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a Department of Thoracic and Cardiovascular Surgery, University of Texas, MD Anderson Cancer Center, Houston, Texas
b Department of Thoracic Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas
c Department of Radiation Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas
d Department of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida
e Department of Surgery, Scott and White Clinic, Temple, Texas
Accepted for publication April 23, 2007.
* Address correspondence to Dr Rice, Department of Thoracic and Cardiovascular Surgery, Box 445, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (Email: drice{at}mdanderson.org).
Presented at the Fifty-third Annual Meeting of the Southern Thoracic Surgical Association, Tucson, AZ, Nov 8–11, 2006.
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Abstract |
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Methods: One hundred consecutive patients underwent EPP. At a median interval of 2.5 months from surgery, 63 patients received IMRT (median dose 45 Gy) with curative intent. Chemotherapy was not routinely administered.
Results: Tumors were right sided in 66 patients (66%) and nonepithelioid in 33 (33%). American Joint Committee on Cancer pathology stage was I in 6 patients (6%), II in 7 (7%), III in 72 (72%), and IV (T4) in 15 (15%). Fifty-four patients (54%) had ipsilateral nodal metastases. Perioperative mortality was 8%. Median overall survival (n = 100) was 10.2 months. For patients who received IMRT (n = 63), median overall and 3-year survival was 14.2 months and 20%. Of these, node-negative patients with epithelioid histology (n = 18) had median and 3-year survival of 28 months and 41%. Distant recurrences occurred in 33 of 61 evaluable patients (54%). Eight patients (13%) had local or regional recurrence, 5 of whom also recurred distally. Only 3 patients (5%) had recurrence within the irradiated field.
Conclusions: Intensity-modulated radiation therapy after EPP results in excellent local control for malignant pleural mesothelioma; however, distant metastases remain a significant problem and limit survival. This provides a strong rationale for combining aggressive local regimens with systemic therapy.
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Introduction |
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The addition of hemithoracic radiotherapy after EPP has recently been shown to reduce local recurrence rates; however, conventional radiation has two significant limitations. First, after EPP, the hemithorax and mediastinum have an irregular shape and are adjacent to critical structures such as the spinal cord, liver, kidneys, esophagus, heart, and contralateral lung, which tolerate radiation poorly. Second, the posterior diaphragmatic sulcus, which may reach as far posteriorly as the L2 vertebra, is difficult to adequately target using conventional techniques [7]. Intensity-modulated radiation therapy (IMRT) has the potential to conform radiation doses tightly to target volumes. In addition, IMRT can reduce normal tissue toxicity compared with standard techniques, and in other disease sites with complex target volumes, IMRT generally results in superior dose distributions compared with those resulting from conventional techniques [8, 9].
Our initial experience with 32 patients with malignant pleural mesothelioma who were treated with IMRT after EPP showed that local control of tumor was excellent, and the regimen was well tolerated [10]. We here review our experience with 100 consecutive patients who were treated with EPP with the intention of receiving IMRT postoperatively.
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Material and Methods |
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The technique for extrapleural pneumonectomy has been well described elsewhere [12]. The diaphragm and pericardium were resected and reconstructed in all cases. The anteromedial and posteroinferior margins of resection and other areas considered to be at high risk for recurrence were marked with radioopaque clips to aid in radiation planning, as previously described [13]. All patients underwent postsurgical staging according to the 2002 American Joint Committee on Cancer (AJCC) Manual for Staging of Cancer, sixth edition.
Adjuvant Therapy
After recovery from surgery, surviving patients of adequate performance status and without tumor recurrence were evaluated for radiation therapy. The techniques of IMRT for mesothelioma have been well described previously [14, 15]. The clinical target volume was irradiated to either 45 Gy or 50 Gy (median 45 Gy), according to a dose escalation protocol. Areas at high risk for recurrence received a boost dose to a total of 60 Gy. Systemic chemotherapy was not routinely administered. Six patients (6%) received neoadjuvant chemotherapy, which included systemic agents for 5 patients and intrapleural cisplatin for 1. Postoperative chemotherapy was administered only to 1 patient.
