19 Unilateral or Bilateral Approach for Unilateral Pulmonary Metastatic Disease

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19

Unilateral or Bilateral Approach for Unilateral Pulmonary Metastatic Disease

Ashish Patel and Malcolm M. DeCamp, Jr.

of evidence, with 1++ being a high-quality review of randomized, controlled trials and 4 being expert opinion. Case control studies are generally assigned level 2, with 2+ given to studies with likelihood of causal relationship. Overall, recommendations are graded from A to D, with an A grade being supported by randomized, controlled trials. Grade B recommendations suggests consistency in the literature.

19.1. Unilateral or Bilateral Approach

Central to the question of a unilateral or bilateral approach to unilateral pulmonary metastatic disease is (1) the principle of achieving a complete resection of all pulmonary disease, (2) the accuracy of preoperative imaging in detecting metastatic disease, (3) the efﬁ cacy of a surgical technique in identifying and resecting all pulmonary disease, and (4) the evidence for improved outcome.

19.2. Complete Resection

The principle of resecting all pulmonary metastatic disease is based on the current understand- ing of cancer pathobiology coupled with decades of observations of patients undergoing pulmonary metastasectomy. Contemporary cancer biology assumes that metastases originate from cells that are shed by primary tumors and dis- seminated through the systemic vascular and lymphatic circulations. Hematogenous meta- The term pulmonary metastasectomy refers to

surgical excision of malignant lesion(s) of the lung of extrapulmonary origin. Several retrospective studies, including the International Reg- istry of Lung Metastases,¹ have observed increased survival following pulmonary metastasectomy when compared to historical control patient cohorts who did not undergo resection. Over the years these observations have led to widespread acceptance of pulmonary metastasectomy in appropriately selected patients. The lack of randomized, controlled trials and the continued evolution in imaging technology, chemothera- peutics, and surgical technique pose signiﬁ cant challenges to clinicians as they struggle with appropriate patient selection for and the optimal surgical approach to metastasectomy.

The criteria for undertaking pulmonary metastasectomy include control of the primary disease site, lack of other systemic metastatic disease, adequate physiological reserve, and the ability to resect all residual disease in the lungs. Bilateral pulmonary metastatic disease, in selected patients, is treated with bilateral resections. The obvious question, therefore, is whether to explore the contralateral lung in a patient with only unilaterally detected pulmonary metastases.

This chapter addresses the question of a unilateral or bilateral approach to unilateral pulmonary metastatic disease. Recommendations are made according to the system of evidence grading proposed by the Scottish Intercollegiate Guide- lines Network (SIGN).² Each study cited with regard to our recommendation is assigned a level

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stases are more likely to become lodged in the ﬁ rst capillary bed encountered following transit to the vascular system. The basis of this theory is supported by the observation that tumors of the gastrointestinal tract drained by the portal venous circulation generally metastasize ﬁ rst to the liver, while the tumors with venous drainage to the systemic circulation (e.g., rectum, kidney, soft-tissue sarcomas) metastasize more frequently to lungs. Histological studies support these theories as 84% of lung metastases receive their major blood supply from the pulmonary arteries while only 16% are supplied exclusively by the bronchial arteries³ (level of evidence 3).

One of the most interesting questions in cancer pathology has been whether metastases can themselves metastasize. A retrospective review of 883 pulmonary metastasectomies performed at the Mayo Clinic identiﬁ ed 70 (8%) patients who had concurrent lymph node dissections at the time of metastasectomy. Fourteen (20%) of these 70 patients had positive nodes suggesting that metastases can metastasize. Three-year survival among patients with negative nodes was much higher (69%) than among patients with positive nodes (38%)⁴ (level of evidence 2+). Thus, any therapy aimed at a complete and curative resection should involve evaluation of regional lym- phatics around the metastasis.

Clinical experience over the last 100 years seems to support the need for complete resection.

The ﬁ rst report of pulmonary metastasectomy is credited to Dr. Weinlechener in Germany, who, in 1882, removed an incidental metastasis of the lung during resection of a chest wall sarcoma.

Unfortunately the patient only survived 24 h⁵ (level of evidence 4). In 1884, Dr. Kronlein resected an incidental metastasis to the lung of a chest wall sarcoma and observed the patient survive over the next 7 years⁶ (level of evidence 4). The ﬁ rst report of pulmonary metastasectomy in America was by Drs. Barney and Churchill in the 1930s, when they removed a metastatic focus of renal cell carcinoma. The patient survived 23 years.

Reports of improved survival among patients undergoing pulmonary metastasectomy for other cell types have led to further aggressive approaches. Osteogenic sarcoma is a highly lethal

neoplasm with 5-year survival of less than 5%

among patients with pulmonary metastases.

When a group of patients with osteogenic sarcoma underwent pulmonary metastasectomy at Memo- rial Sloan-Kettering Cancer Center, the survival improved to 32% at 5 years and 18% at 20 years⁷ (level of evidence 2+). All surgical efforts were focused on removal of all palpable tumors, leading to an overall impression that aggressive removal of all metastases improved survival. The most comprehensive set of retrospective data emerged with the formation of an International Registry of Lung Metastases (IRLM). The registry collected data on 5206 pulmonary metastasectomies from 18 departments of thoracic surgery around the world. The survival statistics were evaluated using Kaplan Meier estimates. The results were published in 1997 and are continu- ally updated. Among the total of 5206 metastasectomies, 4572 were complete resections while 634 were incomplete. The survival after complete metastasectomy was 36% at 5 years, 26% at 10 years, and 22% at 15 years with a median survival of 35 months. Survival among incomplete resections was 13% at 5 years, 7% at 10 and 15 years with a median of 15 months. This observation suggests a strong correlation between survival and complete resection¹ (level of evidence 2++) and is supported by several other smaller series including a recent study by Suzuki and colleagues showing aggressive pulmonary resection of osteosarcoma metastases yielded 42% 10-year survival for complete resection and only 4.2% 6- year survival for incomplete resection⁸ (level of evidence 2++).

Unfortunately, all of the above observations are affected by selection and observer bias typical of retrospective studies. Tumor-speciﬁ c factors also impact survival and may dominate the salu- tary effect of complete resection. This hypothesis is supported by the observations that despite complete resections, overall survival is highly dependent on histology of the tumor. Among patients who had complete resection of all iden- tiﬁ able disease, Mountain and colleagues found 5-year survival of 54% for urinary tract and male genital tract tumors, 46% for osteogenic sarcoma, 33% for soft-tissue tumors, 24% for primary uterine cervix tumors, and only 12% for melanoma⁹ (level of evidence 2+).

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19.3. Imaging

The ability to detect all pulmonary metastases is central to any discussion of approach to pulmonary metastasectomy. Surgical approach has clearly been guided by the improvement in imaging, speciﬁ cally single-breath-hold, helical, and/or multidetector computed tomography (CT) scans.

Early pulmonary metastasectomies, such as those by Weinlechener or Kronlein, were serendipitous. The discovery of X rays and their evolution to chest roentgenograms during the early 20th century allowed for planned metastasectomies, as those reported by Barney and Churchill.

Chest roentgenograms, although helpful in the diagnosis of pulmonary lesions, were not highly sensitive. This is clearly reported by McCormack and coworkers in 1993, where 57/144 (39%) of chest roentgenograms differed in number of lesions detected from intraoperative ﬁ ndings.

Forty-six percent of patients had more lesions than chest roentgenograms detected while 21%

had fewer. The gold standard for detecting all pulmonary lesions became intraoperative palpation, which led to advocacy for operative techniques providing access to both lungs, including bilateral staged thoracotomies, median sternotomy, median sternotomy with lateral thoracotomy, and the clamshell bilateral sterno- thoracotomy¹⁰ (level of evidence 2).

The ubiquitous availability of CT scan in the 1980s led to a re-evaluation of approaches to pulmonary metastasectomies. Some clinicians began to believe that CT could supplant palpation in terms of metastasis detection. Concerned with accuracy of CT scans, McCormack and coworkers also evaluated the sensitivity and specifi city of CT scans in their review of imaging modalities in lung nodule detection. They found that CT fi ndings differed from intraoperative fi ndings among (30/72) 42% of patients. Twenty-fi ve percent of patients had more malignant nodules than found on CT scan, while 17% of patients had more lesions on CT than found at operation. The authors concluded that CT was not adequate replacement for bilateral manual lung palpation.

The CT images, however, were 8-mm axial images.

The authors do not mention whether the lesions were unilateral or bilateral and agree that the

number of tumors found in the study failed to reach statistical signiﬁ cance for survival data¹⁰ (level of evidence 2−).

