Andrea Tisch

Prospective assessment of radiotherapy‐associated cardiac toxicity in breast cancer patients: Analysis of data 3 to 6 years after treatment

Radiation therapy (RT) to the left breast/chest wall has been linked with cardiac dysfunction. Previously, the authors identified cardiac perfusion defects in approximately 50% to 60% of patients 0.5 to 2 years post‐RT. In the current study, they assessed the persistence of these defects 3 to 6 years post‐RT.

Risk of long-term complications after TFG-β1–guided very-high-dose thoracic radiotherapy

PURPOSE To report the incidence of late complications in long-term survivors of very-high-dose thoracic radiotherapy (RT) treated on a prospective clinical trial. METHODS AND MATERIALS Patients with locally advanced or medically inoperable non-small-cell lung cancer received three-dimensional conformal RT to the primary tumor and radiographically involved lymph nodes to a dose of 73.6 Gy at 1.6 Gy twice daily. If the plasma transforming growth factor-beta1 (TGF-beta1) level was normal after 73.6 Gy, additional twice-daily RT was delivered to successively higher total doses until the maximal tolerated dose was reached. Patients within a given dose level were followed for 6 months before escalation to the next dose level was permitted. Late complications were defined according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. RESULTS Thirty-eight patients were enrolled between 1996 and 1999. Twenty-four patients were not eligible for radiation dose escalation beyond 73.6 Gy because of persistently abnormal TGF-beta1 levels. Fourteen patients received dose escalation (80 Gy in 8; 86.4 Gy in 6). Grade 3 or greater late complications occurred in 4 of 24, 1 of 8, and 2 of 6 patients treated to 73.6, 80, and 86.4 Gy, respectively. The corresponding patient numbers with late Grade 4-5 toxicity were 3 of 24, 0 of 6, and 0 of 8. Overall, 7 (18%) of the 38 patients developed Grade 3-5 late toxicity. Nonpulmonary complications predominated (4 of 7). Five (71%) of seven serious complications developed within 11 months after RT; however, the remaining two complications (29%) occurred very late (at 43 and 62 months). The 5-year actuarial risk of late Grade 3-5 complications was 33%. CONCLUSION Long-term survivors of very-high-dose RT for non-small-cell lung cancer have a significant risk of severe treatment-related complications. At these high dose levels, the predominant toxicity may no longer be pulmonary. All Grade 4-5 complications occurred in patients whose dose was limited to 73.6 Gy because of a persistently elevated TGF-beta1. Thus, persistently elevated plasma TGF-beta1 levels toward the end of RT may identify patients at greatest risk of severe complications.

Using Plasma Transforming Growth Factor Beta-1 During Radiotherapy to Select Patients for Dose Escalation

PURPOSE The ability to prescribe treatment based on relative risks for normal tissue injury has important implications for oncologists. In non-small-cell lung cancer, increasing the dose of radiation may improve local control and survival. Changes in plasma transforming growth factor beta (TGFbeta) levels during radiotherapy (RT) may identify patients at low risk for complications in whom higher doses of radiation could be safely delivered. PATIENT AND METHODS Patients with locally advanced or medically inoperable non-small-cell lung cancer received three-dimensional conformal RT to the primary tumor and radiographically involved nodes to a dose of 73.6 Gy (1.6 Gy twice daily). If the plasma TGFbeta level was normal after 73.6 Gy, additional twice daily RT was delivered to successively higher total doses. The maximum-tolerated dose was defined as the highest radiation dose at which < or = one grade 4 (life-threatening) late toxicity and < or = two grade 3 to 4 (severe life-threatening) late toxicities occurred. RESULTS Thirty-eight patients were enrolled. Median follow-up was 16 months. Twenty-four patients were not eligible for radiation dose escalation beyond 73.6 Gy because of persistently abnormal TGFbeta levels. Fourteen patients whose TGFbeta levels were normal after 73.6 Gy were escalated to 80 Gy (n = 8) and 86.4 Gy (n = 6). In the 86.4-Gy group, dose-limiting toxicity was reached because there were two (33%) grade 3 late toxicities. CONCLUSION It is feasible to use plasma TGFbeta levels to select patients for RT dose escalation for non-small-cell lung cancer. The maximum-tolerated dose using this approach is 86.4 Gy.

