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Ann Thorac Surg 2004;78:245-252
© 2004 The Society of Thoracic Surgeons

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Original article: general thoracic

The effect of extent of local resection on patterns of disease progression in malignant pleural mesothelioma

^a Department of Thoracic Surgery, Glenfield Hospital and University Department of Oncology, Leicester, United Kingdom
^b Leicester Royal Infirmary, Leicester, United Kingdom

Accepted for publication January 22, 2004.

^* Address reprint requests to Dr Waller, Department of Thoracic Surgery, Glenfield Hospital, Groby Rd, Leicester, LE3 9QP, UK.
e-mail: david.waller{at}uhl-tr.nhs.uk

	Abstract

Top Abstract Introduction Patients and methods Results Comment Conclusion Acknowledgments References

 
BACKGROUND: We sought to determine whether or not there are differences in disease progression after radical or nonradical (debulking) surgical procedures for malignant pleural mesothelioma.

METHODS: Over a 49-month period, 132 patients with malignant pleural mesothelioma underwent surgery. Fifty-three underwent extrapleural pneumonectomy and 79 underwent nonradical procedures. Time to evidence of clinical disease progression was recorded, as was the site(s) of that disease.

RESULTS: One-hundred nineteen patients were evaluable, of which 59% (22 radical; 48 nonradical) had disease progression. Overall 30-day mortality was 8.5% (7.5% radical; 9% nonradical). The median time to overall disease progression was considerably longer after extrapleural pneumonectomy than debulking surgery (319 days vs 197 days, p = 0.019), as was the time to local disease progression (631 days vs 218 days, p = 0.0018). There was no preponderance of earlier stage disease in the radical surgery group. There was a trend toward prolonged survival in those undergoing radical surgery, but no significant difference between the groups (497 days vs 324 days, p = 0.079). In those who had extrapleural pneumonectomy, time-to-disease progression significantly decreased with N2 disease compared with N0/1 involvement (197 days vs 358 days, p = 0.02).

CONCLUSIONS: Extrapleural pneumonectomy may be preferable to debulking surgery in malignant pleural mesothelioma to delay disease progression and give greater control of local disease. Involvement of N2 nodes is associated with accelerated disease progression and is therefore a contraindication to extrapleural pneumonectomy.

	Introduction

Top Abstract Introduction Patients and methods Results Comment Conclusion Acknowledgments References

 
The incidence of malignant pleural mesothelioma (MPM) continues to increase [1–3] and no single regimen has substantially and repeatedly altered the natural history of the disease for the majority of those affected [4, 5]. Unfortunately, a widespread nihilistic attitude towards MPM among many physicians has, in many cases, limited the role of surgery to that of obtaining histologic diagnosis or achieving symptomatic control of pleural effusions [6].

Lung parenchyma-sparing procedures have been proposed to have a role in patients with prohibitive comorbid conditions [7, 8] and they have led to notable symptomatic improvements [9]. They have been successfully combined with local adjuvant treatments [10, 11]. Despite this, the theoretical benefits of maximal tumor cytoreduction have led to the advocacy of radical surgery as a worthwhile modality in this disease [5, 12–15] and, in this context, multimodality treatments incorporating surgery and chemoradiotherapy have been shown to be feasible [16] and even demonstrated considerable survival benefits in select patients [17, 18]. We sought to evaluate our single-center experience of surgery for MPM in an attempt to assess the contribution of the choice of surgical procedure to differences in the patterns or onset of disease progression comparing radical with nonradical procedures.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment Conclusion Acknowledgments References

