Chest RT Research Articles

Improved Neurocognitive Outcomes with Contemporary Treatments in Survivors of Early Adolescent and Young Adult Hematologic Malignancies from the Childhood Cancer Survivor Study

Background: Neurocognitive impairments in survivors of hematologic malignancies diagnosed specifically during adolescence and early young adulthood (eAYA survivors) are not well described, despite use of intensive neurotoxic therapies. We evaluated how recent shifts in therapeutic approaches have impacted neurocognitive outcomes in survivors diagnosed during eAYA compared to younger survivors and sibling controls. Methods: We identified 1213 eAYA (diagnosed at 15-21 years) and 4538 pediatric (diagnosed at <15 years) survivors of acute lymphoblastic lymphoma (ALL; n= 301 v. 3274), acute myeloid leukemia (AML; n= 77 v. 424), and Hodgkin lymphoma (HL; n= 835 v. 840) as well as 1014 siblings from the Childhood Cancer Survivor Study (>5 year survivors diagnosed 1970-1999) who completed the Neurocognitive Questionnaire ( Table 1). Impairment was defined as a score in worst 10% of the sibling cohort in task efficiency (TE), organization (Org), memory (Mem), and emotional regulation (ER) domains. Survivors were stratified into groups reflective of diagnosis, treatment era, and intensity: HL-chest RT ≥35Gy = HL with chest radiation ≥35Gy (High-risk disease, older regimens); HL-chest RT <35Gy = HL with chest radiation <35Gy (Intermediate risk disease, contemporary regimens); HL-salvage = HL with salvage therapy (High-risk disease, higher intensity regimens), ALL-CRT = ALL with use of cranial radiation (CRT) (Older regimens), ALL-no CRT = ALL without use of CRT (Contemporary regimens), ALL-salvage = ALL with salvage therapy (High-risk disease, higher intensity regimens), AML-chemo = AML with chemotherapy only (Lower risk disease), AML-SCT = AML with history of stem cell transplant (Higher risk disease). The prevalence of neurocognitive impairment compared to siblings was estimated using generalized-estimating-equation logistic regression accounting for potential within-family correlation. Health status and health behaviors were examined as risk factors for neurocognitive impairment. Adjusted odds ratios (OR) and corresponding 95% confidence intervals (CI) are reported. Results: Prevalence of any neurocognitive impairment in the eAYA, pediatric, and sibling groups was 30.8%, 37.7%, and 25.4%, respectively. Prevalence was similar for eAYAs and pediatric survivors of HL (31.0% v. 29.6%, p=0.54) and AML (36.4% v. 40.6%, p=0.49), while lower in eAYA ALL survivors (28.2% v. 38.7%, p<0.01). Compared to siblings, eAYA HL survivors who received salvage therapy were more likely to have impaired Org (OR 2.5, 95% CI 1.2-5.1) and Mem (OR 2.7, 95% CI 1.3-5.8), while those who received high-dose chest RT experienced more Mem impairment (OR 2.0, 95% CI 1.2-3.4) ( Table 2). Compared to siblings, Mem was the most commonly affected domain in eAYA ALL survivors who received CRT (OR 4.0, 95% CI 2.0-7.9); this was not observed in the non-CRT or salvage groups. In a separate analysis of treatment exposures, anthracycline ≥120mg/m 2 uniquely increased prevalence of ER in eAYA ALL survivors (OR 4.7, 95% CI 1.7-12.9). Compared to siblings, survivors of eAYA AML who underwent SCT had higher odds of Mem impairment (OR 5.3, 95% CI 1.9-14.7). In a direct comparison with pediatric AML survivors, eAYA AML survivors were also more likely to have impaired Mem (OR 2.6, 95% CI 1.1-6.2) (data not shown). Being physically active (OR range 0.3-0.7), a never-smoker (OR range 0.5-0.6), and insured (OR range 0.4-0.5) were protective across all domains in eAYA-cancer survivors. Conclusions: Survivors of hematologic cancers diagnosed during eAYA are susceptible to neurocognitive impairment at rates similar to those diagnosed at younger ages for HL and AML but at reduced rates for survivors of ALL. Memory was the most affected domain in eAYA survivors. Contemporary regimens utilizing intermediate-dose (<35Gy) chest RT for HL or omission of cranial RT for ALL attenuated the extent of risk. Future studies should focus on characterizing outcomes across the entire AYA age spectrum.

