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Risk factors for survival after lung metastasectomy in colorectal cancer patients: systematic review and meta-analysis Michel Gonzalez*,1 & Pascal Gervaz2
Abstract Despite the lack of randomized trials, lung metastasectomy is currently proposed for colorectal cancer patients under certain conditions. Many retrospective studies have reported different prognostic factors of poorer survival, but eligibility for pulmonary metastasectomy remains determined by the complete resection of all pulmonary metastases. The aim of this review is to clarify which pre-operative risk factors reported in systematic reviews or meta-analysis are determinant for survival in colorectal metastatic patients. Different criteria have been now identified to select which patient will really benefit from lung metastasectomy. Colorectal cancer (CRC) is the third most common malignancy worldwide, with an estimated incidence of 1.2 million new cases each year [1] . At least 50% of CRC patients will develop metastatic disease that is localized in the lung in 5–15% of them [2] . 25% of patients present initially with synchronous metastases, and 25% patients subsequently develop metachronous metastases; however, 2% of patients only have isolated lung metastases. In the 1990s, these stage IV CRC patients, when left untreated, had a dismal prognosis, with a median survival 1; and disease-free interval 45% for intermediate and low risk patients, and the authors concluded that thoracic surgery should be restricted to this group of patients. Lymph node involvement which was not included as a criteria in this prognostic model although Pfannschmidt et al. [11] reported, in a series of 245 patients who underwent systematic lymph node dissection during pulmonary metastasectomy, that median survival were 21 and 64 months in patients with or without thoracic lymph nodes metastases, respectively. Recently, two surgical series have demonstrated the importance of lymph node involvement on survival [12,13] . The pre-operative lymph node staging including PET-CT, mediastinoscopy or EBUS might be necessary tools for patient selection. Nine series only have focused on the outcome of patients who underwent resection of both hepatic and pulmonary metastases [2] . Interestingly, survival rates are comparable to patients operated for lung metastases only. Salah et al. [14] performed a pooled analysis of patients operated for both hepatic and pulmonary metastases. He observed a 5-year survival rate of 54%. Two prognostic factors were associated with poor survival on univariate analysis: thoracic lymph node involvement and size of largest nodule >2 cm. However, in multivariate analysis, thoracic lymph node involvement was the only parameter, which correlated with decreased survival. These results suggest that previous liver resection do not contraindicate pulmonary metastasectomy when indicated. Recurrence rate after pulmonary resection of CRC metastases is frequent and the lung is involved in approximately 50% of the patients. Only a minority of these patients will fulfill the criteria for repeated resection due to limited residual lung capacity or diffuse recurrence. Seven studies have reported the outcome of patients who underwent repeated pulmonary resection [2] . The 5-year survival rates after first lung resection range from 29 to 85%. These
future science group
Risk factors for survival after lung metastasectomy in colorectal cancer patients results highlight the importance of follow-up and aggressive management of recurrence, when it is possible. Salah et al. [15] observed that 20% of patient will benefit of repeated resection, with a 5-year survival rate of 58%. In conclusion, there is actually no prospective randomized studies on CRC lung metastasectomy, but based upon the outcome of >2000 patients and >100 series, the following assumptions can be made: surgical resection of CRC metastases can be performed safely with low morbidity rate; prolonged disease-free survival is possible, at the condition that R0 resection is achievable; currently reported 5-year survival rates are similar (30–50%) to those of patients References 1
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J. Clin. 61(2), 69–90 (2011).
2
Gonzalez M, Ris HB, Krueger T, Gervaz P. Colorectal cancer and thoracic surgeons: close encounters of the third kind. Expert Rev. Anticancer Ther. 12(4), 495–503 (2012).
3
Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N. Engl. J. Med. 351(4), 337–345 (2004).
4
Giantonio BJ, Levy DE, O’dwyer P J et al. A Phase II study of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: results from the Eastern Cooperative Oncology Group study E2200. Ann. Oncol. 17(9), 1399–1403 (2006).
5
Treasure T. Pulmonary metastasectomy for colorectal cancer: weak evidence and no randomised trials. Eur. J. Cardiothorac. Surg. 33(2), 300–302 (2008).
Supplement
who undergo hepatectomy for CRC liver metastases; and hilar/mediastinal lymph node metastases may be considered a contra-indication to lung metastasectomy. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript. involvement at the time of pulmonary metastasectomy: experiences in 245 patients. Ann. Thorac. Surg. 81(2), 448–454 (2006).