Follow-Up
Patients were followed up with regular CT scans of the chest every 3 to 4 months. In accordance with criteria previously adopted in other studies of radiation therapy after EPP [7, 16], local tumor progression was defined as an increasing radiographic abnormality within, or partially within, the irradiated field. Recurrences adjacent to, but not within, the irradiated field were classified as marginal miss recurrences. Recurrences in proximity to, but not immediately adjacent to the irradiated field were classified as regional recurrences. Tumor recurrence in the contralateral hemithorax or abdominal cavity were classified as distant recurrence.
Statistical Methods
Survival was measured from the date of surgery in all cases. Survival probabilities were calculated by the method of Kaplan and Meier. Univariate Cox regression analysis was used to determine the prognostic significance of preoperative and tumor-related variables on overall and disease-free survival. Factors associated with a p value of 0.25 or less were included as variables in a multivariable Cox regression model, using stepwise backwards elimination of variables. A p value of 0.05 or less was considered to be statistically significant.
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Results |
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Seventy-three patients (73%) had at least 1 postoperative complication (Table 2). The majority of cardiac events were atrial arrhythmias, which were easily treated medically. Two patients had fatal myocardial infarction, one intraoperatively and the other on the first postoperative day, despite having had normal preoperative cardiac evaluations. Acute respiratory distress syndrome occurred in 8 patients (8%) and was fatal in 3, and 17 patients (17%) had postoperative pneumonia. There were 2 cases (2%) of bronchopleural fistula within 30 days of surgery; however, delayed fistulae developed in 2 other patients at 2.6 and 2.9 months postoperatively. Three bronchopleural fistulae followed right pneumonectomy, and only 1 occurred during postoperative radiation treatment. One patient had fatal pulmonary embolism on the third postoperative day; however, 2 other patients died of pulmonary embolism at 4 and 9 months after surgery. Technical complications included 1 case of cardiac herniation in a patient who had undergone right-sided EPP, 2 cases (2%) of diaphragmatic mesh dehiscence with liver herniation, bleeding requiring reoperation in 4 (4%), pleural space infection in 6 (6%), left recurrent laryngeal nerve injury in 2 (2%), chylothorax in 2 (2%), and 1 case of fatal intraoperative hemorrhage from a tumor that was adherent to the superior vena cava.
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Survival
Median, 2-year, and 3-year survival for the entire cohort (n = 100) was 10.2 months, 26%, and 19%, respectively (Fig 1). Patients with epithelioid tumors (n = 67) had median, 2-year, and 3-year survival of 15 months, 36%, and 27%, respectively, whereas median survival of biphasic and sarcomatoid tumors was significantly shorter at 6 and 3 months, respectively (p < 0.001; Fig 2,
Table 3). Of 9 patients with sarcomatoid tumors, none survived longer than 15 months, and only 1 of 24 patients with biphasic histology lived longer than 3 years. Factors significant on multivariate analysis for longer survival included female sex, epithelioid histology, negative nodes, and lower preoperative white blood cell count (Table 4). For disease-free survival, female sex, epithelioid histology, and negative nodes were independent predictive factors (data not shown).
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Factors significant for longer survival on multivariate analysis included epithelioid histology and absence of nodal metastases. Although significant on univariate analysis (p = 0.039), female sex was not significant in the multivariate model. Patients with epithelioid tumors and negative nodes and who received IMRT (n = 18) had median, 2-year, and 3-year survival of 28 months, 61%, and 41%, respectively. Because a recent report suggested that IMRT after EPP resulted in a high rate of fatal pneumonitis, we examined late deaths after radiation treatment. Of 63 patients, there were only 2 deaths within 6 months of IMRT from radiation pneumonitis; however, an additional 4 patients died of pneumonia during this period. These data are presented in detail elsewhere [16, 17]. Thirteen patients (13%) are currently alive at a median of 35 months from surgery, and 8 patients (8%) are without evidence of disease.