Excellent results of screening for subsequent breast cancers in long-term survivors of childhood Hodgkin's lymphoma-Results of a population-based study.

Subsequent breast cancer (SBC) represents a major complication in childhood cancer survivors and screening for SBC in survivors after incidental irradiation of breasts is recommended. In this article, we report the results and discuss benefits of SBC screening in female pts treated for Hodgkin's lymphoma (HL) in Slovenia in a period of 45 years. Between 1966 and 2010, 117 females were treated for HL under the age of 19 in Slovenia. One hundred five of them survived for 5 years and were included in our study. They were 3-18 (med. 15) years old at diagnosis and followed for 6-52 (med. 28) years. Eighty-three percent of them had chest RT with a median dose of 30 Gy. Ninety-seven (92%) of 105 pts were regularly followed according to the international guidelines including yearly screening mammography/breast MRI in those who received chest RT. We diagnosed 10 SBCs in eight pts 14-39 (med. 24) years after diagnosis at the age of 28-52 (med. 42) years. At 40 years of follow-up, cumulative incidence of SBCs in females who got chest RT was 15.2%. Seven of eight patients (with 9 SBCs) got chest RT with 24-80 (med. 36) Gy at the age of 12 to 18 (median 17) years. Two patients in this group got bilateral SBC. One patient got invasive SBC after being treated with ChT containing high-dose of anthracyclines without chest RT at the age of 13. All eight invasive SBCs were invasive ductal cancers, HER2 receptors negative, all but one with positive hormonal receptors. Six invasive cancers were of stage T1N0, one T1N1mi, only one, diagnosed before era of screening, was of T2N1. None of 8 pts died of SBC. After introduction of regular breast screening in our female patients, who received chest RT in childhood, all SBCs were of early stage and no patients died of SBC. Survivors of pediatric HL should be informed about the risk of late sequelae of treatment for HL, including SBC. Regular follow-up with breast cancer screening and breast self-examination is of vital importance in those treated with chest RT.

Abstract 10979: Long Term Risk of Coronary Artery Disease in Breast Cancer and Lymphoma Patients After Chemotherapy Plus Radiation Treatment vs Chemotherapy Only

Introduction: patients exposed to chest, breast or mediastinal RT, may present with accelerated atherosclerosis and CAD due to diffuse micro and macrovascular fibrosis. However, CAD risk has not been well established in a community-based study. Aims: Describe CAD risk in patients treated with chemotherapy with and without RT and evaluate the cumulative incidence of CAD (coronary revascularization, MI and abnormal stress test and coronary angiogram). Methods: From 1985-2010, we identified 744 patients with a new diagnosis of breast cancer or lymphoma, using the Rochester Epidemiology Project (REP) who received chemotherapy with or without RT. CAD risk was assessed by a proportional hazards model for time to event. RT was treated as a time dependent co-variable, with index date being chemotherapy start date, significance was considered as a p<.05. Characteristics were evaluated by a multivariable Cox model to consider RT and time censoring. Results: 744 patients treated with chemotherapy were identified, of these 488 (65.6%) had breast cancer, 256 (34.4%) lymphoma, and 367 (49%) also received RT. The mean total RT dose was 5.5 ± 1.2 (Gy) for those that had CAD and 5.4 (Gy) ± 1.1 for non-CAD patients, p=0.4. The cumulative incidence of CAD events (accounting for death as a competing risk) at 5 and 10 years of follow-up was 1.9% (CI 1.14-3.2) and 3.06% (CI 2.01-4.7), respectively p<.05 figure1. Baseline differences between those receiving RT or not, were not significant for DM and HTN; however, males and ages 70-79 were less likely to receive RT, table1. In a multivariable model, there was no difference in the CAD outcomes between those with and without RT, HR= 1.21 [0.48-3.06] p=.69, after adjusting for age, gender, DM, and HTN and those <49 y/o had a lower risk of CAD. Table2 Conclusion: In this REP retrospective cohort study, the risk of developing a CAD event was similar between chemotherapy plus RT and chemotherapy only regimens, even after considering gender, age, HTN and DM.

