not differ between right- and left-sided pneumonectomy. Major complications negatively affected 5-year survival with right-sided pneumonectomies.
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
|---|
The long-term benefits and risks of pneumonectomy (especially right-sided) after neoadjuvant chemoradiation therapy remain controversial. The purpose of this study was to evaluate the perioperative risks and long-term survival associated with pneumonectomy for advanced non-small cell lung cancer (NSCLC) after concurrent chemoradiation therapy.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
|---|
Institutional Review Board approval was obtained to perform this retrospective review. Individual patient consent was waived for this retrospective study.
The age, gender, chemoradiation therapy regimen, histopathology, preoperative and postoperative T N M stage, 90-day mortality, major complications, and survival were recorded. Major complication were defined as bronchopleural fistula (BPF), cardiac arrhythmia, acute respiratory distress syndrome (ARDS), respiratory secretions requiring bronchoscopic intervention, pneumonia, myocardial infarction, pulmonary embolism, and recurrent laryngeal nerve injury.
Clinical Considerations
Locally advanced disease was defined as the presence of central disease (T3 N0), or positive mediastinal lymph nodes (N2 disease). Mediastinal lymphadenopathy was confirmed by cervical mediastinoscopy or radiographic evidence of disease, including (1) the presence of lymphadenopathy in the mediastinum greater than 2.0 cm on short axis, or (2) the presence of the aforementioned lymphadenopathy with positive findings on positron emission tomography (PET), defined as more than maximum standard uptake value of 2.5. Radiographic staging alone was relied on more frequently in the earlier time period, whereas PET scan and mediastinoscopy were used more systematically later in the study period. Patients with contralateral mediastinal lymph node involvement (N3 status 1) and limited stage IV disease (isolated brain 4) were also included but the number was very small.
The study excluded patients who were initially given chemoradiation therapy in a neoadjuvant setting but in whom progressive disease developed that precluded surgical resection.
Chemotherapy was given concurrently with split-course radiotherapy in all of the regimens used. Chemotherapy consisted of platinum-based regimens. Before 1994, the regimen consisted of cisplatin and 5-fluorouracil. Etoposide was added later. After 1994, the regimen changed to carboplatin, paclitaxel, and etoposide; eventually, etoposide was eliminated. There were some variations in these regimens. The mean split-course radiation dose was 4299 cGy (range, 4000 to 4500 cGy), although there were minor variations.
Right-sided and left-sided pneumonectomies were performed in a standard fashion. No special distinction was given to pneumonectomies requiring intrapericardial dissection. Carinal pneumonectomies were not included in this analysis. Pneumonectomies performed for other malignancies such as mesothelioma, metastatic disease, and neuroendocrine malignancies were excluded.
Lymphadenectomy, and not lymph node sampling, was performed for all of the pneumonectomies. The right-sided resections underwent dissection of the level 2, 4, 7, 8, 9, 10, and 11 lymph node stations. The left-sided resections underwent dissection of the level 5, 6, 7, 8, 9, 10, and 11 lymph node stations.
For right-sided resection, routine stump coverage with a pleural or pericardial fat pad buttress was performed. Closure of the bronchus was routinely accomplished by stapling.
Statistical Methods
Kaplan-Meier 5-year survival curves were generated based on the time from pneumonectomy. All univariate comparisons of survival were made with log-rank tests and represent virtually all of the p values in this article. The exception to this was in the use of 
2 analysis to generate a p value in comparing the differences in the 90-day perioperative mortality between left-sided and right-sided resections. A multivariate analysis using a Cox proportional hazard regression model was performed to evaluate the effect of several covariates on the side of resection. Additional clinical considerations and values of p 
0.1 on univariate analysis were determined the factors that would be used as the variables. Statistical analysis was performed using SAS 9.1 software (SAS Institute Inc, Cary, NC). Significance was defined as p < 0.05.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
|---|
Overall, complications occurred in 43 of the 129 patients (33%), including BPF in 16 (12%) and ARDS in 3 (2%; Table 1). Other complications were cardiac arrhythmias, empyema without BPF, respiratory secretions or pneumonias requiring bronchoscopic intervention, recurrent laryngeal nerve injury, myocardial infarction, esophageal injury, intraoperative hemorrhage.
|
Overall 5-year survival was 33% (Fig 1). Univariate analysis of several factors on 5-year survival was performed (Table 2). Survival of right-sided (32%) vs left-sided resections (34%) was not significantly different (Fig 2).
