Recurrence Dynamics for Non–Small-Cell Lung Cancer: Effect of Surgery on the Development of Metastases Romano Demicheli, MD, Marco Fornili, PhD, Federico.

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Recurrence Dynamics for Non–Small-Cell Lung Cancer: Effect of Surgery on the Development of Metastases Romano Demicheli, MD, Marco Fornili, PhD, Federico Ambrogi, PhD, Kristin Higgins, MD, Jessamy A. Boyd, MD, Elia Biganzoli, PhD, Chris R. Kelsey, MD Journal of Thoracic Oncology Volume 7, Issue 4, Pages 723-730 (April 2012) DOI: 10.1097/JTO.0b013e31824a9022 Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Cause-specific hazard rate estimates for first event (local recurrence [LR] plus distant metastasis [DM] plus second primary [SP]) in 1506 patients undergoing surgery with curative intent for early-stage non–small-cell lung cancer. Time origin at surgery. A, Hazard rate within a 2-month interval. Smoothed curves are obtained by a Kernel-like smoothing procedure. Standard deviation estimates for single points are also reported. B, Hazard rate obtained by the piecewise exponential regression approach described in the Methods section. Vertical linesrepresent 95% pointwise confidence intervals. Journal of Thoracic Oncology 2012 7, 723-730DOI: (10.1097/JTO.0b013e31824a9022) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 Cause-specific hazard rate estimates for local recurrence, distant metastasis, and second primary in 1506 patients undergoing surgery with curative intent for early-stage non–small-cell lung cancer. Time origin at surgery. A, Hazard rate within a 2-month interval. Smoothed curves are obtained by a Kernel-like smoothing procedure. B, Hazard rate obtained by the piecewise exponential regression approach described in the Methods section. Vertical lines represent 95% pointwise confidence intervals. Journal of Thoracic Oncology 2012 7, 723-730DOI: (10.1097/JTO.0b013e31824a9022) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 Cause-specific hazard rate estimates for distant metastasis in 795 men (right) and 711 women (left) undergoing surgery with curative intent for early-stage non–small-cell lung cancer. Time origin at surgery. A, Hazard rate within a 2-month interval. Smoothed curves are obtained by a Kernel-like smoothing procedure. Standard deviation estimates for single points are also reported. B, Hazard rate obtained by the piecewise exponential regression approach described in the Methods section. Vertical lines represent 95% pointwise confidence intervals. Journal of Thoracic Oncology 2012 7, 723-730DOI: (10.1097/JTO.0b013e31824a9022) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

Figure 4 Cause-specific hazard rate estimates for distant metastasis in 711 women undergoing surgery with curative intent for early-stage non–small-cell lung cancer and in 251 premenopausal patients with axillary lymph node invasion who were treated with mastectomy alone for early-stage breast cancer. Time origin at surgery. A, Hazard rate within a 2-month interval. Smoothed curves are obtained by a Kernel-like smoothing procedure. B, Hazard rate obtained by the piecewise exponential regression approach described in the Methods section. Vertical lines represent 95% pointwise confidence intervals. Journal of Thoracic Oncology 2012 7, 723-730DOI: (10.1097/JTO.0b013e31824a9022) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

Figure 5 Outline of the metastatic process. Tumor cells leave the primary as single cells and seed the distant tissue where they may lodge for some time in a quiescent state or go on proliferating. Quiescent cells can be induced to proliferate by intrinsic or microenvironmental changes and will grow toward nonangiogenic micrometastases (and angiogenic ones in the presence of antiangiogenic factors) that cannot grow more than the size of avascular foci. The further growth phase implies the absence or the removal of angiogenesis inhibitors to release those already capable of inducing neovascularization, or the switch to an angiogenic phenotype of a subset of tumor cells within not-yet angiogenic micrometastases. After the beginning of the vascular phase micrometastases may grow until overt clinical recurrence. There is evidence that the presence of the primary tumor may exert some kind of homeostatic effect upon distant metastases, resulting in inhibited proliferation and/or enhanced apoptosis. In the presurgical condition the primary tumor may restrain transitions, thus concurring to, if not determining, the cellular and micrometastatic dormancy. Primary tumor removal, consequently, will enhance transitions and fuel the metastatic process. Journal of Thoracic Oncology 2012 7, 723-730DOI: (10.1097/JTO.0b013e31824a9022) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions