Commentary (Yang): Surgical Treatment of Metastatic Pulmonary Soft-Tissue Sarcoma

The criteria for successfully resecting pulmonary metastasis have not changed since they were originally described by Ehrenhaft in 1958.[1] They are (1) that the primary tumor site has been removed without evidence of local recurrence, (2) that no extrathoracic organ metastasis exists, and (3) that pulmonary disease has been completely removed without compromising pulmonary function.

Although other factors such as tumor type, disease-free interval, and number of metastases have had some influence on patient selection for pulmonary metastasectomy, none have consistently been shown to correlate with long-term survival. Certainly “debulking” procedures or tumor resection with the intent of leaving residual disease should be avoided, even though theoretically these strategies might be advantageous in reducing tumor load to make adjuvant therapy more effective.

Improvements in operative techniques and perioperative care have allowed surgeons to be more aggressive in selecting patients for resection of pulmonary metastases. Despite these advances, long-term survival following surgery has not changed significantly over the past 3 decades. This is likely due to the following reasons: (1) surgery is performed in the setting of systemic disease, (2) chemotherapy and radiation have been ineffective and have their own limitations, and (3) although the biology of metastatic disease is better understood, translation into clinical applicability remains remote compared to other solid tumor systems.

Selecting Appropriate Candidates for Surgery

Nevertheless, most thoracic surgeons have adopted an aggressive approach to the treatment of metastatic pulmonary disease. In the course of evaluating patients for surgery, particular attention should be paid to preoperative pulmonary function, just as it is for patients undergoing lung resection for primary lung cancer. Patients who have received combined-modality therapy are at increased risk for developing adult respiratory distress syndrome in the perioperative period.

In this report, Chao and Goldberg give a thorough, well-organized review of the current role of surgery for pulmonary metastases from soft-tissue sarcoma. Osteogenic sarcomas were omitted presumably because of better response rates to chemotherapy. Compared to other subgroups of pulmonary metastatic lesions, soft-tissue sarcomas usually metastasize to the lung only, are found in a comparatively younger patient population, and are relatively more chemo- and radioresistant. For these reasons, surgery remains the only option in a small select group of low-risk patients.

Various prognostic indicators are presented that might influence the selection of an appropriate surgical candidate. These include age, gender, lesion location, stage of primary tumor, disease-free interval, tumor-doubling time, and number of metastases resected. Although a multivariate analysis of these factors may provide a more accurate prediction of postresection survival, these remain heterogeneous with respect to the different soft-tissue sarcoma histologies.

Current Surgical Options

Chao and Goldberg also accurately describe the current operative approaches to resecting pulmonary metastases. It is generally accepted that effective postoperative pain control and early mobilization with good pulmonary toilet are essential for reducing perioperative morbidity and mortality. This is achieved through liberal use of analgesia, consideration of sternotomy and muscle-sparing incisions, and minimization of the amount of resected lung parenchyma, especially in patients who may eventually require multiple resections.

With respect to the video-assisted thoracic surgery technique, Chao and Goldberg have also correctly outlined the many drawbacks, reflecting the cautious view that most thoracic surgeons have taken in using this approach for therapeutic purposes. Open resection, with manual palpation and inspection, remains the gold standard. Video-assisted thoracic surgery should be reserved for diagnostic biopsies and for staging in the post–adjuvant therapy patient.

Novel Strategies

The failure of standard therapy in soft-tissue sarcoma has led to the development of novel strategies employing currently available chemotherapeutic agents. Since systemic toxicities remain a barrier to the use of higher doses of these agents, regional drug delivery to the pulmonary system has been performed in a manner similar to limb perfusion for melanoma and isolated liver perfusion for advanced hepatic malignancies.

Like these other systems, regional infusion has the advantage of delivering higher concentrations of drugs, while minimizing systemic complications. However, as described in this article, the current limitations of this approach include the lack of effective agents, cumbersome delivery systems, and the need for surgery to implement these delivery systems with associated perioperative complications.

Although more is known about the biological and molecular events associated with osteosarcomas, tumor suppressor genes such as p53 and the retinoblastoma gene play important roles in growth inhibition and cell cycle progression of soft-tissue sarcomas. Like other solid tumors, these p53 mutations or deletions have been shown to have a negative impact on survival, which is likely the result of the loss of wild type p53 (wt p53).[2,3]

Some researchers have shown that these mutations can lead to the development of chemoresistant tumors. Pollock[4] reintroduced wt p53 into a p53-mutated leiomyosarcoma, and the result was enhanced chemosensitivity measured ex vivo by a soft agar colony formation assay. Understanding these genetic alterations may someday add to the armamentarium of prognostic indicators in predicting recurrence and provide novel methods in gene therapies.

Summary

This review strengthens the argument that complete surgical resection of soft-tissue sarcoma pulmonary metastases provides the best chance of cure in patients with soft-tissue sarcoma metastatic to the lungs. The use of prognostic indicators in selecting appropriate surgical candidates remains an inexact science but should be used in developing novel multidisciplinary treatment therapies. Surgery does not affect the biology of the disease but should be used to understand the biology of metastasis in an effort to better define alterations at the molecular level that may lead to novel treatment strategies.

References:

1. Ehrenhaft JL, Lawrence MS, Sensenig DM: Pulmonary resection for metastatic lesions. Arch Surg 77:606-612, 1958.

2. Hieken TJ, Das Gupta TK: Mutant p53 expression: A marker of diminished survival in well-differentiated soft tissue sarcoma. Clin Cancer Res 2:1391-1395, 1996.

3. Schneider-Stock R, Ziegeler A, Haeckel C, et al: Prognostic relevance of p53 alterations and Mib-1 proliferation index in subgroups of primary liposarcomas. Clin Cancer Res 5:2830-2835, 1999.

4. Pollock RE, Lang A, Ge T: Reintroduction of wild type p53 enhances sarcoma chemosensitivity (abstract). Proc Am Soc Clin Oncol 16:501a, 1997.