|
|
|
|
|
|
|
|
|
|
Comment |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
|---|
The overall mortality associated with pneumonectomy has been reported to be 6% to 12% [7–10]. Despite a few reports citing 30-day and 90-day mortality rates within ranges similar to when no neoadjuvant chemotherapy has been used [11–14], the addition of neoadjuvant therapy to pneumonectomy has been thought to increase the already elevated mortality [5, 15]. Right-sided pneumonectomy specifically has been associated with a mortality of 12% to 37%, even in the absence of neoadjuvant chemoradiation therapy [7, 10, 16, 17]. When distinguished by laterality, right-sided pneumonectomy has been associated with increased mortality rates of 24% to 36% [5, 18, 19]. On the other hand, there has been evidence to the contrary as other investigators have found that after neoadjuvant chemotherapy, right-sided pneumonectomy can have either a significantly lower mortality or no increased mortality compared with pneumonectomies in general [1, 13, 20–22].
The overall perioperative mortality in this study was 16%. The definition of perioperative mortality occurring within a 90-day window from the date of the operation rather than a 30-day window was because several of the deaths within 90 days were considered related to the pneumonectomy. Furthermore, the 90-day mortality rate has been substantially greater than 30-day rate and is believed to be a more accurate representation of the sequelae associated with pneumonectomies [5, 13, 15]. Perioperative deaths appeared to be intimately associated with complications that developed during the postoperative stay or during the close postoperative follow-up period.
Although long-term survival did not differ, the difference in outcomes was fairly dramatic when the 90-day perioperative mortality rate between left- and right-sided pneumonectomies was evaluated. From our extensive clinical experience, we believe that the higher 90-day perioperative mortality rate for right-sided pneumonectomy simply does not represent an anecdotal finding that only approaches significance; rather, we believe this is a very real and meaningful concern that warrants more attention than the statistical analysis supports. This series represents one of the larger neoadjuvant chemoradiation therapy followed by pneumonectomy-only experiences; however, it still may have had insufficient power to drive the observed difference to significance.
A review of the data (not shown) revealed that the date of the operation did not affect the morbidity and mortality observed for the entire series. Although there was some minor variability among the surgeons performing the pneumonectomies, these resections were performed, largely, in a similar manner using a stapled bronchial closure for either left- or right-sided resection, with routine pericardial fat pad or pleural flap coverage on the right side.
The 30% incidence of morbidity in this series was similar to that associated with pneumonectomies after neoadjuvant therapy [11]. The findings from the multivariate analysis underscored the negative effect of the development of major perioperative complications demonstrated by the univariate analysis. This investigation supports previous observations and provides additional information with respect to the use of concurrent neoadjuvant chemoradiation therapy that suggests the development of BPFs negatively affect survival [15, 23]. This complication is more prone to develop in right-sided pneumonectomies even without neoadjuvant chemotherapy [17]. Reports showing an absence in an increased incidence of BPFs between right and left-sided pneumonectomies [13] notwithstanding, most clinicians intuitively believe and others have, in fact, demonstrated a higher BPF incidence in right-sided pneumonectomies after neoadjuvant chemoradiation therapy [15]. The multivariate analysis performed by Gudbjartsson and colleagues [24] demonstrated an association between BPF formation and right pneumonectomy after preoperative chemoradiation therapy.
Observations such as these, as well as the results reported in this article, support the role of any reasonable measures to prevent bronchial stump disruption. Also, the right-sided stumps in this series were routinely buttressed with pleura or pericardial fat pad. Although it could be argued that this technique did not result in a significant decrease in the incidence of BPFs after pneumonectomy, it is possible that the incidence of BPFs could have been higher without this added measure.
The 2% incidence of ARDS in this series was on the lower end of spectrum of the 0.5% to 11% incidence that has been reported after pneumonectomy, either with or without induction therapy [3, 13, 17, 24–27]. However, the 90-day mortality rate of 100% that we observed is consistent with the high perioperative mortality rate reported in other studies [6, 25–27]. All of the ARDS cases occurred after right-sided pneumonectomy, supporting the recommendations of judicious administration of intravenous fluids, prevention of mediastinal shifting, and promotion of aggressive pulmonary toilet [28].