Abstract 5414: Epigenetic age acceleration and chronic health conditions among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort

Abstract Background: The epigenetic clock becomes an important biomarker in aging research, where epigenetic age (EA) approximates chronological age with high accuracy and epigenetic age acceleration (EAA) demonstrates superior performance in predicting health outcomes in the general population. The utility of EAA among adult survivors of childhood cancer is largely unknown. We aimed to compare EAA between childhood cancer survivors and non-cancer controls, and evaluate associations between EAA, treatment exposures, health behaviors, and chronic health conditions (CHCs) among survivors. Methods: Genome-wide methylation data were generated with Infinium EPIC BeadChip on blood derived DNA from 2139 survivors and 282 community controls with no prior history of cancer. EAA was estimated as the residual value from the fit of a simple linear regression of EA (using Levine's clock) on chronological age (i.e., age at DNA sampling). Cumulative doses of chemotherapy and region-specific radiation exposures were abstracted from medical records. Health behaviors including physical activity, diet, tobacco smoking, and alcohol consumption were assessed from questionnaires and categorized as favorable, intermediate and unfavorable. Multivariable piecewise-exponential regression model was employed to evaluate associations of EAA with 59 clinically assessed CHCs. Results: EA was highly correlated with chronological age with the same Pearson coefficient (r = 0.88) in survivors and controls; however, EAA was significantly higher in survivors than controls, overall (adjusted least square mean [ALSM] = 0.63 vs. -3.61 years, P<0.001) and across primary diagnoses (ranging from ALSM = -1.27 in central nervous system tumor to 4.61 in Hodgkin lymphoma). Among survivors, significantly higher EAA was associated with exposures to chest RT, abdomen/pelvic RT, alkylating agents, glucocorticoids, or epipodophyllotoxins. Compared to survivors with favorable health behaviors (ALSM = 0.26), EAA was higher in survivors with intermediate (1.07, P = 0.04) or unfavorable health behaviors (1.45, P = 0.03). After adjusting for attained age, sex, age at diagnosis, and treatment, significant linear trends across tertiles of EAA were identified in associations with occurrences of five CHCs: hypertension (Relative Rate = 1.83 for survivors with EAA in the 3rd vs. the 1st tertile, 95% CI = 1.17-2.83); myocardial infraction (2.91, 1.27-7.21); obesity (1.39, 1.17-1.66); obstructive pulmonary deficit (1.86, 0.95-3.77); and peripheral sensory neuropathy (2.04, 0.99-4.26). Conclusion: EAA is significantly higher in childhood cancer survivors than non-cancer controls and is associated with treatment exposures, health behaviors, and CHCs. Clinically, EAA may inform intervention strategies including health coaching to prevent or delay the onset of CHCs among survivors of childhood cancer. Citation Format: Na Qin, Zhenghong Li, Nan Song, John Easton, Heather Mulder, Emily Plyler, Geoffery Neale, Emily Walker, Carmen L. Wilson, Melissa M. Hudson, Yutaka Yasui, Leslie L. Robison, Jinghui Zhang, Kirsten K. Ness, Zhaoming Wang. Epigenetic age acceleration and chronic health conditions among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5414.

Initial reporting of NRG-LU001 (NCT02186847), randomized phase II trial of concurrent chemoradiotherapy (CRT) +/- metformin in locally advanced Non-Small Cell Lung Cancer (NSCLC).