Symptomatic Cardiac Events Following Radiation Therapy for Left-Sided Breast Cancer: Possible Association with Radiation Therapy—Induced Changes in Regional Perfusion

Our group has demonstrated that tangential radiation therapy (RT) to the left breast or chest wall can cause perfusion changes in the anterior myocardium. We assess if RT-induced perfusion changes are associated with the development of symptoms consistent with cardiac dysfunction. Between 1998 and 2001, 114 patients were enrolled into an institutional review board-approved prospective study and had pre-RT and serial post-RT (range, 6-24 months) single photon emission computed tomography (SPECT) scans to assess changes in regional cardiac perfusion. Thirty-one patients were excluded. The incidence of cardiac symptoms in patients with and without RT-induced perfusion defects was compared using a 2-tailed Fishers exact test. With a median follow-up of 16 months (range, 6-24 months), 10 of 83 evaluable patients had > or = 1 episode of transient chest pain, occurring 0-14 months after RT (median, 6 months). The rates of chest pain in the patients with and without new perfusion defects were 9 of 31 and 1 of 52, respectively (P = 0.0004). A similar result was found when patients were segregated based on the use of chemotherapy. Two of these 10 cases were diagnosed as pericarditis. No patient had myocardial infarction or congestive heart failure. Cardiac symptoms occur more frequently in patients with perfusion abnormalities by SPECT after RT than in patients with normal SPECT scans, suggesting that such perfusion defects may be clinically significant. One confounding factor is that women who know they have RT-induced perfusion defects may be more likely to report episode of chest pain. Long-term follow-up will be necessary to better assess the clinical significance of RT-induced perfusion defects.

Carboplatin/paclitaxel or carboplatin/vinorelbine followed by accelerated hyperfractionated conformal radiation therapy: Report of a prospective phase I dose escalation trial from the Carolina Conformal Therapy Consortium

Purpose To prospectively determine the maximum-tolerated dose of accelerated hyperfractionated conformal radiotherapy (RT; 1.6 Gy bid) for unresectable locally advanced lung cancer (IIB to IIIA/B) following induction carboplatin/paclitaxel (C/T) or carboplatin/vinorelbine (C/N). Methods Induction chemotherapy, C/T or C/N, was followed by escalating doses of conformally-planned RT (73.6 to 86.4 Gy in 6.4-Gy increments). Concurrent boost methods delivered 1.6 and 1.25 Gy bid to the gross and clinical target volumes, respectively. Results Between November 1997 and February 2002, 44 patients were enrolled (median age, 59 years; 59% male; stage III, 98%; median tumor size, 4 cm). Thirty-nine patients completed induction chemotherapy: 19 had a partial response, seven progressed, 15 had no response, and three were not assessable. Chemotherapy-associated toxicities were similar in the two chemotherapy groups. The incidence of grade ≥ 3 RT-induced toxicity was 1/13, 2/14, and 4/12 at 73.6, 80, and 86.4 Gy, respect...

SU‐FF‐T‐366: Radiation Dose Response Curve of Human Cerebral Cortex Measured with [F‐18]‐FDG and [O‐15]‐H2O PET Imaging

Purpose: To study radiotherapy (RT)‐induced dose‐dependent functional changes in the human cerebral cortex region using serial 18 F‐FDG and 15 O‐ H 2 O PETimaging before and after RT. Method and Materials: Eleven human subjects were enrolled in an IRB‐approved prospective study to quantitatively measure changes in post‐RT brain function. 18 F‐FDG and 15 O‐H 2 O PETimages were taken pre‐RT, and again at 3 weeks and 6 months post‐RT, to quantitatively assess for RT‐induced changes in relative metabolism and relative regional blood flow (RBF). The 3 week and 6 month follow‐up evaluations were available for 7 and 6 patients, respectively. Follow‐up images were registered to their corresponding pre‐RT baseline images, as well as to the treatment planning CT/MRI scans, for quantitative analysis. Relative changes in regional 18 F‐FDG and 15 O‐H 2 O PET activities were related to regional RT dose. Regions of the cerebral cortex receiving 40–50Gy. Initially, relative RBF increases (generally <10%) were observed on 15O‐H2O PETimaging (3 week follow‐up), but were much less significant at the 6‐month follow‐up. Conclusion: The response of cerebral cortex tissue to RT can be detected, in a dose‐dependent manner, using 18 F‐FDG PET. The magnitude of the changes, however, was typically small (<8%). Initially there were increases in relative RBF, but no discernable changes were seen at 6 months followup in 15 O‐H 2 O PET. Further studies are needed for more conclusive results. Results from neuropsychological testing will be used to assess the potential clinical impact of the changes measured by PET.