The overall 5-year survival in this series was 33%. This figure is consistent with that reported for pneumonectomies performed after neoadjuvant therapy [21]. Downstaging of disease suggested a survival benefit in this series. This effect was greatest among patients who achieved a complete response of the primary tumor and lymph nodes (T0 N0) with neoadjuvant therapy. Even without complete tumor sterilization, the results of this study suggest that when the mediastinal lymph nodes alone were downstaged, especially to an N0 status, there was a survival benefit. This finding was consistent with other investigations of nodal downstaging positively affecting long-term survival [29, 30].
As expected, the presence of pathologically positive N2 disease in this series was associated with a worse survival compared with N0 disease. Nonetheless, survival after resection of N2 disease was still acceptable given that patients had locally advanced disease at the onset of treatment. Also, when patients with N2 disease were evaluated by laterality of resection, 6 of 20 (30%) who underwent left-sided and 7 of 34 (21%) who underwent right-sided pneumonectomy were still alive 5 years after their resections. Although not an ideal rate of survival, this suggests that pneumonectomy in the presence of pathologically positive N2 disease should not be considered as devastating as is often believed if discovered either intraoperatively or postoperatively, even when performing a right-sided pneumonectomy.
However, given the high perioperative mortality rate and the lower 5-year survival, when right-sided pneumonectomy is being contemplated after neoadjuvant chemoradiation therapy, we recommend invasive mediastinal restaging to confirm the absence of persistent N2 lymph node disease. Having the benefit of this retrospective study, we believe that right-sided pneumonectomy should not be offered in the subset of patients with positive N2 involvement after therapy. Understood in this recommendation is that extenuating circumstances may justify a right-sided pneumonectomy. Despite the possibility of a potentially fatal complication, if this operation is to be considered, a lower—yet still acceptable—5-year survival can still be achieved. It is up to the discretion of the clinician to select the optimal patient to undergo a pneumonectomy under these specific conditions.
This study has several limitations. First, as with all retrospective studies, the data were collected post hoc.
Second, a tissue diagnosis for mediastinal lymph node involvement was not secured in most patients. The argument against this was that we showed a survival with positive N2 disease to be acceptable. These findings were consistent with Mansour and colleagues' [22] reported 5-year survivals for the patients who underwent induction chemotherapy. Clinical criteria of N2 disease using imaging studies alone have been reported in investigations that have demonstrated the absence of any detrimental effect of neoadjuvant therapy [3, 14].
Third, an attempt was made to collect pulmonary function studies of the patients undergoing surgical resection. However, these data were incomplete or not collected in approximately one-third of the study population. Therefore, it was not possible to determine preoperative pulmonary condition of the patients.
Similarly, a fourth limitation was that it was difficult to determine if other preoperative comorbidities that were documented in patients preoperatively contributed to the deaths observed in the postoperative period. Therefore, our survival did not represent a disease-specific mortality. In reality, had the patients who died from their other comorbidities been excluded, this would have only increased the observed survival.
Finally, the downstaged groups that were compared represented a heterogeneous group of patients, and this heterogeneity may have diluted the comparisons made regarding downstaging.
In conclusion, this study demonstrated that with respect to pneumonectomy, side does matter under certain circumstances. In general, long-term survival can be achieved after concurrent chemoradiation therapy irrespective of side of pneumonectomy. The greatest survival benefit derived from neoadjuvant therapy resulted when there was a complete response or nodal downstaging.
The risk of early perioperative death, BPF, and ARDS was higher for right-sided pneumonectomy, but overall, 5-year survival did not differ between right-sided and left-sided resections. The development of any major perioperative complication, however, negatively affected long-term survival after right-sided pneumonectomies. Even when positive mediastinal lymph nodes were removed, reasonable long-term survival was achieved. However, we believe that when right-sided pneumonectomy is being contemplated after neoadjuvant therapy, the presence of persistent positive N2 disease should preclude resection due to the high perioperative morbidity and lower long-term survival. This reason alone, above all others, is justification for performing invasive mediastinal restaging before resection is considered.
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
|---|
DR KIM: The most consistent and constant change throughout the experience was probably in the surgeons performing the operations. If you look at the entire experience, we are talking about four surgeons. I'm sure that how each individual surgeon approached their pneumonectomy varied to some degree.
That being said, we stapled the bronchus in all of these cases. For the right side, it was routine that we performed stump coverage with either a pleural flap or pericardial fat pad. So there were certain constancies in that respect.
From the chemotherapy standpoint, there were variations in the management as the regimens evolved. Ultimately, there were basically four iterations total, but they were all platinum-based regimens.