The superiority of manual palpation over axial CT in detection and diagnosis of pulmonary lesions was further challenged by the advent of helical CT in the 1990s. Unlike axial CT that take axial scans over several breaths each at distance of 8mm, the helical CT takes continuous spiral scans (2.5- to 8-mm collimation) during a single breath suspended at full inspiration. Faster image acquisition results in lower distortion due to respiratory or cardiac motion and higher resolu- tion. Several studies reported average detection of 20% more nodules by spiral CT compared to conventional CT¹¹ (level of evidence 3). Retro- spective analyses were once again performed to resolve the sensitivity and speciﬁ city of helical CT. In a retrospective review of 34 patients who underwent both helical CT and manual lung palpation, Parsons and colleagues report only (69/88) 78% sensitivity¹² (level of evidence 2−). This is similar to sensitivity of helical CT in detecting lung lesions reported by Waters and colleagues (56%), Diederich and colleagues (77%), Ambrogi and coworkers (84%), and Margaritora and coworkers (82%)^13–16 (level of evidence 2−).

The integrated use of helical CT (2.5- to 5-mm collimation) with F-18 ﬂ uorodeoxyglucose positron tomography (FDG-PET) has become a common part of the evaluation of primary lung cancer. F-18 Fluorodeoxyglucose positron tomography scans have detected occult metastatic disease and helped patients avoid nontherapeutic resections for non-small cell lung cancer patients in up to 10% of cases. Recalling the criteria for documented control of extra thoracic disease and the increased relevance of mediastinal spread of pulmonary metastases, Pastorino and colleagues evaluated the use of FDG-PET in the workup of pulmonary metastasectomies. Eighty-six patients underwent 89 PET scans prior to surgery deemed otherwise resectable by helical CT scan. Surgery was avoided or deferred in 19 of 86 (21%) patients based on PET ﬁ ndings, which included 11 extrathoracic metastases, 2 primary recurrences, 2 cases of mediastinal adenopathy, and 4 cases with confounding benign disease. FDG-PET sensitivity was 100% for detecting lung metastases and 100% for mediastinal staging compared to

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95% and 71% for spiral CT scans¹⁷ (level of evidence 2+).

Advances in imaging technology continue to provide diagnostic assistance in patient selection for pulmonary metastasectomy. The combina- tion of improved imaging and lack of a convinc- ing survival advantage to open palpation, along with availability of minimally invasive surgical techniques, continues to stimulate surgeons to evaluate less morbid approaches to pulmonary metastasectomy.

19.4. Surgical Approach

Once unilateral pulmonary metastases are detected radiographically, the surgeon has several therapeutic options, including bilateral thoracotomies, median sternotomy, clamshell thoracotomy, unilateral thoracotomy, or video-assisted thoracic surgery (VATS).

The decision regarding surgical approach is infl uenced by sensitivity and specifi city of imaging, surgeon’s familiarity with the technique, operative risk, and currently available literature on surgical experience. The sensitivity and specifi city of imaging has been discussed above with contemporary practice favoring both an inspiratory helical CT for optimal lesion detection complimented by an integrated FDG-PET/

CT study to evaluate the primary site, regional nodal basins, and to exclude other extrathoracic disease. The surgeon’s familiarity with technique plays a minor role as most centers have expertise in traditional open thoracic techniques and VATS. The operative risk is minimal and accept- able regardless of the operative technique. John- ston reported no operative mortality in 53 median sternotomies in 1983¹⁸ (level of evidence 3). Pas- torino and coworkers had a similar experience with 0 early deaths in 56 consecutive sternotomies for sarcoma¹⁹ (level of evidence 3). There are no reported, statistically relevant differences in major morbidity or mortality between thoracotomies and sternotomies for resection of lung metastases. A VATS approach has similar low morbidity and may have advantages of decreased pain, creating fewer adhesions making re- intervention more feasible, and a shorter hospital stay.

The most aggressive approaches to unilateral pulmonary metastasectomy are median sternotomy, clamshell thoracotomy, or bilateral thoracotomy, each of which allow palpation of the contralateral lung. The studies supporting these approaches, however, are increasingly dated given the availability of improved imaging. Pro- ponents of median sternotomy cite a single incision, low morbidity, and ability to palpate the contralateral lung through the same incision as advantages to the approach. Johnston, in 1983, championed median sternotomy for its low morbidity and 53% more nodules found at sternotomy than detected by chest tomography¹⁸ (level of evidence 3). Van der Veen and colleagues report 82 sternotomies with CT discordance in 49% of cases²⁰ (level of evidence 2−). Reports favoring sternotomy also cite softer end points such as reduced pain and earlier recovery of pulmonary function when compared to thoracotomies²¹ (level of evidence 3).