6
V N. NCCN Clinical Practice Guidelines in Oncology. www.nccn.org
7
Pfannschmidt J, Dienemann H, Hoffmann H. Surgical resection of pulmonary metastases from colorectal cancer: a systematic review of published series. Ann. Thorac. Surg. 84(1), 324–338 (2007).
12 Hamaji M, Cassivi SD, Shen KR et al. Is
Pfannschmidt J, Hoffmann H, Dienemann H. Reported outcome factors for pulmonary resection in metastatic colorectal cancer. J. Thorac. Oncol. 5(6 Suppl. 2), S172–S178 (2010).
13 Renaud S, Alifano M, Falcoz PE et al. Does
8
9
Gonzalez M, Poncet A, Combescure C, Robert J, Ris HB, Gervaz P. Risk factors for survival after lung metastasectomy in colorectal cancer patients: a systematic review and meta-analysis. Ann. Surg. Oncol. 20(2), 572–579 (2013).
10 Salah S, Watanabe K, Welter S et al. Colorectal
cancer pulmonary oligometastases: pooled analysis and construction of a clinical lung metastasectomy prognostic model. Ann. Oncol. 23(10), 2649–2655 (2012). 11 Pfannschmidt J, Klode J, Muley T,
lymph node dissection required in pulmonary metastasectomy for colorectal adenocarcinoma? Ann. Thorac. Surg. 94(6), 1796–1800 (2012). nodal status influence survival? Results of a 19-year systematic lymphadenectomy experience during lung metastasectomy of colorectal cancer. Interact. Cardiovasc. Thorac. Surg. 18(4), 482–487 (2014). 14 S. Salah FA, Gonzalez M., Gervaz P. et al.
Hamed: pulmonary metastasectomy in colorectal cancer patients with previously resected liver metastasis: pooled analysis. J. Clin. Oncol. doi:10.1245/s10434-014-41739 (2014) (Epub ahead of print). 15 Salah S, Watanabe K, Park JS et al. Repeated
resection of colorectal cancer pulmonary oligometastases: pooled analysis and prognostic assessment. Ann. Surg. Oncol. 20(6), 1955–1961 (2013).
Dienemann H, Hoffmann H. Nodal
future science group
www.futuremedicine.com
33
Risk factors for survival after lung metastasectomy in colorectal cancer patients: systematic review and meta-analysis Michel Gonzalez*,1 & Pascal Gervaz2
Abstract Despite the lack of randomized trials, lung metastasectomy is currently proposed for colorectal cancer patients under certain conditions. Many retrospective studies have reported different prognostic factors of poorer survival, but eligibility for pulmonary metastasectomy remains determined by the complete resection of all pulmonary metastases. The aim of this review is to clarify which pre-operative risk factors reported in systematic reviews or meta-analysis are determinant for survival in colorectal metastatic patients. Different criteria have been now identified to select which patient will really benefit from lung metastasectomy. Colorectal cancer (CRC) is the third most common malignancy worldwide, with an estimated incidence of 1.2 million new cases each year [1] . At least 50% of CRC patients will develop metastatic disease that is localized in the lung in 5–15% of them [2] . 25% of patients present initially with synchronous metastases, and 25% patients subsequently develop metachronous metastases; however, 2% of patients only have isolated lung metastases. In the 1990s, these stage IV CRC patients, when left untreated, had a dismal prognosis, with a median survival 1; and disease-free interval 45% for intermediate and low risk patients, and the authors concluded that thoracic surgery should be restricted to this group of patients. Lymph node involvement which was not included as a criteria in this prognostic model although Pfannschmidt et al. [11] reported, in a series of 245 patients who underwent systematic lymph node dissection during pulmonary metastasectomy, that median survival were 21 and 64 months in patients with or without thoracic lymph nodes metastases, respectively. Recently, two surgical series have demonstrated the importance of lymph node involvement on survival [12,13] . The pre-operative lymph node staging including PET-CT, mediastinoscopy or EBUS might be necessary tools for patient selection. Nine series only have focused on the outcome of patients who underwent resection of both hepatic and pulmonary metastases [2] . Interestingly, survival rates are comparable to patients operated for lung metastases only. Salah et al. [14] performed a pooled analysis of patients operated for both hepatic and pulmonary metastases. He observed a 5-year survival rate of 54%. Two prognostic factors were associated with poor survival on univariate analysis: thoracic lymph node involvement and size of largest nodule >2 cm. However, in multivariate analysis, thoracic lymph node involvement was the only parameter, which correlated with decreased survival. These results suggest that previous liver resection do not contraindicate pulmonary metastasectomy when indicated. Recurrence rate after pulmonary resection of CRC metastases is frequent and the lung is involved in approximately 50% of the patients. Only a minority of these patients will fulfill the criteria for repeated resection due to limited residual lung capacity or diffuse recurrence. Seven studies have reported the outcome of patients who underwent repeated pulmonary resection [2] . The 5-year survival rates after first lung resection range from 29 to 85%. These
future science group
Risk factors for survival after lung metastasectomy in colorectal cancer patients results highlight the importance of follow-up and aggressive management of recurrence, when it is possible. Salah et al. [15] observed that 20% of patient will benefit of repeated resection, with a 5-year survival rate of 58%. In conclusion, there is actually no prospective randomized studies on CRC lung metastasectomy, but based upon the outcome of >2000 patients and >100 series, the following assumptions can be made: surgical resection of CRC metastases can be performed safely with low morbidity rate; prolonged disease-free survival is possible, at the condition that R0 resection is achievable; currently reported 5-year survival rates are similar (30–50%) to those of patients References 1
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J. Clin. 61(2), 69–90 (2011).