Lastly, the administration of the split course radiation therapy was modified. Early in the series, our radiation oncologists would use a shorter course of therapy with higher fractionated dosages. Over time, the interval for the administration of radiation therapy increased with a concomitant lowering of the dosage. The use of three preoperative cycles did not vary.
DR SWANSON: And the tests didn't cluster by time?
DR KIM: No, they did not and that is actually something we reviewed. It appeared that there was an even distribution over the entire time period.
DR PAUL DE LEYN (Leuven, Belgium): Thank you for this very nice presentation. It clearly shows that you can indeed perform right pneumonectomy in selected cases after chemoradiotherapy.
I have two questions. My first question is your incidence of bronchopleural fistula after right pneumonectomy is 12%. This is quite high despite buttressing the bronchus. Can you tell us something about the technique, and do you use nowadays another technique to buttress the bronchial stump?
And then the second question. In patients with persistent N2 disease, you had 5-year survival of 24%, which is very good. How were these patients selected? How did you stage your patients? Did you use PET? How did you restage your patients?
DR KIM: With respect to your first question, technically not much has changed. We are still buttressing with pericardial fat, pleura, and mediastinal tissue. When we looked at our numbers, the incidence of BP fistulas on the right surprised us. We didn't expect it to be that high.
A review of our operative records indicated that, technically, each pneumonectomy was performed in a similar manner with the aforementioned stapled closures and buttressing with pericardial fat pad, pleura, or mediastinal tissue. Muscle flaps and intercostal muscle were not used. Many of these cases were advanced cancers and extensive dissection was required.
With respect to your second question regarding our 5-year survival of 28% for resections with positive N2 lymph nodes, we did not employ any special algorithm in patient selection. We relied on restaging with the CT scan after the third cycle of neoadjuvant therapy. In the early part of the series, clinically positive N2 disease was defined by CT evidence of nodes larger than 2 cm in largest dimension. Selected cases had mediastinoscopy. PET scan coupled with CT scan was a major factor in the later portion of the series.
DR JEAN DES LAURIERS (Quebec, Canada): I would like to know how reliable is a mediastinoscopy after you have done a previous one and the patient has had radiotherapy over the mediastinum. I ask this question because you recommend that patients be restaged surgically which usually means by way of mediastinoscopy. From my experience, it would be very difficult to have accurate sampling and do a safe operation in such patients.
DR KIM: Based on our data, we now recommend that invasive mediastinal staging be considered. Cervical mediastinoscopy does not necessarily have to be the approach used. Bronchoscopic-guided needle biopsy or EUS for certain nodal stations is certainly an acceptable alternative.
Repeat cervical mediastinoscopy following neoadjuvant therapy, like repeat cervical mediastinoscopy in any other setting, warrants greater caution in avoiding the pitfalls. In the future, EBUS may be the method to initially stage mediastinal nodes with cervical mediastinoscopy reserved for restaging.
DR DES LAURIERS: Is Dr Faber your mediastinoscopist? I don't know if he is—he's right here, yeah.
DR JOSHUA R. SONETT (New York, NY): I enjoyed your presentation. I think it's another third or fourth series that bespeaks to the safety of pneumonectomy after chemo and radiation since the Intergroup trial.
I would just say that the buttressing is not all equal, and most of your complications and probably mortality were related to the BPF on the right. And if you switch to muscle flaps, either intercostal muscle or serratus, you may see that BPF rate go to an amazingly low rate. That's all, no other question.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  A. W. Kim, D. J. Boffa, Z. Wang, and F. C. Detterbeck An analysis, systematic review, and meta-analysis of the perioperative mortality after neoadjuvant therapy and pneumonectomy for non-small cell lung cancer J. Thorac. Cardiovasc. Surg., January 1, 2012; 143(1): 55 - 63. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. W. Kim, M. J. Liptay, P. Bonomi, W. H. Warren, S. Basu, E. C. Farlow, and L. P. Faber Neoadjuvant Chemoradiation for Clinically Advanced Non-Small Cell Lung Cancer: An Analysis of 233 Patients Ann. Thorac. Surg., July 1, 2011; 92(1): 233 - 243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. G. Fernandez, S. D. Force, A. Pickens, P. D. Kilgo, T. Luu, and D. L. Miller Impact of Laterality on Early and Late Survival After Pneumonectomy Ann. Thorac. Surg., July 1, 2011; 92(1): 244 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Krasna Reply to the Editor J. Thorac. Cardiovasc. Surg., March 1, 2010; 139(3): 807 - 807. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
N1 or N1 