The most signiﬁ cant argument to challenge a bilateral approach to unilateral disease has been lack of survival advantage to the contralateral exploration. Roth and colleagues compared median sternotomy and thoracotomy for soft- tissue sarcomas in 1986. Eighty-two patients underwent complete resection of their metastases, 42 each by sternotomy and thoracotomy with a follow-up of 2 years. The groups were matched for disease-free interval, number of nodules resected, and tumor doubling time. There was no difference in survival between the two groups.

The authors concluded that, although median sternotomy allows detection of unsuspected bilateral metastases, it does not offer survival advantage to unilateral thoracotomy²² (level of evidence 2+).

Younes and colleagues evaluated the need for bilateral thoracotomy in patients with unilateral pulmonary metastases using a retrospective database from a single institution (1990–1997).

Two hundred sixty-seven consecutive patients included 179 patients with unilateral lung nodules and 88 patients with bilateral nodules. Unilateral thoracotomy was performed for unilateral disease and bilateral for bilateral disease, respectively.

Contralateral recurrence-free survival over 6 months, 1 year, and 5 years was 95%, 89%, and 78%, respectively. When patients with

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contralateral recurrence were compared with patients with bilateral metastases on admission, there was no signiﬁ cant difference in overall survival. Contralateral recurrence was only linked to histology and number of unilateral metastases.

Given these results, the authors concluded that most patients with unilateral disease only have unilateral disease and delaying contralateral thoracotomy until lesions appear does not affect survival²³ (level of evidence 2+). These ﬁ ndings have been conﬁ rmed by similar observations including those by Gadd and coworkers for soft-tissue sarcoma as well as by Matthay and coworkers and Pogrebniak and colleagues^24–26 (level of evidence 2+). Additionally, there is no correlation between survival and unilateral or bilateral disease^27,28 (level of evidence 2+).

Video-assisted thoracoscopic surgery is playing an increasing role in pulmonary metastasectomy.

The fi rst reports of VATS metastasectomy were by Dowling and colleagues in 1993. Seventy-two patients with peripheral lung lesions identifi ed by CT received wedge resections using a stapler or Nd:YAG laser. Sixty-three of 73 (86%) of resected nodules were pathologically confi rmed to be metastatic lesions. Sixty-fi ve of 72 (90%) patients underwent resection for diagnosis while only 7 underwent resection for potential survival benefi t²⁹ (level of evidence 2). Liu and colleagues used VATS to resect lung metastases in 47 patients. Digital lung palpation was used to iden- tify additional nodules and to locate and resect all nodules detected on preoperative imaging.

Five patients were found to have additional nodules and these were resected. The authors concluded that VATS was a useful technique for metastasectomy but failed to provide follow-up survival data³⁰ (level of evidence 2−). In 1996, McCormack and coworkers published a prospective study comparing VATS to thoracotomy.

Patients underwent VATS resection followed by immediate thoracotomy to carefully palpate the lung for missed lesions. Four (22%) patients had no additional lesions while 10 (56%) had additional malignant lesions. The remaining four (22%) had additional benign lesions. Based on these ﬁ ndings, VATS was not recommended for metastasectomy although the survival advantage to the resection of the “VATS-blind” nodules remains unknown³¹ (level of evidence 2−).

Although the role of VATS is questioned for pulmonary metastasectomy, it is indispensable for diagnostic purposes. Pulmonary nodules in patients with a history of prior malignancy often are radiographically uncharacteristic of metastases and require diagnosis by excisional. More importantly there is a signiﬁ cant rate of primary lung cancer among patients with prior extrathoracic malignancy. In a study of 50 patients with a history of malignancy by Adkins and colleagues, 18% of lung lesions were benign, 18% represented a new primary lung cancer, and 64% were metastatic lesions.³² The probability of the lesion being metastatic versus a new primary lesion is dependent on the primary histology. Ninety percent of lung lesions among patients with melanoma or sarcoma are metastatic. Fifty percent of the lung lesions are metastatic in patients with gastrointestinal, genitourinary, or gynecological malignancy. Because of the high prevalence of tobacco-related carcinogen exposure throughout the aero–digestive tract, only 33% of lung lesions in patients with head and neck cancers are metastatic.³³ With continued improvement in imaging techniques, and lack of evidence demonstrating increased survival following more radical explor- atory operations, VATS will continue to play a role in pulmonary metastasectomy.

