The roles of surgery, stereotactic radiation, and ablation for treatment of pulmonary metastases
2021; Elsevier BV; Volume: 163; Issue: 2 Linguagem: Inglês
10.1016/j.jtcvs.2021.01.143
ISSN1097-685X
AutoresMara B. Antonoff, Constantinos T. Sofocleous, Matthew R. Callstrom, Quynh-Nhu Nguyen,
Tópico(s)Testicular diseases and treatments
ResumoCentral MessageLocal therapies offer clear benefit to patients with pulmonary metastatic disease, and a multidisciplinary approach should be used to establish individualized treatment decisions.See Commentaries on pages 503 and 510. Local therapies offer clear benefit to patients with pulmonary metastatic disease, and a multidisciplinary approach should be used to establish individualized treatment decisions. See Commentaries on pages 503 and 510. For patients with extrapulmonary primary malignancies, the lung is the most frequent site of metastatic spread.1Corsini E.M. Antonoff M.B. Is pulmonary metastasectomy effective in prolonging survival?.in: Ferguson M. Difficult Decisions in Thoracic Surgery: An Evidence-Based Approach. Springer, Cham2020: 279-289Crossref Google Scholar Pulmonary metastatic disease is experienced commonly in colorectal cancer (CRC), sarcomas, melanoma, head and neck cancers, breast cancer, and tumors of the urinary tract, with numerous other malignancies known to additionally spread to the lungs.2Jamil A. Kasi A. Cancer, metastasis to the lung. StatPearls. StatPearls Publishing, Treasure Island, FL2020https://www.ncbi.nlm.nih.gov/books/NBK553111/Google Scholar,3Cheung F.P. Alam N.Z. Wright G.M. The past, present and future of pulmonary metastasectomy: a review article.Ann Thorac Cardiovasc Surg. 2019; 25: 129-141Crossref PubMed Scopus (30) Google Scholar Historically, systemic therapy has been considered standard of care for stage IV cancer, given the systemic nature of the disease; however, options for local therapy of metastatic pulmonary nodules are expanding, with substantial evidence for efficacy in terms of optimal local control for prolonging life, delaying recurrence, and enabling patients to experience freedom from chemotherapy.4Petrella F. Diotti C. Rimessi A. Spaggiari L. Pulmonary metastasectomy: an overview.J Thorac Dis. 2017; 9: S1291-S1298Crossref PubMed Scopus (33) Google Scholar With regard to the benefits of local therapy for pulmonary metastatic disease, the existing literature can be challenging to interpret, given the broad heterogeneity of the populations included, spanning numerous histologies, extents of disease burden, and types of treatment.5Schweiger T. Lang G. Klepetko W. Hoetzenecker K. Prognostic factors in pulmonary metastasectomy: spotlight on molecular and radiological markers.Eur J Cardiothorac Surg. 2014; 45: 408-416Crossref PubMed Scopus (16) Google Scholar Even within focused series, there can be vast differences among patient outcomes related to the type of surgical resection or modality of ablative therapy. Although it would be inappropriate to offer local therapy for all patients with pulmonary metastatic disease, it is well established that there are substantial benefits to selected populations of patients. In addressing the role of local therapies for pulmonary metastatic disease, there are a number of highly relevant questions that must be considered: (1) Is this disease biology appropriate for local therapy? (2) Is this patient a good candidate for local therapy? (3) What is the optimal timing for providing local therapy to this patient? (4) What is the most suitable local modality for treating this patient? Pertaining to disease biology, it is known that certain tumor histologies have a tendency to lead to prolonged disease-free intervals (DFIs) after local therapy, whereas others tend to recur quickly. In general, the demonstration of disease stability and absence of extrathoracic metastases are well accepted as factors that are associated with better outcomes after local therapy.6Erhunmwunsee L. Tong B.C. Preoperative evaluation and indications for pulmonary metastasectomy.Thorac Surg Clin. 2016; 26: 7-12Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Furthermore, the ability to locally address all sites of disease is a particularly important consideration with regard to higher-risk interventions.1Corsini