8502 Background: Metformin, a diabetes agent that inhibits mitochondria complex I, enhances radiotherapy and chemotherapy responses in pre-clinical models of NSCLC. NRG-LU001 examined whether metformin can improve outcomes of curative CRT in locally advanced (LA)-NSCLC. Methods: The primary endpoint of this trial was 1-year progression free survival (PFS). Unresected, non-diabetic, stage IIIA/B NSCLC patients were randomized (1:1) to either carboplatin-paclitaxel chemotherapy concurrent with chest RT (60Gy), followed by consolidation carboplatin-paclitaxel chemotherapy (Control Arm) or the same and oral metformin (2000mg daily) during cytotoxic therapy (Experimental Arm). PFS and overall survival (OS) were estimated with the Kaplan-Meier method; time to local-regional progression (TTLRP), time to distant metastasis (TTDM) were estimated using the cumulative incidence method. Adverse events (AEs) were graded with CTCAE v.4.0. Results: Between Aug.2014 and Dec.2016, 170 patients were accrued. Analysis was planned at 102 PFS events (Feb. 2019). There was no significant difference in rates or grade of toxicity between the two arms. 1- and 2-year PFS was 60.4% (95% CI: 48.5, 70.4) and 40.1% (95% CI: 29.0, 51.0) in Control vs 51.3% (95% CI: 39.8, 61.7) and 34.5% (95% CI: 24.2, 45.1) in the Metformin arm (multivariable Cox proportional HR=1.20 (95% CI: 0.81, 1.78), p=0.36). OS at 2 years was 65.4% (95% CI: 53.5, 75.0) for Control vs 64.9% (95% CI: 53.1, 74.5) for the Metformin arm (HR=1.03 (95% CI: 0.64, 1.68)), while deaths due to disease were 90% vs 71%, respectively. No significant differences were found for TTLRP or TTDM. Conclusions: NRG-LU001 center reported outcomes show that oral daily metformin was well-tolerated in combination with CRT treatment for LA-NSCLC. However, metformin did not improve PFS and OS and did not alter the rates of local-regional failure or distant metastasis. Acknowledgements: TT and HS are Co-Principal Investigators. This project was supported by National Cancer Institute (NCI) grants: U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG SDMC), UG1CA189867 (NCORP), U24CA180803 (IROC). Clinical trial information: NCT02186847.

Obstructive and restrictive pulmonary dysfunction in long-term lymphoma survivors after high-dose therapy with autologous stem cell transplantation

Background: Obstructive and restrictive dysfunction in long-term lymphoma survivors (LSs) after high-dose therapy with autologous stem-cell transplantation (HDT-ASCT) has not been addressed systematically previously.Material and methods: LSs treated in Norway 1987–2008 with HDT-ASCT who performed spirometry, measurement of static lung volumes and echocardiography 2012–2014 at either Oslo or St. Olavs University Hospitals was eligible. Smoking data were recorded by questionnaire. Treatment data were collected from medical records or hospital databases. Factors associated with obstructive and restrictive impairments (dichotomous outcomes) were examined by Poisson regression. Linear regression with the margins post-estimation command was used to derive adjusted mean values of forced expiratory volume in 1 s (FEV1). We used the normative reference data recommended by the European Respiratory Society for calculating percent predicted values.Results: A total of 226 LSs were studied, of whom 11.5 and 5.8% had obstructive and restrictive impairment, respectively. For women and men, mean FEV1 was 2.31 and 3.34 l corresponding to 11.4%- and 11.1%-points below that predicted from norms, respectively. In multivariable regression analyses, cumulative doxorubicin dose (400–775 mg/m2) and current smoking were associated with increased risk of obstructive impairment, and chest RT (>13–66 Gy) was associated with increased risk of restrictive impairment. Currently smoking LSs within the highest doxorubicin category (400–775 mg/m2), had the lowest adjusted mean FEV1.Conclusions: Despite intensive cancer treatment, our analysis showed modest reductions in obstructive parameters among long-term LSs after HDT-ASCT compared to normative reference data. To limit obstructive impairments in LSs after HDT-ASCT, we suggest that targeted smoking-cessation advice is directed towards patients who have received high cumulative doses of doxorubicin.