19.5. Conclusion

The fi eld of pulmonary metastasectomy continues to evolve. Historically, it has progressed from serendipitous open resection of unexpected pulmonary metastases to planned bilateral explora- tions to minimally invasive resections supported by advanced imaging techniques. The justifi ca- tion of pulmonary metastasectomy lies in the feasibility of the procedure and the observed improvement in survival. Extensive retrospective studies point to complete resection of pulmonary metastases as a factor associated with improved survival. Traditionally this linkage has led surgeons to explore both lungs during metastasectomy. Advances in imaging technology, including helical CT and PET scans, and the integration of these anatomical and metabolic studies into a single fused image, is providing increasing diagnostic sensitivity and specifi city useful in guiding

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selection of patients appropriate for pulmonary metastasectomy. The same images provide a useful “roadmap” for the surgeon seeking to achieve a complete resection.

19.6. Recommendation

The absence of data demonstrating improved survival after routine lung palpation without radiologically identifi ed contralateral disease justifi es a unilateral approach to unilaterally detected pulmonary nodules. A planned course of cross-sectional imaging follow-up for recur- rent metastases is prudent. The precise role of VATS in pulmonary metastasectomy is poorly defi ned. Given continued advancement in both imaging and operative technology, this role is expected to grow. This is a grade B recommendation given the overall consistency in the literature and the presence of at least one 2++ level study.

8. Suzuki M, Kimura H, Ando S, et al. Pulmonary metastasectomy for osteosarcomas and soft tissue sarcomas. Gan To Kagaku Ryoho 2004;31:1319–1323.

9. Mountain CF, McMurtrey MJ, Hermes KE. Surgery for pulmonary metastasis: a 20 year experience.

Ann Thorac Surg 1984;38:323–330.

10. McCormack PM, Ginsberg KB, Bains M, et al.

Accuracy of lung imaging in metastases with implications for the role of thoracoscopy. Ann Thorac Surg 1993;56:863–866.

11. Remy-Jardin J, Remy-Jardin M, Giraud F. Pulmo- nary nodules: detection with thick section spiral CT versus conventional CT. Radiology 1993;187:513–

520.

12. Parsons AM, Detterbeck FC, Parker LA. Accuracy of helical CT in the detection of pulmonary metastases: is intraoperative palpation still necessary?

Ann Thorac Surg 2004;78:1910–1918.

13. Waters DJ, Coakley FV, Cohen MD, et al. The detection of pulmonary metastases by helical CT:

a clinicopathologic study in dogs. J Comput Assist Tomogr 1998;22:235–240.

14. Diederich S, Semik M, Lentschig MG, et al. Helical CT of pulmonary nodules in patients with extra- thoracic malignancy: CT-surgical correlation. AJR Am J Roentgenol 1999;172:353–360.

15. Ambrogi V, Paci M, Pompeo E, Mineo TC. Tran- sxiphoid video-assisted pulmonary metastasectomy: relevance of helical computed tomography occult lesions. Ann Thorac Surg 2000;70:1847–1852.

16. Margoritora S, Porziella V, D’Andrilli A, et al.

Pulmonary metastases: can accurate radiological evaluation avoid thoracotomic approach? Eur J Cardiothorac Surg 2002;21:1111–1114.

17. Pastorino U, Veronesi G, Landoni C, et al. Fluro- deoxyglucose positron emission tomography improves preoperative staging of respectable lung metastasis. J Thorac Cardiovasc Surg 2003;126:

1906–1910.

18. Johnston MR. Median sternotomy for resection of pulmonary metastases. J Thorac Cardiovasc Surg 1983;85:516–522.

19. Pastorino U, Valenta M, Gasparini M, et al. Median sternotomy and multiple lung resections for meta- static sarcomas. Eur J Cardiothorac Surg 1990;4:

477–481.

20. Van der Veen AH, van Geel AN, Hop WCJ, Wiggers T. Median sternotomy: the preferred incision for resection of lung metastases. Eur J Surg 1998;164:

507–512.

21. Cooper JD, Nelems JM, Pearson FG. Extended indications for median sternotomy in patients requiring pulmonary resection. Ann Thorac Surg 1978;26:413–420.

The absence of data demonstrating improved survival after routine lung palpation without radiographically identiﬁ ed contralateral disease justiﬁ es a unilateral approach to unilaterally detected pulmonary nodules (level of evidence 2++ to 3; recommendation grade B).

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