 
Over a 49-month period, 132 patients underwent surgery for MPM. There were 121 men (92%) and 11 women (8%), with a median age at the time of diagnosis of 60 years (range 41–79 years). Fifty-three patients (40%) underwent radical surgery (median age 57 years) and 79 patients underwent nonradical procedures (median age 62.5 years). Within the nonradical group, 52 patients (39%) had open procedures (47 patients had tumor decortication and 5 patients had pleurectomy) and 24 (19%) had video-assisted thoracoscopic (VATS) interventions (6 patients had decortication and 18 patients had pleurectomy). Three patients (2%) had a localized chest wall tumor resection only and were further considered as part of the nonradical open-surgery group. Radical surgery, defined as extrapleural pneumonectomy (EPP), has been described in detail previously [19]. In variation to published techniques, the peritoneal cavity is opened with removal of the hemidiaphragm, which is then reconstructed with a single Gortex patch (W. L. Gore & Associates, Flagstaff, AZ). The hemipericardium is reconstructed with Prolene mesh (Ethicon, Somerville, NJ) in all cases. All patients undergoing radical surgery have a mediastinal lymphadenectomy of stations 4, 7, and 10 at the time of surgery. Any station 5 nodes are removed in left-sided resections. All lesser lung parenchyma-sparing resections ranging from parietal pleurectomy to parietal and visceral surface tumor decortication with removal of the pericardium and hemidiaphragm [8] constituted nonradical procedures. Two patients due to undergo EPP were found to have unexpected local invasion at thoracotomy and so underwent tumor decortication. Patients undergoing surgical diagnostic biopsy or pleurodesis alone were excluded.

Radiologic assessment was initially performed with posteroanterior (PA) chest roentgenogram and then with computed tomography (CT). Contrast-enhanced magnetic resonance imaging (CEMRI) was used as indicated, most frequently in the radical surgery cohort [20]. Fitness for surgery was assessed according to British Thoracic Society guidelines [21]. Operation selection was dependent on the apparent stage of disease after appropriate clinical and radiologic investigation, the presence or absence of confounding comorbid conditions, and fully informed discussion with the patient. Patients in the radical surgery group had nonsarcomatoid tumors confirmed preoperatively in accordance with local policy.

Using information from preoperative imaging, operative findings, and pathologic detail, the tumor (T) status, nodal (N) status, and the overall stage was obtained using accepted tumor-node-metastasis (TNM) systems [22, 23]. In the nonradical group, where pathologic information regarding mediastinal lymphadenopathy was incomplete, nodal status was derived from cross-sectional imaging (Table 1).

Patient demographic and operative details were collated using the departmental database and individual case notes were reviewed. Information regarding disease progression was categorized as either local, distant, or both. Where information was incomplete or absent, that patients' general practitioner was contacted in an attempt to collect as much complete information as possible.

Disease progression was defined as clinical or radiologic evidence of tumor with or without symptoms and with or without histologic or cytologic confirmation. In some cases, the presence or absence of tumor was confirmed or refuted at post-mortem examination. The boundaries of the pleural envelope on the operated side defined the distinction between local and distant progression. All noncontiguous disease outside of the pleural cavity was considered to be distant progression. This included distinct mediastinal lymphadenopathy arising after the original operative procedure, but did not include direct invasion into the mediastinum which was considered local progression.

Statistical analysis
Comparison of preoperative variables, patient demographics, and the distribution of the pattern of detected disease progression in the two groups at the time of investigation and according to T and N stage in the radical surgery group alone was compared with the ² test. The Kaplan–Meier method [24] was used to plot survival and time to progression curves with differences assessed using the log-rank test.

	Results

Top Abstract Introduction Patients and methods Results Comment Conclusion Acknowledgments References

 
There were four perioperative deaths (7.5%) in the radical surgery group and seven perioperative deaths (9%) in the nonradical surgery group. The overall 30-day mortality was 8.5% (11 patients). The median follow-up in the radical surgery group was 19 months (range 2–49 months, mean 22 months) and the median follow-up in the nonradical surgery group was 30 months (range 1–49 months, mean 26 months).