E.M. Antonoff M.B. Is pulmonary metastasectomy effective in prolonging survival?.in: Ferguson M. Difficult Decisions in Thoracic Surgery: An Evidence-Based Approach. Springer, Cham2020: 279-289Crossref Google Scholar Finally, it is relevant to consider that some tumors have alternative management strategies that are well tolerated by patients, such as those who can be managed by oral hormonal agents, whereas other diseases may be treatable only by highly toxic chemotherapeutic agents or may not even treatable with systemic drugs at all. All of these elements of disease biology are pertinent to the discussion of offering local therapy. As with therapeutic interventions for any medical condition, one must consider not only the best way to treat the disease but also whether the patient is an appropriate candidate for the treatment. For local therapy to the lung, patient comorbidities are particularly germane, as this may often weigh heavily in the decision as to which form of local therapy is offered. For patients to be surgical candidates, one must consider pulmonary reserve, frailty, and general ability to tolerate both a general anesthetic and the surgical recovery. For less-invasive ablative therapies, pulmonary function remains relevant, but with less stringent limitations than for surgery. Beyond comorbidities, other patient-related factors include social support, compliance with medical advice, and emotional well-being. Optimal timing and sequencing of specific local intervention are imperative to ensure successful patient outcomes. In some circumstances, patients may benefit from upfront systemic treatment to reduce tumor volume, which may increase efficacy of subsequent radiation or ablative therapies and/or reduce the amount of parenchyma required for resection. However, if tumors are particularly responsive to systemic therapy, small subcentimeter nodules may be difficult to localize, both radiographically and intraoperatively. Thus, the interplay of systemic therapy with local therapies is an important component of the multidisciplinary discussion. While limited studies have delved into this relationship between local and systemic therapies, it is the subject of a current ongoing trial in lung-limited metastatic CRC.7Chemotherapy and/or metastasectomy in treating patients with metastatic colorectal adenocarcinoma with lung metastases. ClinicalTrials.gov.https://clinicaltrials.gov/ct2/show/NCT03599752Date accessed: August 24, 2020Google Scholar There are a variety of modalities available for treatment of pulmonary metastases and numerous considerations guiding the applicability of each modality. Ultimately, for some patients, there may be an obvious best approach, whereas for others, there may be multiple reasonable strategies. Still yet for others, complete local control of pulmonary metastases may be best achieved with a hybrid approach. From here, we aim to delve into the realms of surgery, radiation, and transthoracic ablative therapies, identifying the best uses for each, with the overarching goal of highlighting the rationale for offering local therapy to patients with pulmonary metastatic disease. While novel approaches to local therapy have emerged in recent years, surgery has been the mainstay of local therapy for pulmonary metastatic disease. The predominance of literature supporting this approach has been composed of retrospective reviews. Although variability in patient populations and treatments has rendered a range of outcomes, in general, there is clear demonstration of improvement in prognosis for appropriately selected surgical patients.1Corsini E.M. Antonoff M.B. Is pulmonary metastasectomy effective in prolonging survival?.in: Ferguson M. Difficult Decisions in Thoracic Surgery: An Evidence-Based Approach. Springer, Cham2020: 279-289Crossref Google Scholar The greatest volume of data related to local therapy for pulmonary metastatic disease—and particularly related to surgical resection—addresses CRC, as this is the most common malignancy to spread to the lungs, with up to 18% of patients developing pulmonary metastatic disease.8Lumachi F. Chiara G.B. Tozzoli R. Del Conte A. Basso S.M. Factors affecting survival in patients with lung metastases from colorectal cancer. A short meta-analysis.Anticancer Res. 2016; 36: 13-19PubMed Google Scholar There is an abundance of single-institution retrospective reviews evaluating the benefits of surgery in this population, which have been summarized through several meta-analyses and systematic reviews. A meta-analysis published by Gonzalez and colleagues9Gonzalez M. Poncet A. Combescure C. Robert J. Ris H.B. Gervaz P. Risk factors for survival after lung metastasectomy in colorectal cancer patients: a systematic review and meta-analysis.Ann Surg Oncol. 