Stage I-II NSCLC Treated With SABR or VATS Lobectomy
Stage I-II NSCLC Treated With SABR or VATS Lobectomy
This retrospective study was approved by the institutional ethics board. VATS was introduced at the VU University Medical Center (VUMC) in 2007 and subsequently implemented in five regional hospitals, where each procedure was carried out jointly with an experienced VUMC surgeon. Lobectomy was carried out using the complete VATS technique, as previously described. Details of patients with a clinical or pathological diagnosis of T1-3N0M0 NSCLC and treated with VATS lobectomy at all six centers were accessed through a database. All disease staging was carried out using UICC TNM-7. A diagnosis of clinical stage I–II disease was made after guideline-specified staging, including a CT scan of the thorax and upper abdomen and FDG-PET scans. Findings suspicious of nodal metastases required confirmatory biopsy, generally using minimally invasive endoscopic techniques. A nodal dissection was routinely carried out in accordance with guidelines.
Details of all patients treated with SABR at the VUMC since November 2003 were collected in a prospective institutional database. SABR was delivered in an outpatient setting, using risk-adapted fractionation schemes, as previously described, using more fractions and a lower dose per fraction for larger tumors and those adjacent to critical normal organs. Fractionation schemes had a biologically effective dose of >100 Gy10, with the scheme of 12 fractions of 5 Gy being the sole exception. Individualized target volumes encompassing all motion on four-dimensional CT scans were used for treatment planning and no active motion management, including respiratory gating, was used. Treatment plans were optimized to limit high-dose regions to organs at risk.
Patients were excluded from the matching procedure if they had any of the following: synchronous lung tumor, previous lung malignancy or severe COPD as defined by GOLD class 4. Propensity score matching reduces bias and confounding by matching patients on numerous baseline variables, using a multivariable logistic regression model. A total of 86 VATS and 527 SABR patients were eligible for matching, which was carried out by investigators blinded to treatment outcome. Patient data were anonymized and outcome data removed before propensity score matching using the following covariates: gender, age, clinical tumor stage, tumor diameter, location of the tumor, pretreatment tumor histology, lung function (FEV1%), Charlson comorbidity score and WHO performance score. Matching was carried out using a ratio of 1:1, and a caliper distance of 0.025, without replacement.
The probability of malignancy in matched patients without a pretreatment pathological diagnosis was calculated using a combination of clinical, radiological and FDG-PET findings, as described previously for a Dutch population.
Post-treatment follow-up generally consisted of a contrast-enhanced CT scan of the thorax and abdomen carried out at 2 to 3 months, 6-monthly for 2 years, and annually thereafter. FDG-PET scans were only repeated in case of suspected relapse in patients who were considered fit enough to receive therapy. For patients who were unable or unwilling to attend the follow-up at the treating hospital, the general practitioner or lung physician was contacted for follow-up.
For SABR patients, locoregional failure was defined as a recurrence in, or adjacent to, the planning target volume and/or in the ipsilateral hilum or mediastinum. Locoregional failure following VATS was considered present when recurrences arose at, or adjacent to, surgical resection margins and/or in the ipsilateral hilum or mediastinum. Freedom from progression (FFP) was defined as freedom from any tumor recurrence. Every recurrence had to be either biopsy-confirmed or PET-positive and discussed in a multidisciplinary team. SABR patients suspected of local recurrence, but in whom no tissue diagnosis was available, were scored as having a recurrence.
Time-to-event outcomes were analyzed using the Kaplan–Meier method and the median follow-up was calculated using the reverse Kaplan–Meier method. Cases were censored when death was observed. In order to compare time-to-event outcomes between VATS and SABR groups, P-values were calculated using the Cox regression stratified by matched pairs. Toxicity was scored according to Common Terminology Criteria for Adverse Events version 4.0. The chi-square test was used to compare toxicity, and the Student t-test was used to compare the likelihood of malignancy between groups. All statistical analyses were two-sided, with P ≤ 0.05 indicative of statistical significance, and carried out using SAS version 9.2 or the Statistical Package for Social Sciences (SPSS), version 15.0.