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Comment |
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Our current data show that the use of IMRT can provide effective local tumor control after EPP. Overall locoregional recurrences (which included in-field, marginal misses, and regional recurrences) occurred in only 13% of patients, and true local (in-field) recurrences were documented in only 3 patients (5%), of whom 2 also had distant metastases. Of the 3 cases (5%) of marginal miss recurrences, 2 occurred early in our experience and were undoubtedly due to failure to appreciate the true preoperative extent of the tumor. One patient recurred at the medial edge of the anterior pleural reflection, and in retrospect the radiation treatment contours did not adequately cover this region. We now place titanium clips at the medial and inferior margins of dissection to better identify the volume at risk, and carefully compare preoperative CT scans with the planning CT to ensure that the full extent of the tumor and pleural reflections are covered by the radiation field. Another patient treated early in our series failed at the ipsilateral diaphragmatic crus at the L1 vetrebral level, and upon review of the initial treatment plan, it was evident that the radiation field did not extent this far. We agree with Yajnik and others that the radiation field should encompass the ipsilateral crus to the level of the L2 vertebra. The third marginal miss occurred in a contralateral anterior diaphragmatic lymph node. The node was not evident on the planning CT scan, was remote from the reconstructed pericardium, and was not located in an area that one would normally target with radiation. With close attention to the preoperative tumor extent, and with collaboration between the radiation oncologist, physicist, and surgeon, local recurrences can be avoided in the vast majority of cases.
Despite good local control, we observed a significant number of patients who developed distant recurrences. The incidence and pattern of distant recurrences are similar to what has been shown in other series of EPP. For example, Baldini and coworkers [4] reported failure in the contralateral chest in 33% of patients and abdominal failure in 26%. More recently, Rusch and colleagues [17] showed that distant recurrences occurred in 64% of patients after EPP with hemithoracic radiation at sites that included the lung, bone, and liver. Fifteen patients in our study had evidence of intrapulmonary metastases, and others developed recurrences in the liver, bone, and adrenal glands. Indeed, several autopsy studies have revealed distant metastases in 75% to 80% of cases [19, 20]. The high rate of distant failure provides a strong rationale for the incorporation of systemic treatment into the treatment algorithm for patients with this disease. Although we did not routinely administer chemotherapy to patients in the current study, it is now our practice to include systemic therapy either preoperatively or after surgery and radiation.
Thirty-day postoperative mortality after EPP has been reported to be as high as 31%; however, in most recent studies, the rates are significantly lower (3.2% to 11%) [2, 3, 21–23]. Our 30-day postoperative mortality rate of 8% lies well within this range, and although higher than the lowest reported rates, likely reflects the fact that the majority of patients had relatively advanced disease and that almost a third of patients were over 65 years of age. Rates of postoperative events were similar to other series reported in the literature. Overall survival was probably most influenced by the overwhelming preponderance of advanced stage tumors (87% p-stage III or IV). In agreement with previous studies, we found that nonepithelioid histology and nodal metastases independently predicted shorter survival [2, 3, 24]. Interestingly, sex had a major impact on outcome, with women experiencing significantly longer overall survival than men. However, when we analyzed only patients who received IMRT, sex was no longer predictive. This suggests that the effect of sex may have less to do with oncologic advantage than with differences in postoperative survival. In fact, histology and nodal status were similar among men and women, and all deaths that occurred within 90 days of surgery were of men. A detrimental effect of male sex on survival after surgery for mesothelioma has also been reported by others [2, 25], and male sex also appears to be an important negative prognostic factor for other thoracic malignancies such as lung cancer [26]. Other factors that predicted poor outcome on univatiate analysis included elevated preoperative white blood cell count and platelet count, as has previously been reported by others [5, 25]. However, only elevated white blood cell count was significant on multivariate analysis, and its low hazard ratio raises questions regarding its clinical importance.