2013; 20: 572-579Crossref PubMed Scopus (279) Google Scholar in 2013, reporting on nearly 3000 patients treated with metastasectomy, showed 5-year survival after resection of up to 68%. In this study, median DFI ranged 19-39 months, with longer DFI being associated with greater survival (hazard ratio [HR] for shorter DFI, 1.59). Survival was also better among patients without intrathoracic nodal disease or multiple pulmonary nodules (HR for nodal involvement, 1.65; HR for >1 nodule, 2.04).9Gonzalez M. Poncet A. Combescure C. Robert J. Ris H.B. Gervaz P. Risk factors for survival after lung metastasectomy in colorectal cancer patients: a systematic review and meta-analysis.Ann Surg Oncol. 2013; 20: 572-579Crossref PubMed Scopus (279) Google Scholar In 2016, Lumachi and colleagues8Lumachi F. Chiara G.B. Tozzoli R. Del Conte A. Basso S.M. Factors affecting survival in patients with lung metastases from colorectal cancer. A short meta-analysis.Anticancer Res. 2016; 36: 13-19PubMed Google Scholar analyzed outcomes from 15 retrospective studies, describing a median 5-year survival of 45% after surgery, with some patient cohorts achieving 5-year survival as high as 72%. This study, as well as a subsequent meta-analysis published in 2018, corroborated the findings that patients with the best prognosis following surgical resection were those with longer DFI, fewer pulmonary nodules, and absence of intrathoracic nodal disease.8Lumachi F. Chiara G.B. Tozzoli R. Del Conte A. Basso S.M. Factors affecting survival in patients with lung metastases from colorectal cancer. A short meta-analysis.Anticancer Res. 2016; 36: 13-19PubMed Google Scholar,10Zabaleta J. Iida T. Falcoz P.E. Saleh S. Jarabo J.R. Correa A.M. et al.Individual data meta-analysis for the study of survival after pulmonary metastasectomy in colorectal cancer patients: a history of resected liver metastases worsens the prognosis.Eur J Surg Oncol. 2018; 44: 1006-1012Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Mutational status has also been shown to prognosticate outcome after resection of colorectal pulmonary metastases, with patients harboring mutant APC showing prolonged survival, whereas KRAS mutations have been associated with poorer outcomes after resection.8Lumachi F. Chiara G.B. Tozzoli R. Del Conte A. Basso S.M. Factors affecting survival in patients with lung metastases from colorectal cancer. A short meta-analysis.Anticancer Res. 2016; 36: 13-19PubMed Google Scholar,11Corsini E.M. Mitchell K.G. Mehran R.J. Rice D.C. Sepesi B. Walsh G.L. et al.Colorectal cancer mutations are associated with survival and recurrence after pulmonary metastasectomy.J Surg Oncol. 2019; 120: 729-735PubMed Google Scholar An additional prognostic factor for survival after pulmonary metastasectomy relates to the location of the primary CRC; patients with rectal tumors display shorter disease-free survival after pulmonary metastasectomy than those with colon tumors,12Cho J.H. Hamaji M. Allen M.S. Cassivi S.D. Nichols F.C. Wigle D.A. et al.The prognosis of pulmonary metastasectomy depends on the location of the primary colorectal cancer.Ann Thorac Surg. 2014; 98: 1231-1237Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar while patients whose initial tumors arose in the left-sided segments of colon (vs right-sided) tend to demonstrate the greatest survival benefit after lung resection.13Corsini E.M. Mitchell K.G. Correa A. Morris V.K. Antonoff M.B. MD Anderson Pulmonary Metastasectomy Working GroupEffect of primary colorectal cancer tumor location on survival after pulmonary metastasectomy.J Thorac Cardiovasc Surg. 2021; 162: 296-305Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Surgery has also been shown to extend survival for patients with metastatic