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L. Marks

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    E02 - Radiation Toxicity (ID 2)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      E02.1 - Cardiac Toxicity of Radiotherapy (ID 377)

      14:00 - 15:30  |  Author(s): L. Marks

      • Abstract
      • Presentation
      • Slides

      In patients receiving radiation for a diversity of diagnoses (e.g. Hodgkin’s Disease, breast cancer, seminoma), multiple studies demonstrate that incidental irradiation of the heart can increase the cardiac morbidity and mortality. While there is limited data in patients irradiated for lung cancer, RT-induced heart disease is likely clinically important and care should be taken to minimize incidental cardiac irradiation. Breast Cancer: Dose-response and evolution of techniques: In patients irradiated for breast cancer, there is a fairly well-defined dose/volume response for radiation-induced cardiac injury. The radiation techniques used to treat patients with breast cancer have evolved over the last several decades with a corresponding marked reduction in incidental cardiac doses (and corresponding decreased cardiac risks). For example, it has been estimated that mean heart doses were in the range of 10-15 Gy with anterior photon fields (directed to the internal mammary nodes), ≈5 Gy with tangents and medial IMN electrons, 1-2 Gy with partly-wide tangents, and <1 Gy with conformal cardiac blocking and breath hold. The cardiac implications for patients with breast cancer can be large. In some older studies the detrimental cardiac effects of radiation totally off-set the improvements in cancer-specific survival provided by RT. More modern radiation techniques clearly reduce the cardiac exposure and appear to reduce the frequency or RT-induced heart disease. However, the follow-up duration in the studies utilizing these modern techniques is not as long as are the follow-up durations in the studies using the older techniques. Thus, the long-term safety of “modern” RT can still be questioned. Timing of RT-associated heart injury in patients irradiated for breast cancer: In a classic meta-analysis (Cuzick; Recent Results Cancer Research 111:108-129, 1988; and JCO 12:452, 1994), post-mastectomy RT was associated with a reduction in overall survival at follow-up times >15 years post-RT. This observation helped fuel the traditional belief (recently being challenged) is that RT-induced cardiac injury is manifest at only extended follow-up intervals. This led our group and others to look for more short-term subclinical surrogates for RT-induced cardiac injury. Summary of our prospective study: We prospectively assessed RT-induced changes in regional myocardial perfusion in patients being treated for left-sided breast cancer using modern CT-based techniques. We noted a volume-dependent new perfusion abnormalities 6-24 months post-RT. These perfusion defects largely persist up to 6 years post-RT. The distribution of the perfusion defects follows the path of the tangential radiation field, and not the territory of a coronary artery, and thus represent microvasculature (rather than named coronary artery) injury. In patients with greater than 5% of the left ventricle within the tangential field, the incidence of new perfusion abnormalities si >50%. The functional consequences of these perfusion defects are uncertain. At short follow-up times, they are associated with a slightly increased rate of regional wall motion abnormalities. These wall motion abnormalities, however, do not always persist long-term. There are minimal, if any changes in ejection fraction noted in patients with perfusion defects. However, in patients with "severe" perfusion defects (scored by the summed rest score, SRS), there is suggestion that there might be a more meaningful reduction in ejection fraction (Marks 63:214, 2005, Lind IJROBP 55:914, 2003, Prosnitz Cancer, 110:1840, 2007). The clinical relevance of these perfusion defects remains uncertain. Perfusion defects may represent a reduction in collateral circulation making the patient more prone to develop ischemia when they (at a much later date) develop coronary artery disease. Therefore, care should be taken to minimize cardiac exposure for patients receiving left-sided RT. The use of conformal blocking (heart block), respiratory gating, and electron beam techniques are often useful to reduce cardiac exposure. Reconsideration of the timing of RT-induced cardiac injury in light of the recent analysis by Darby et al (NEJM 368:11, 2013): Darby’s report suggests that RT-induced cardiac injury in patients with breast cancer is clinically manifest relatively soon post-RT (i.e. within a few years), and that the cumulative risk increases continually up to 20 years post-RT. This suggests that the microvascular changes seen in our study (noted above) might have a clinical relevance in the short post-RT interval. Therefore, an alternative interpretation Cuzick et al (cited above) is that there is a clinically-meaningful increase in cardiac mortality in the 1-15 year post-RT interval, but that this is offset by the reduction in breast-cancer specific mortality during that time (resulting in a no net change in overall survival vs. the control group). At >15 years, the excess cardiac events exceed the cumulative anti-cancer effects, leading to the reduced overall survival noted. Lung Cancer: In patients early-stage lung cancer (N0-1), post-operative RT (PORT) is associated with an excess mortality within 0-5 years (Lancet 352:257; ’98). While the causes of the excess deaths are not noted in most studies, at least one study has noted increased cardiac deaths in this setting (Dautzenberg Cancer 86:265, ‘99). Two more-recent studies of “smaller field-PORT” (Mayer: Chest 112:954, ’97; Tradella Radio Oncol 62:11, 2002) demonstrate an improvement in overall survival with PORT, again suggesting that there is a delicate balance between RT-induced reductions in cancer-specific death and normal tissue-induced injury (Miles, IJROBP 68:1047, ‘07), totally analogous to the situation with breast cancer (Marks & Prosnitz, IJROBP 48:625, 2000). With definitive RT for lung cancer, RT-induced cardiac injury is not often reported. However, this might be under-reported as the symptoms of cardiac dysfunction (e.g. dyspnea) might be ascribed to lung disease. Better sparing of the heart during definitive RT for lung cancer is likely to improve the overall outcome. There are no clear dose/volume limits for the heart in patients with lung cancer (Gagliardi IJROBP 2010). Non-axial beams are often useful in reducing cardiac exposure, especially in patients with lower lobe tumors (Quaranta Journal Applied Clinical Medical Physics, 11:3010, 2010). Some portions of the heart might be particularly important in the genesis of RT-induced cardiac injury (e.g. pericardium, coronary arteries, left ventricle) and thus sophisticated techniques to redistribute incidental cardiac dose might be helpful. Dr Marks’s department receives grants from, or has relations with, from Elekta, Siemens, Accuray, Morphormics. Supported by NIH CA069579.