In conclusion, we found that IMRT after extrapleural pneumonectomy was feasible for about two thirds of patients. This aggressive bimodal strategy was effective at preventing local recurrences; however, distant metastases occurred frequently and limited survival. The patients included in this study were treated during a period when there were no chemotherapeutic agents with proven efficacy. Our results indicate that despite excellent local control, treatment of malignant pleural mesothelioma with local modalities only is unlikely to impact survival. With the advent of more potent doublet chemotherapeutic regimens such as cisplatin and pemetrexed, there is now a strong rationale to include systemic regimens with aggressive local therapies in the hope of improving control of this relentless disease.
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Discussion |
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The first deals with operative mortality. As you explained, the in-house mortality, less than 30 days or in-house, was 11%, and the 90-day mortality was 17%. Why was this so high, and was there a learning curve associated with this procedure over the year’s interval presented?
And the second reflects the challenge in long-term survival in these patients. How were they staged, and if they were staged, was this performed concurrently with the extrapleural pneumonectomy or as a separate procedure?
Thirdly, did the surgeon participate in the creation of the intensity-modulated radiation fields? Even with clips placed by the surgeon at the time of the operation, the extent of the disease and the subsequent fields may be underestimated by the radiation oncologist, who would benefit from close discussion and guidance from the surgeon and creation of the IMRT fields collaboratively, as the surgeon has an intimate knowledge of the extent of the disease.
Finally, who would you recommend operating upon and when? Obviously the epithelial histology and no negative patients appear to have the best benefit from EPP and intensity-modulated radiation therapy, but this excludes patients with biphasic histology or sarcomatoid histology. Induction therapy may carry great promise but potentially increase an already high morbidity and mortality. Would you recommend this to be done, particularly given the high incidence of distant metastases?
I applaud the efforts that you and your radiation oncology colleagues have made with this technique of radiation therapy in reducing to a very manageable level the local recurrence in this very challenging disease. I applaud your courage in tackling this complex operation, critically reviewing your results, and presenting them publicly. Thank you.
DR RICE: Thank you, Bill, for those thoughtful questions. Before I answer them, I will make one comment. I would just reiterate that clearly we are far from hitting a home run with this disease, however, our experience has shown that for the first time we are really able to get reliable local control in this tumor, and I know of no other solid tissue malignancy where that is the most important factor in at least beginning to address the tumor. You have got to get local control. We are finding that distant control is a problem now.
In terms of our operative mortality, I was hopeful that our operative mortality would have all occurred at the beginning of our experience, but really, we had an equal number of 30-day deaths at least in the first half as compared to the second half. We are learning. We now routinely obtain D-dimers on patients undergoing surgery, and if they are elevated, we will be more aggressive about anticoagulation early. We treat everybody with oral Plavix, although that is rather empiric, after their surgery. And the operative mortality rate, if you look at the current series, really ranges anywhere from 3.2% to 11%. The study by Rusch and coworkers that I quoted had an 11% 30-day mortality.
In terms of staging, we are very aggressive about performing preoperative surgical staging on these patients, really to rule out transdiaphragmatic or peritoneal carcinomatosis or contralateral mediastinal nodal involvement. Unfortunately, as you know, the current staging system is a surgically based staging system and therefore is really not applicable to stage patients in the preoperative setting. That is why I showed postoperative staging and not preoperative staging. Preoperative staging is highly inaccurate and really not useful at this time.
The third question regarding participation of the surgeon in the radiation treatment planning, every single patient who we do postoperative radiation therapy on, the surgeon who performs the operation is involved in the contouring of the ipsilateral hemithorax at the time of radiation treatment planning. So there is very, very close collaboration between the surgeon, the radiation oncologist and the radiation physics in the treatment of these patients, and that is critical.
And the last question, who you should operate on, well, I don’t think we know the answer to that. In this current day we have made strides in improved chemotherapy for this disease. We don’t know what the benefit of adjuvant or neoadjuvant chemotherapy is. I think that we would all like to operate on these patients in the context of a clinical trial, and to some extent we have been able to do that. There was a recent trial of neoadjuvant therapy, which was a multi-institutional trial which recently closed. We will eagerly await the results.