Histopathology
Histologic breakdown is detailed in Table 1. Sixteen patients (12%) in the radical surgery group were found to have microscopically involved resection margins, most frequently at sites of previous drain or VATS ports, which were macroscopically completely excised at surgery. These areas were irradiated after recovery from surgery. In the nonradical surgery group, although there was no formal quantification of tumor bulk, all patients had as a minimum, sufficient tumor debulking to ensure complete expansion of the lung on the operated side at the end of the procedure.

Overall disease progression
Of the 132 patients, 119 were evaluable and of these, 70 patients (53%) had evidence of disease progression. Pathologic confirmation was obtained and recorded in only 4 patients (6%). Two patients were in the radical surgery group (histology from an empyema cavity in one and ascitic fluid cytology in another) and 2 patients were in the nonradical surgery group (histology from a chest wall mass in one and ascites cytology in another). Of the 119 patients, at the time of analysis, 22 patients (18%) had died without evidence of tumor progression, 27 patients (23%) were alive without progression, 10 patients (8%) were alive with progression, and 60 patients (51%) had died with disease progression. Patients who died with no evidence of disease progression included those who died in the perioperative period. Causes of death included cardiac arrest secondary to acute right ventricular failure and respiratory failure from lower respiratory tract infection and pulmonary embolism.

The median time to first evidence of disease progression was notably longer in the radical surgery group compared with the nonradical surgery group (Fig 1). This difference was maintained irrespective of the approach to debulking (thoracotomy or VATS) (Fig 2). There was a significant difference in the distribution of disease progression between the two groups (p = 0.0071) with a greater proportion of those patients undergoing nonradical surgery having local disease progression (Table 2).

View larger version (20K): [in this window] [in a new window]   Fig 1. Time to evidence of disease progression. The median time to disease progression in the radical surgery group was 319 days compared with 197 days in the nonradical surgery group, p = 0.019.

View larger version (24K): [in this window] [in a new window]   Fig 2. Time to evidence of disease progression (subdivided into three operative groups). The marked difference in time to evidence of progression was preserved when the nonradical group was subdivided into open and thoracoscopic procedures (319 days in the radical group and 177 days and 232 days, respectively, in the nonradical groups, p = 0.038). (VATS = video-assisted thorascopic surgery.)

View this table: [in this window] [in a new window]   Table 2. Sites of First Disease Progression After Surgery (p = 0.0071, df = 2, 2)

View larger version (134K): [in this window] [in a new window]   Fig 3. Ipsilateral chest wall progression after extrapleural pneumonectomy.

View larger version (117K): [in this window] [in a new window]   Fig 4. Abdominal progression after extrapleural pneumonectomy.

View larger version (121K): [in this window] [in a new window]   Fig 5. Pleural cavity progression after nonradical surgery.

View larger version (20K): [in this window] [in a new window]   Fig 6. Time to evidence of local disease progression. The median time to evidence of local disease progression in the radical surgery group was 631 days compared with 218 days in the nonradical surgery group, p = 0.0018.

The effect of histologic subtype on disease progression
In the radical surgery group, epithelial histology was associated with delayed disease progression when compared with the biphasic subtype (364 days; 275 days, p = 0.008). This was also seen in the nonradical surgery group (epithelial 223 days; biphasic 162 days; sarcomatoid 62 days, p = 0.0005). When those patients with only epithelial disease were considered, radical surgery patients had a significantly longer median time-to-disease progression than did those from the nonradical surgery group (Fig 7).

View larger version (21K): [in this window] [in a new window]   Fig 7. Time to evidence of disease progression (comparing radical and nonradical surgery groups with epithelial histology only). When considering those patients with epithelial histology alone, the median time to evidence of disease progression in the radical surgery group was 364 days compared with 223 days in the nonradical surgery group, p = 0.0035. (EPP = extra-pleural pneumonectomy.)