Materials and Methods
This retrospective study was approved by the institutional ethics board. VATS was introduced at the VU University Medical Center (VUMC) in 2007 and subsequently implemented in five regional hospitals, where each procedure was carried out jointly with an experienced VUMC surgeon. Lobectomy was carried out using the complete VATS technique, as previously described. Details of patients with a clinical or pathological diagnosis of T1-3N0M0 NSCLC and treated with VATS lobectomy at all six centers were accessed through a database. All disease staging was carried out using UICC TNM-7. A diagnosis of clinical stage I–II disease was made after guideline-specified staging, including a CT scan of the thorax and upper abdomen and FDG-PET scans. Findings suspicious of nodal metastases required confirmatory biopsy, generally using minimally invasive endoscopic techniques. A nodal dissection was routinely carried out in accordance with guidelines.
Details of all patients treated with SABR at the VUMC since November 2003 were collected in a prospective institutional database. SABR was delivered in an outpatient setting, using risk-adapted fractionation schemes, as previously described, using more fractions and a lower dose per fraction for larger tumors and those adjacent to critical normal organs. Fractionation schemes had a biologically effective dose of >100 Gy10, with the scheme of 12 fractions of 5 Gy being the sole exception. Individualized target volumes encompassing all motion on four-dimensional CT scans were used for treatment planning and no active motion management, including respiratory gating, was used. Treatment plans were optimized to limit high-dose regions to organs at risk.
Patients were excluded from the matching procedure if they had any of the following: synchronous lung tumor, previous lung malignancy or severe COPD as defined by GOLD class 4. Propensity score matching reduces bias and confounding by matching patients on numerous baseline variables, using a multivariable logistic regression model. A total of 86 VATS and 527 SABR patients were eligible for matching, which was carried out by investigators blinded to treatment outcome. Patient data were anonymized and outcome data removed before propensity score matching using the following covariates: gender, age, clinical tumor stage, tumor diameter, location of the tumor, pretreatment tumor histology, lung function (FEV1%), Charlson comorbidity score and WHO performance score. Matching was carried out using a ratio of 1:1, and a caliper distance of 0.025, without replacement.
The probability of malignancy in matched patients without a pretreatment pathological diagnosis was calculated using a combination of clinical, radiological and FDG-PET findings, as described previously for a Dutch population.
Post-treatment follow-up generally consisted of a contrast-enhanced CT scan of the thorax and abdomen carried out at 2 to 3 months, 6-monthly for 2 years, and annually thereafter. FDG-PET scans were only repeated in case of suspected relapse in patients who were considered fit enough to receive therapy. For patients who were unable or unwilling to attend the follow-up at the treating hospital, the general practitioner or lung physician was contacted for follow-up.
For SABR patients, locoregional failure was defined as a recurrence in, or adjacent to, the planning target volume and/or in the ipsilateral hilum or mediastinum. Locoregional failure following VATS was considered present when recurrences arose at, or adjacent to, surgical resection margins and/or in the ipsilateral hilum or mediastinum. Freedom from progression (FFP) was defined as freedom from any tumor recurrence. Every recurrence had to be either biopsy-confirmed or PET-positive and discussed in a multidisciplinary team. SABR patients suspected of local recurrence, but in whom no tissue diagnosis was available, were scored as having a recurrence.
Time-to-event outcomes were analyzed using the Kaplan–Meier method and the median follow-up was calculated using the reverse Kaplan–Meier method. Cases were censored when death was observed. In order to compare time-to-event outcomes between VATS and SABR groups, P-values were calculated using the Cox regression stratified by matched pairs. Toxicity was scored according to Common Terminology Criteria for Adverse Events version 4.0. The chi-square test was used to compare toxicity, and the Student t-test was used to compare the likelihood of malignancy between groups. All statistical analyses were two-sided, with P ≤ 0.05 indicative of statistical significance, and carried out using SAS version 9.2 or the Statistical Package for Social Sciences (SPSS), version 15.0.
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