sarcoma. A review by Marulli and colleagues14Marulli G. Mammana M. Comacchio G. Rea F. Survival and prognostic factors following pulmonary metastasectomy for sarcoma.J Thorac Dis. 2017; 9: S1305-S1315Crossref PubMed Scopus (23) Google Scholar demonstrated 5-year survival ranging from 15%-51%, with tumor histology being particularly important to likelihood of survival after resection, in that patients with osteosarcoma fared substantially better than those with soft-tissue sarcoma.14Marulli G. Mammana M. Comacchio G. Rea F. Survival and prognostic factors following pulmonary metastasectomy for sarcoma.J Thorac Dis. 2017; 9: S1305-S1315Crossref PubMed Scopus (23) Google Scholar Among soft-tissue sarcomas, resection of leiomyosarcoma metastases appears to have the greatest impact in prolonging survival.14Marulli G. Mammana M. Comacchio G. Rea F. Survival and prognostic factors following pulmonary metastasectomy for sarcoma.J Thorac Dis. 2017; 9: S1305-S1315Crossref PubMed Scopus (23) Google Scholar,15Chudgar N.P. Brennan M.F. Munhoz R.R. Bucciarelli P.R. Tan K.S. D'Angelo S.P. et al.Pulmonary metastasectomy with therapeutic intent for soft-tissue sarcoma.J Thorac Cardiovasc Surg. 2017; 154: 319-30 e311Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Similar to the data for colorectal metastases, patients with sarcomatous pulmonary metastases appear to achieve the best survival after pulmonary resection when they have fewer nodules, longer DFIs, and negative margins at the time of surgery.14Marulli G. Mammana M. Comacchio G. Rea F. Survival and prognostic factors following pulmonary metastasectomy for sarcoma.J Thorac Dis. 2017; 9: S1305-S1315Crossref PubMed Scopus (23) Google Scholar,15Chudgar N.P. Brennan M.F. Munhoz R.R. Bucciarelli P.R. Tan K.S. D'Angelo S.P. et al.Pulmonary metastasectomy with therapeutic intent for soft-tissue sarcoma.J Thorac Cardiovasc Surg. 2017; 154: 319-30 e311Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Surgical therapy has further been found to be beneficial for pulmonary metastases from renal cell cancer as well as melanoma. For renal cell cancer, pulmonary metastasectomy has been shown to portend a 5-year survival in the range of 36%-53%.16Ripley R.T. Downey R.J. Pulmonary metastasectomy.J Surg Oncol. 2014; 109: 42-46Crossref PubMed Scopus (21) Google Scholar,17Zhao Y. Li J. Li C. Fan J. Liu L. Prognostic factors for overall survival after lung metastasectomy in renal cell cancer patients: a systematic review and meta-analysis.Int J Surg. 2017; 41: 70-77Crossref PubMed Scopus (31) Google Scholar Similar benefit has been demonstrated in melanoma.16Ripley R.T. Downey R.J. Pulmonary metastasectomy.J Surg Oncol. 2014; 109: 42-46Crossref PubMed Scopus (21) Google Scholar,18Hanna T.P. Chauvin C. Miao Q. Rizkalla M. Reid K. Peng Y. et al.Clinical outcomes after pulmonary metastasectomy for melanoma: a population-based study.Ann Thorac Surg. 2018; 106: 1675-1681Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar As has been seen for CRC and sarcoma, patients with pulmonary metastatic disease from renal cell cancer and melanoma also appear to have greater benefit from metastasectomy when fewer lesions are present, DFI is longer, intrathoracic nodes are uninvolved, and surgical resection is complete.4Petrella F. Diotti C. Rimessi A. Spaggiari L. Pulmonary metastasectomy: an overview.J Thorac Dis. 2017; 9: S1291-S1298Crossref PubMed Scopus (33) Google Scholar,16Ripley R.T. Downey R.J. Pulmonary metastasectomy.J Surg Oncol. 2014; 109: 42-46Crossref PubMed Scopus (21) Google Scholar,17Zhao Y. Li J. Li C. Fan J. Liu L. Prognostic factors for overall survival after lung metastasectomy in renal cell cancer patients: a systematic review and meta-analysis.Int J Surg. 2017; 41: 70-77Crossref PubMed Scopus (31) Google Scholar Germ cell tumors (GCTs) represent another tumor for which pulmonary metastasectomy may be of benefit, and although these malignancies are relatively rare among the general population, it is recognized that more than 10% of patients with this diagnosis develop pulmonary metastatic disease.19Farazdaghi A. Vaughn D.J. Singhal S. Pulmonary metastasectomy for germ cell tumors.Ann Thorac Cardiovasc Surg. 2019; 25: 289-295Crossref PubMed Scopus (4) Google Scholar Pulmonary