2
Gonzalez M, Ris HB, Krueger T, Gervaz P. Colorectal cancer and thoracic surgeons: close encounters of the third kind. Expert Rev. Anticancer Ther. 12(4), 495–503 (2012).
3
Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N. Engl. J. Med. 351(4), 337–345 (2004).
4
Giantonio BJ, Levy DE, O’dwyer P J et al. A Phase II study of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: results from the Eastern Cooperative Oncology Group study E2200. Ann. Oncol. 17(9), 1399–1403 (2006).
5
Treasure T. Pulmonary metastasectomy for colorectal cancer: weak evidence and no randomised trials. Eur. J. Cardiothorac. Surg. 33(2), 300–302 (2008).
Supplement
who undergo hepatectomy for CRC liver metastases; and hilar/mediastinal lymph node metastases may be considered a contra-indication to lung metastasectomy. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript. involvement at the time of pulmonary metastasectomy: experiences in 245 patients. Ann. Thorac. Surg. 81(2), 448–454 (2006).
6
V N. NCCN Clinical Practice Guidelines in Oncology. www.nccn.org
7
Pfannschmidt J, Dienemann H, Hoffmann H. Surgical resection of pulmonary metastases from colorectal cancer: a systematic review of published series. Ann. Thorac. Surg. 84(1), 324–338 (2007).
12 Hamaji M, Cassivi SD, Shen KR et al. Is
Pfannschmidt J, Hoffmann H, Dienemann H. Reported outcome factors for pulmonary resection in metastatic colorectal cancer. J. Thorac. Oncol. 5(6 Suppl. 2), S172–S178 (2010).
13 Renaud S, Alifano M, Falcoz PE et al. Does
8
9
Gonzalez M, Poncet A, Combescure C, Robert J, Ris HB, Gervaz P. Risk factors for survival after lung metastasectomy in colorectal cancer patients: a systematic review and meta-analysis. Ann. Surg. Oncol. 20(2), 572–579 (2013).
10 Salah S, Watanabe K, Welter S et al. Colorectal
cancer pulmonary oligometastases: pooled analysis and construction of a clinical lung metastasectomy prognostic model. Ann. Oncol. 23(10), 2649–2655 (2012). 11 Pfannschmidt J, Klode J, Muley T,
lymph node dissection required in pulmonary metastasectomy for colorectal adenocarcinoma? Ann. Thorac. Surg. 94(6), 1796–1800 (2012). nodal status influence survival? Results of a 19-year systematic lymphadenectomy experience during lung metastasectomy of colorectal cancer. Interact. Cardiovasc. Thorac. Surg. 18(4), 482–487 (2014). 14 S. Salah FA, Gonzalez M., Gervaz P. et al.
Hamed: pulmonary metastasectomy in colorectal cancer patients with previously resected liver metastasis: pooled analysis. J. Clin. Oncol. doi:10.1245/s10434-014-41739 (2014) (Epub ahead of print). 15 Salah S, Watanabe K, Park JS et al. Repeated
resection of colorectal cancer pulmonary oligometastases: pooled analysis and prognostic assessment. Ann. Surg. Oncol. 20(6), 1955–1961 (2013).
Dienemann H, Hoffmann H. Nodal
future science group
www.futuremedicine.com
33