PL 04.01 Where We Are Now, and Where We Will Be in 10 years: From North American Perspective

PL 04.01 Where We Are Now, and Where We Will Be in 10 years: From North American Perspective

OC-0245: Clinical evidence that end-of-range proton RBE exceeds 1.1: lung density changes following chest RT

OC-0245: Clinical evidence that end-of-range proton RBE exceeds 1.1: lung density changes following chest RT

An integrative cross-tumors approach identifies FOSL1 as an oncogene dependency in KRAS-driven lung cancer

The Ontario Clinical Oncology Group (OCOG) – ALMERA trial (NCT02186847) is a Canadian multicenter randomized phase II trial funded by the Canadian Institute for Health Research, which is designed to examine whether metformin has chemo-radio-sensitization activity as well as activity as a single agent in advanced localized NSCLC. A total of 94 patients will be randomized in this screening trial to standard CRT with or without treatment with 2000mg of metformin, which is delivered during CRT (2 cycles of cisplatin based chemotherapy, concurrent with chest RT of 63 Gy in 30 fractions) but continues also as a single agent for a total of 12 months. ALMERA is designed to detect a 20% improvement in lung cancer progression free survival at 12 months. This trial is now open in several centers across Canada. The primary outcome is 12 month Progression Free Survival (PFS) and secondary outcomes include 1 and 2 y overall survival (OAS), time to loco-regional progression, distant progression free survival, adverse events and collection of biospecimens for biomarker studies. These will involve investigation of circulating serum and blood cell biomarkers of metformin activity and tumor biomarkers such as tumor histology, TP53, LKB1 and K-Rasmutation status. When completed ALMERAwill provide some of the first prospective evidence on the potential of metformin to improve the outcomes of standard cytotoxic therapy in locally advanced NSCLC. Biospecimen collect will allow us to investigate serum and tumors biomarkers ofmetformin response. Comparison of the results of ALMERA with other studies, like NRG-LU001, may be able to provide evidence on the value of metformin as maintenance therapy and assist in the design of future phase III trials with metformin in the setting of locally advanced NSCLC.

Impact of Prophylactic Dexamethasone on Pain Flare Following Spine Stereotactic Body Radiation Therapy (SBRT)

anatomic site. Follow-up was completed on 55 patients (71%). Median follow-up time from the initial consult was 43 days (range, 31-77). The median Palliative Performance Status increased from 50 to 65 (p Z 0.97). The median patient reported overall health score, improved from 5 to 7 (p Z 0.07). Among patients who received chest RT, 88% reported stable or improved levels of shortness of breath following RTwith a median score of 3 prior to treatment, and 2 post-treatment (p Z 0.01) and 91% reported stable or better cough compared with a median baseline score of 2 and 1 post treatment (p Z 0.01). In patients who received RT for bone metastases, median pain scores decreased from 4 to 0.5 (pZ 0.01). Compared to baseline, bone pain was more likely to be relieved by an analgesic following RT (p Z 0.07) and less likely to interfere with sleep (p Z 0.03). Daily dexamethasone consumption decreased from 7 mg to 1.3 mg following whole brain RT (p < 0.01). The 3 and 6 month overall survival was 63% and 52%, respectively; median survival was not met at time of analysis. Conclusions: Despite the burden of symptoms that patients present with at consultation, the services provided by the clinic seemed to be associated with an improvement in patient reported outcomes. Overall health, respiratory symptoms and bony pain in particular seem to improve at follow-up. These positive findings, combined with prior evidence that the rapid access clinic improves the delivery of care to this patient group compared to standard practice, highlight the continued value of the clinic at our center and may provide support for extending this clinic model to other primary tumor sites. Author Disclosure: S. Lefresne: None. R.A. Olson: None. R. Cashman: None. W. Jiang: None. P. Kostuik: None. K. Levy: None. M. Liu: None. H. Carolan: None. M. Mckenzie: None. E. Berthelet: None.