resection for GCT has been used for approximately 40 years with excellent retrospective results. Timing for lung surgery is thought to be particularly important in this patient population, just as in management of the primary GCT, with emphasis placed on performing metastasectomy after completion of cisplatin-based chemotherapy and normalization of serum tumor markers.20Krege S. Beyer J. Souchon R. Albers P. Albrecht W. Algaba F. et al.European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus Group (EGCCCG): part II.Eur Urol. 2008; 53: 497-513Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar With regard to surgical technique, it is commonly accepted that, for metastasectomy, parenchymal-sparing strategies should be emphasized, which contrasts somewhat to the management of primary lung cancer. Rationale for such an approach is based on the frequent need for resection of multiple nodules, the potential need for future resections and/or ablative therapy, the lack of data demonstrating benefit for more extensive anatomic resections, and the expectation of less postoperative morbidity.1Corsini E.M. Antonoff M.B. Is pulmonary metastasectomy effective in prolonging survival?.in: Ferguson M. Difficult Decisions in Thoracic Surgery: An Evidence-Based Approach. Springer, Cham2020: 279-289Crossref Google Scholar,21Phillips J.D. Hasson R.M. Surgical management of colorectal lung metastases.J Surg Oncol. 2019; 119: 629-635Crossref PubMed Scopus (6) Google Scholar,22Lo Faso F. Solaini L. Lembo R. Bagioni P. Zago S. Soliani P. et al.Thoracoscopic lung metastasectomies: a 10-year, single-center experience.Surg Endosc. 2013; 27: 1938-1944Crossref PubMed Scopus (28) Google Scholar Thus, the most frequent approach is a stapled wedge resection, whereas lobectomies may be used for larger tumors, central tumors, or the presence of multiple metastases within a given lobe.21Phillips J.D. Hasson R.M. Surgical management of colorectal lung metastases.J Surg Oncol. 2019; 119: 629-635Crossref PubMed Scopus (6) Google Scholar Of course, it should be noted that surgical technique is key, with high risk of recurrence with inadequate margins.23Nelson D.B. Tayob N. Mitchell K.G. Correa A.M. Hofstetter W.L. Sepesi B. et al.Surgical margins and risk of local recurrence after wedge resection of colorectal pulmonary metastases.J Thorac Cardiovasc Surg. 2019; 157: 1648-1655Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar While circumstances for more extensive resection than wedge or lobectomy are exceedingly uncommon, highly selected patients may be considered for pneumonectomy for solitary, central tumors after a prolonged DFI demonstrating disease stability and absence of any disease elsewhere.24Nichols F.C. Pulmonary metastasectomy: role of pulmonary metastasectomy and type of surgery.Curr Treat Options Oncol. 2014; 15: 465-475Crossref PubMed Scopus (6) Google Scholar,25Handy J.R. Bremner R.M. Crocenzi T.S. Detterbeck F.C. Fernando H.C. Fidias P.M. et al.Expert consensus document on pulmonary metastasectomy.Ann Thorac Surg. 2019; 107: 631-649Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar The optimal operative approach for pulmonary metastasectomy has been highly debated. Studies evaluating intraoperative efficacy of thoracoscopy versus thoracotomy have demonstrated superior ability to find nodules anticipated by imaging upon thoracotomy and manual palpation, as well as greater likelihood of finding and removing additional nodules not detected on imaging.26Eckardt J. Licht P.B. Thoracoscopic or open surgery for pulmonary metastasectomy: an observer blinded study.Ann Thorac Surg. 2014; 98 (discussion 469-70): 466-469Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar,27Macherey S. Doerr F. Heldwein M. Hekmat K. Is manual palpation of the lung necessary in patients undergoing pulmonary metastasectomy?.Interact Cardiovasc Thorac Surg. 2016; 22: 351-359Crossref PubMed Scopus (24) Google Scholar Regardless, multiple investigators have failed to show differences in 5-year survival based on surgical approach.16Ripley R.T. Downey R.J. Pulmonary metastasectomy.J Surg Oncol. 