Predictors of disease progression
In those patients who underwent EPP, patients with N0 or N1 disease were seen to have a significantly longer median time from operation to evidence of overall disease progression than those with N2 disease (Fig 8). There was, however, no significant difference in the distribution of disease progression according to T stage (p = 0.29) or N stage (p = 0.14) in the radical surgery group at the time of analysis and N2 disease did not lead to more rapid distant disease progression (p = 0.22). Isolated local disease developed in only 1 out of 16 patients with incomplete resection margins as the first evidence of progression.

View larger version (18K): [in this window] [in a new window]   Fig 8. Disease progression within the radical surgery group (stratifying for nodal stage). Within the radical surgery group alone, the median time-to-disease progression in those patients with N0/N1 disease was 358 days compared with 197 days for those patients with N2 disease, p = 0.02.

	Comment

Top Abstract Introduction Patients and methods Results Comment Conclusion Acknowledgments References

 
This retrospective review of the patterns of disease progression after radical and nonradical surgical procedures represents one of a limited number of direct comparisons to date [13, 25]. It demonstrates a considerable delay in time-to-clinical disease progression between the two groups of patients which was maintained for local progression alone. In addition to this, a greater proportion of patients in the radical surgery group were found to have stage 3 and stage 4 disease compared with the nonradical group (88% vs 41%, respectively). It is conceded that, had more frequent cross-sectional imaging been employed in the follow-up of these patients, it is possible that the interval-to-onset of disease progression may be different. However, clinical evidence of disease progression is far more realistic and important to the patients themselves. That was the primary reason for choosing this particular end-point.

The main aim of nonradical operative procedures was to allow complete lung expansion and prevent the reaccumulation of malignant pleural fluid in an attempt to improve quality of life by reducing dyspnea. Given the less extensive nature of the surgical procedures involved and that complete macroscopic clearance of tumor is rarely achieved in nonradical surgery for MPM, it was not surprising to find the high incidence of local disease progression (48% of all progression, 71% of the nonradical group). This is very much consistent with the published data. In a comparative study from Pass and associates [13], locoregional recurrence was noted in 90% of patients undergoing debulking pleurectomy and in a phase II trial from Rusch and associates [26], local recurrence was again noted in the majority of patients (80%) despite the use of intrapleural and systemic chemotherapy. It is noteworthy that in the radical group, this figure is much reduced (10% of all progression, 32% of the radical group). Combining the figures of those who presented with local progression and those with local and distant progression, local progression overall in the radical surgery group becomes 68%. This is comparable with three previous studies that examined the patterns of failure after EPP with or without adjuvant chemotherapy and radiotherapy, where the percentages of local disease recurrence were 67% [27], 54% [28] and 83% [29]. However, the different end-point considerations and data presentation make comparisons liable to inaccuracies. For example, in a study from Aziz and associates [30], local recurrence is given as 12% of the total number of patients undergoing EPP. It is unclear as to whether any patients suffered disease recurrence in more than one site, but considering local disease only and looking at the total number of patients in the radical group and not just those with progression, in this study the figures are again comparable with 13% of all EPP patients with evidence of local disease progression first.

One of the study limitations is the lack of histologic or cytologic confirmation of progression. This information was only available from 4 patients. Given the nature of MPM, if the attending clinician was satisfied by history and examination (coupled with diagnostic imaging) that disease progression was apparent, pathologic confirmation might never be sought. Only in times of diagnostic difficulty would a patient be exposed to yet another procedure, likely to have little bearing on the plan of management. It is probable that this would explain the low rates of pathologic confirmation of disease progression.

Despite published examples of the potential benefits of multimodality therapy [17, 31, 32], current UK practice rarely considers aggressive multimodality management of patients with pleural mesothelioma. It is the experience of the authors that, after surgery for this disease, most patients are advised that adjuvant treatment should be postponed until a time of symptom recurrence. This is based largely on the lack of randomized controlled-trial evidence for any therapy in this condition [33]. This explains the almost single-modality treatment seen in this narrative. In an attempt to encourage the use of adjuvant chemotherapy and also to assess its feasibility, neoadjuvant chemotherapy has been used in a small number of patients.