My own personal bias is that I think every patient who has mesothelioma, perhaps except the rare cases of a stage I patient, every patient ought to get trimodality treatment, including systemic treatment. I also feel strongly that most patients who come to my clinic who have clear evidence of nodal disease or of nonepithelial histology undergo neoadjuvant treatment. We currently do not offer operations anymore to patients who have sarcomatoid tumors because they just don’t do well. Thank you.
DR DANIEL L. MILLER (Atlanta, GA): That was a great presentation, David. At MD Anderson you and your colleagues have a long history of treating patients with pleural mesothelioma. I applaud you for your dedication in the treatment of this extremely lethal disease. I have several questions. First of all, in your series that you presented today, 40 of the 100 patients had positive N2 disease, which is usually a poor prognostic sign. What clinical staging studies were performed to evaluate the mediastinum for nodal involvement and of the 40 patients who were found to have N2 disease how many patients had undergone mediastinoscopy prior to resection?
Secondly, I was very surprised to see that none of your patients received chemotherapy as part of a multimodality treatment regiment for the treatment of pleural mesothelioma. The lack of chemotherapy may have accounted for your high distant recurrence rate and overall poor survival. Why was chemotherapy not used?
Finally, in looking back at this series of patients who was treated for pleural mesothelioma what is MD Anderson’s current stage-specific treatment for patients with pleural mesothelioma? Thank you, David.
DR RICE: Well, I think my conclusions support what you are saying. Clearly, this is not a disease that we are going to solve with local therapy only. At the time that we started doing this, there was no established chemotherapeutic regimen for this disease, as you know; in fact, it was not until 2003 when the first Vogelzang data came out on the combined cisplatin and pemetrexed, and even today we do not know the combined effect or efficacy of chemotherapy in this setting. There are a lot of retrospective trials out there. There is no prospective evaluation that I know of.
In terms of mediastinoscopy, every single patient in this study underwent mediastinoscopy to evaluate for contralateral nodal disease. We were at a time also, when in providing radiation to N2 patients, when we did not know what the effect would be. We do now know. We now know that N2 is a bad thing, but it was not clear at the time that hemithoracic radiation in the setting of N2 disease would not sterilize those nodes. And so I think you are right. We are constantly learning this disease. We are in the infancy of treating mesothelioma with aggressive management. Hopefully we will do better with trimodality therapy.
DR PUTNAM: Just one final comment. Doctor Miller’s comments certainly reflect the critical need for careful clinical investigations in this disease as well as other thoracic neoplasms. The value of clinical trials in supporting these types of models of care are very important. If each physician in this room put 2 patients into a clinical trial each year, and that is all, we could close a significant number of trials, initiate some, and establish some answers for questions that have heretofore been unknown to all.
DR RICE: Bill, that is a great point. And as I said, there was a recent closure of a multi-institutional prospective trial evaluating neoadjuvant chemotherapy in the treatment of this disease, and I think that more trials are clearly needed. We eagerly await the result of the mesothelioma and radical surgery trial which is being conducted by the MRC in Great Britain, which is comparing chemotherapy alone and supportive care versus preoperative chemotherapy and radiation. But I agree and your point is well taken.
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  H. I. Pass, G. J. Brewer, R. Dick, M. Carbone, and S. Merajver A phase II trial of tetrathiomolybdate after surgery for malignant mesothelioma: final results. Ann. Thorac. Surg., August 1, 2008; 86(2): 383 - 389. [Abstract] [Full Text] [PDF]
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T. C. Mineo, V. Ambrogi, E. Pompeo, A. Baldi, F. Stella, P. Aurea, and M. Marino The value of occult disease in resection margin and lymph node after extrapleural pneumonectomy for malignant mesothelioma. Ann. Thorac. Surg., May 1, 2008; 85(5): 1740 - 1746. [Abstract] [Full Text] [PDF]
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