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    P3.12 - Poster Session 3 - NSCLC Early Stage (ID 206)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.12-017 - The lack of impact of pre-operative PET on the risk, and pace, of subsequent failure following surgery for early stage non-small cell lung cancer? (ID 2901)

      09:30 - 16:30  |  Author(s): L. Marks

      • Abstract

      PET scans are generally believed to be more sensitive than are CT in detecting metastatic disease and thus are widely used in the pre-operative assessment of patients with early-stage lung cancer. Given the increased sensitivity afforded with PET, one would expect the PET-staged patients to be “more favorable” than their “CT-staged only” patients (i.e. “stage migration”). The PET-staged patients should theoretically have a lower rate of subsequent distant failure. Further, among those who fail, the PET-staged patients should theoretically fail at a later time post-operatively (compared to their CT-only-staged patients). We herein compare the clinical outcomes in a group of patients with early stage lung cancer staged pre-operatively with CT with or without PET scan.

      The records of 335 patients undergoing curative surgery at UNC hospital between January 1996 through December 2006 were retrospectively reviewed, with extensive data extraction including staging, treatment, and outcome data. Univariate and multivariate analysis were performed to identify predictors for clinical outcome. Failure times in sub-groups were calculated with the Kaplan–Meier method and compared via log-rank test. The rate and pace of recurrence were considered. Independent factors adversely affecting failure were determined with Cox regression.

      Figure 1112/335 patients (33%) had pre-operative staging PET scans. For the overall group (n= 335), and for the N0 (n=256) and N1 (n=79) subgroups, there was no evidence that the use of a pre-operative PET scan was associated with a lesser rate of subsequent distant failure, or a slower rate of distant failure (p>0.05 on uni- and multi-variate analyses) (Figure-1). On multivariate analysis, the predictors of distant failure included lympho-vascular invasion (p=0.02, HR=1.3), T stage (T1-2 vs T3) (p=0.009, HR=1.4) and N stage (N0 vs N1) (p=0.007, HR=1.5). The predictors for recurrent disease included lympho-vascular invasion (p=0.004, HR=1.8), T stage (p=0.001, HR=1.3) and N stage (p=0.004, HR=1.7).

      The use of a pre-operative PET scan did not significantly alter the rate, or the pace, of distant recurrence or relapse of any kind, in patients undergoing surgery for non-small cell lung cancer (compared to CT-only staged patients). The retrospective nature of this study limits its validity. However, the PET-scanned patients were treated more recently, and were therefore perhaps more favorable (with both shorter follow up and with access to more modern interventions).