In this series, the patients in the radical surgery group experienced substantially better performance status and had better preoperative prognoses. There were also more patients with epithelial histology than in the nonradical group. Although this reflects the unavoidable bias from a lack of randomization inherent to a retrospective study, it also explains to some degree the decision-making process in terms of patient selection for a particular operation. There were 15 patients in the radical surgery group who were found to have pathologic stage IV disease. Although in 1 patient this was due to transdiaphragmatic involvement of tumor (which may have been identified by laparoscopic assessment), the other 14 patients had transmural pericardial involvement which was not identified preoperatively. This did not compromise resectability and there is evidence to suggest that it may not be as considerable in terms of prognosis as previously thought [20].

The study revealed that patients with N2 disease were found to progress over a notably shorter period of time than those with N0/N1 disease. The obvious assertion is that they have more advanced occult disease initially. If this were the case, it is likely that patients with N2 disease would present with evidence of distant progression before local disease. This is not borne out by the findings in this study, however, at present, the numbers available for this subset analysis is small. Also, increased systemic dissemination would seem unlikely to be a reason for the observed high rates of local disease progression even in N2 disease. Previously, cross-sectional imaging determined nodal size and was relied upon before radical surgery. As work within our unit has shown that nodal size does not predict malignancy [34], it is now routine to perform cervical mediastinoscopy before radical resection. In a number of cases, this explains the pathologic finding of N2 disease.

There are limitations in the staging of the nonradical surgery patients in this series which may underestimate the presence of N2 positive disease in this group. Because of the less extensive nature of the surgery, few people in the nonradical cohort underwent lymphadenectomy and therefore pathologic correlation with preoperative cross-sectional imaging was very limited. This may mean that the true pathologic stage of the nonradical surgery group would be closer to that seen in the radical group. However, there is currently no evidence suggesting that the results can be explained solely by stage differences.

The definitions of local and distant disease progression were an attempt to separate those patients with disease progression due to tumor growth within the operated pleural cavity and those with true metastatic spread. However, the situation is less clear with abdominal progression. Through correlation of survival data with the degree of pleural involvement, Boutin and associates were able to show that the parietal and diaphragmatic pleural surfaces were the first to become involved with tumor [35]. Furthermore, the Butchart staging system describes direct penetration of tumor through the diaphragm into the peritoneal cavity as stage III [36]. There is no doubt that this does occur, but it would also seem possible to have distinct metastatic abdominal progression. In this study, 4 patients within the radical surgery group had evidence of abdominal disease progression with no radiologic evidence of disease within the pleural cavity on cross-sectional imaging (Fig 4). Interestingly, the peritoneal cavity is opened in all the patients undergoing EPP at our center without a disproportionate increase in abdominal progression which may question the protective value of the intact peritoneum.

	Conclusion

Top Abstract Introduction Patients and methods Results Comment Conclusion Acknowledgments References

 
The assessment and management policies within this unit have markedly evolved over time. A greater number of patients are now undergoing radical surgery than at the beginning of the study period.

This work adds further weight to the contention that maximal tumor cytoreduction by EPP in medically fit patients is preferable to debulking surgery in the management of patients with MPM because it delays the onset of overall disease progression by providing greater local disease control. Furthermore, the observation that N2 nodal involvement is associated with accelerated disease progression emphasizes the importance of this factor in operative selection. Future work should focus on the potential survival benefit offered by EPP balanced against the detrimental effect on quality of life.

	Acknowledgments

Top Abstract Introduction Patients and methods Results Comment Conclusion Acknowledgments References

 
The authors thank James J. Entwisle, MD, FRCR, and Kanagaratnam Jeyapalan, MD, FRCR, for their assistance in the radiologic assessment of these patients. Duncan J. Stewart is supported by a University Hospitals of Leicester NHS Trust Research Fellowship.

	References

Top Abstract Introduction Patients and methods Results Comment Conclusion Acknowledgments References

 

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