2014; 109: 42-46Crossref PubMed Scopus (21) Google Scholar,28Greenwood A. West D. Is a thoracotomy rather than thoracoscopic resection associated with improved survival after pulmonary metastasectomy?.Interact Cardiovasc Thorac Surg. 2013; 17: 720-724Crossref PubMed Scopus (28) Google Scholar Further complicating the issue, it should be recognized that such studies may fail to show survival differences based on operative approach because of the inclusion of such widely disparate disease biology within the patient cohorts. A recent consensus document emphasizes minimally invasive approaches where feasible.25Handy J.R. Bremner R.M. Crocenzi T.S. Detterbeck F.C. Fernando H.C. Fidias P.M. et al.Expert consensus document on pulmonary metastasectomy.Ann Thorac Surg. 2019; 107: 631-649Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar Ultimately, as it has been demonstrated that the perioperative benefits of thoracoscopy compared with thoracotomy are nearly equalized when enhanced recovery pathways are applied,29Van Haren R.M. Mehran R.J. Mena G.E. Correa A.M. Antonoff M.B. Baker C.M. et al.Enhanced recovery decreases pulmonary and cardiac complications after thoracotomy for lung cancer.Ann Thorac Surg. 2018; 106: 272-279Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar the specific operative approach should be left to the operating surgeon, based on the number of nodules, their exact anatomic locations, and other patient-specific factors. At the time of surgery for pulmonary metastatic disease, there has not been a clear survival benefit demonstrated by the performance of lymphadenectomy,30Seebacher G. Decker S. Fischer J.R. Held M. Schafers H.J. Graeter T.P. Unexpected lymph node disease in resections for pulmonary metastases.Ann Thorac Surg. 2015; 99: 231-236Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar although, again, this may be consequent to inclusion of heterogeneous patient populations. It is clear that those patients who have intrathoracic nodal disease tend to have worse survival after pulmonary metastasectomy,31Sihag S. Muniappan A. Lymph node dissection and pulmonary metastasectomy.Thorac Surg Clin. 2016; 26: 315-323Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar which may both give pause to the notion of operating in the setting of known nodal disease and further emphasize the possible prognostic utility of nodal sampling during planned operations.1Corsini E.M. Antonoff M.B. Is pulmonary metastasectomy effective in prolonging survival?.in: Ferguson M. Difficult Decisions in Thoracic Surgery: An Evidence-Based Approach. Springer, Cham2020: 279-289Crossref Google Scholar,25Handy J.R. Bremner R.M. Crocenzi T.S. Detterbeck F.C. Fernando H.C. Fidias P.M. et al.Expert consensus document on pulmonary metastasectomy.Ann Thorac Surg. 2019; 107: 631-649Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar Prospective studies evaluating the role of pulmonary metastasectomy have been lacking until recently. The Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer trial aimed to evaluate the additive benefit of surgery compared with active surveillance, but closed in December 2016 because of poor recruitment.32Treasure T. Farewell V. Macbeth F. Monson K. Williams N.R. Brew-Graves C. et al.Pulmonary metastasectomy versus continued active monitoring in colorectal cancer (PulMiCC): a multicentre randomised clinical trial.Trials. 2019; 20: 718Crossref PubMed Scopus (92) Google Scholar Subsequent analyses of the dataset demonstrated that patients in the control (nonoperative) group had better survival than had been assumed.33Milosevic M. Edwards J. Tsang D. Dunning J. Shackcloth M. Batchelor T. et al.Pulmonary metastasectomy in Colorectal Cancer: updated analysis of 93 randomized patients - control survival is much better than previously assumed.Colorectal Dis. 2020; 22: 1314-1324Crossref PubMed Scopus (85) Google Scholar However, this study was limited by several factors, including the fact that the majority of patients enrolled displayed highly favorable characteristics in terms of DFI and number of nodules, and that systemic agents were used by about one-half of the patients in both groups, yet were not standardized. Thus, we uphold that one of the goals and benefits of local therapy (including surgery, radiation, or ablative therapy) is to provide patients with potential freedom from systemic agents. While completed clinical trials are lacking in the area of pulmonary metastasectomy, another multicenter trial is currently underway, under the umbrella of the Thoracic Surgery Oncology Group (TSOG), examining multimodality management of risk-stratified patients with lung-limited metastatic CRC.7Chemotherapy and/or metastasectomy in treating patients with metastatic colorectal adenocarcinoma with lung metastases. ClinicalTrials.gov.https://clinicaltrials.gov/ct2/show/NCT03599752Date accessed: August 24, 2020Google Scholar,34Thoracic Surgery Oncology GroupAmerican Association for Thoracic Surgery.https://www.aats.org/aatsimis/AATSWeb/Resources/Thoracic_Surgery_Oncology_Group/AATSWeb/Association/About/Resources/Thoracic_Surgery_Oncology_Group.aspx?hkey=c1bdc51c-3317-4728-8eb1-ae89784a4858Date accessed: August 30, 2020Google Scholar The primary goals of this study (TSOG 103) are to evaluate the additive benefit of chemotherapy on recurrence-free survival in low-risk patients undergoing metastasectomy, as well as to assess the role of surgery in prolonging overall survival among high-risk patients undergoing systemic therapy. While we currently use a variety of patient- and disease-related factors to determine the best modality of treatment, management algorithms in the future may depend on genomic and biomarker status. For example, as noted earlier with CRC, the mutational status may affect the likelihood of prolonged survival after metastasectomy, and, thus, those with APC mutations may be best advised to undergo resection.11Corsini E.M. Mitchell K.G. Mehran R.J. Rice D.C. Sepesi B. Walsh G.L. et al.Colorectal cancer mutations are associated with survival and recurrence after pulmonary metastasectomy.J Surg Oncol. 2019; 120: 729-735PubMed Google Scholar Moreover, our fund of knowledge regarding genetic and tumor markers in pulmonary metastatic disease continues to grow, enabling us to further optimize our recommendations for individual patients in the future. In the TSOG 103 trial, while primary endpoints evaluate the interplay of various treatment modalities on survival outcomes, additional exploratory objectives involve the evaluation of changes in circulating tumor DNA after surgical resection or chemotherapy.7Chemotherapy and/or metastasectomy in treating patients with metastatic colorectal adenocarcinoma with lung metastases. ClinicalTrials.gov.https://clinicaltrials.gov/ct2/show/NCT03599752Date accessed: August 24, 2020Google Scholar,34Thoracic Surgery Oncology GroupAmerican Association for Thoracic Surgery.https://www.aats.org/aatsimis/AATSWeb/Resources/Thoracic_Surgery_Oncology_Group/AATSWeb/Association/About/Resources/Thoracic_Surgery_Oncology_Group.aspx?hkey=c1bdc51c-3317-4728-8eb1-ae89784a4858Date accessed: August 30, 2020Google Scholar It is hoped that such information can set the groundwork for future trials such that biomarker status may be used to guide timing and choice of treatment modality for patients with pulmonary metastatic disease. Although surgery has traditionally been the primary local modality for treating metastases, less invasive alternatives such as stereotactic ablative body radiation (SABR) and thermal ablation are becoming more widely accepted, either as primary therapy for select patient cohorts or as consolidative therapy after surgery.35Benson A.B. Venook A.P. Al-Hawary M.M. Cederquist L. Chen Y.J. Ciombor K.K. et al.NCCN guidelines insights: colon cancer, version 2.2018.J Natl Compr Canc Netw. 2018; 16: 359-369Crossref PubMed Scopus (408) Google Scholar As a convenient, noninvasive, safe alternative to surgery, SABR allows high ablative radiation doses to be delivered by using highly conformal techniques that avoid exposure of nearby critical normal tissues and can provide excellent local control with minimal toxicity. In this era of significant improvement in systemic therapy extending survival for patients with multiple metastases, there are continual studies demonstrating the role for SABR for a number of different primary histologies. For example, one meta-analysis of 15 studies showed that SABR for 686 pulmonary metastases from CRC led to local control rates of 81% at 1 year, 66% at 2 years, and 60% at 3 years. These local control rates were worse for pul
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