Proton versus photon radiation therapy for patients with high‐risk neuroblastoma: The need for a customized approach

Proton therapy for treatment for high-risk neuroblastoma may offer sparing of organs at risk (OAR) when compared to intensity-modulated X-ray therapy (IMXT). Double-scattered proton plans and IMXT plans delivering 2,160 cGy to the primary tumor site and other residual disease were developed for 13 consecutive HR-NBL patients. Radiation doses to target volumes and OAR were calculated to determine the optimal modality for each. All patients received radiation (5/13 ≥ 2 sites). No patient has experienced local recurrence or clinical organ toxicity. Coverage was excellent using both protons and IMXT: median % dose delivered to 95% clinical target volume was 99% and 100%, respectively. For nine patients with lateralized disease, proton therapy offered sparing of the contralateral kidney both with regard to median dose and dose to 20% (median <1 cGy vs. 362 cGy, P = 0.01; median 100 cGy vs. 634 cGy, P = 0.02, respectively). Proton therapy did not reduce ipsilateral kidney dose, and for 2 select patients with lateralized disease IMXT improved overall bilateral renal sparing. Proton therapy improved median bowel (median 33 cGy vs. 590 cGy, P = 0.01), total body (median <1 cGy vs. 30 cGy, P = 0.15), and liver dose (median <1 cGy vs. 529, P < 0.001). When chest RT was required, proton therapy decreased median heart dose and mean lung dose. For most patients (11/13), proton therapy offered the optimal combination of target coverage and organ sparing, and is a feasible treatment for HR-NBL. We recommend a customized approach with careful evaluation of renal dosimetry; IMXT may be preferred for select patients.

Early CT and FDG-metabolic tumour volume changes show a significant correlation with survival in stage I–III small cell lung cancer: A hypothesis generating study

Background Many patients with stage I–III small cell lung cancer (SCLC) experience disease progression short after the completion of concurrent chemoradiotherapy (CRT). The purpose of the current study was to evaluate whether CT or FDG metabolic response early after the start of chemotherapy, but before the beginning of chest RT, is predictive for survival in SCLC. Methods Fifteen stage I–III SCLC patients treated with concurrent CRT with an FDG-PET and CT scan available before the start of chemotherapy and after or during the first cycle of chemotherapy, but before the start of radiotherapy, were selected. The metabolic volume (MV) was defined both within the primary tumour and in the involved nodal stations using the 40% (MV40) and 50% (MV50) threshold of the maximum SUV. Metabolic and CT response was assessed by the relative change in MV and CT volume, respectively, between both time points. The association between response and overall survival (OS) was analysed by univariate cox regression analysis. The minimum follow-up was 18 months. Results Reductions in MV40 and MV50 were −36 ± 38% (126.4 to 68.7 cm 3) and −44 ± 38% (90.2 to 27.8 cm 3), respectively. The median CT volume reduction was −40 ± 64% (190.6 to 113.8 cm 3). MV40 and MV50 changes showed a significant association with survival (HR = 1.02, 95% CI: 1.00–1.04 ( p = 0.042); HR = 1.02, 95% CI: 1.00–1.04 ( p = 0.048), respectively), indicating a 2% increase in survival probability for 1% reduction in metabolic volume. The CT volume change was also significantly correlated with survival (HR = 1.01, 95% CI: 1.00–1.03, p = 0.007). Conclusions This hypothesis generating study shows that both the early CT and the MV changes show a significant correlation with survival in SCLC. A prospective study is planned in a larger patient cohort to allow multivariate analysis, with the final aim to select patients early during treatment that could benefit from dose intensification or alternative treatment.

Chronic medical conditions, health status, and health care practices at 25 years in 5-year survivors of Wilms tumor: A report from the Childhood Cancer Survivor Study.

9514 Background: High proportions of children with Wilms Tumor (WT), cured by surgery, chemotherapy, ± irradiation (RT), risk late effects of therapy. Methods: Self-reported chronic medical conditions (CMCs), health status, and health care practices were analyzed in this retrospective cohort including 1,256 5-yr survivors of WT diagnosed 1970-1986 and a sibling comparison group (n=4023). The risk of specific CMCs was analyzed by treatment. Results: The cumulative incidence at 25 yrs of any CMC was 51% and severe/disabling CMC was 11%. Compared to the siblings, WT survivors were twice as likely to report a CMC (hazard ratio [HR]2.0, 95% confidence interval (CI), 1.8-2.4) and almost five- times more likely to have a severe/disabling CMC (HR4.7, 95%CI, 3.6-6.1). The HR of specific CMCs were: congestive heart failure (CHF) 23.6 (95% CI, 10.8- 51.5), renal failure 50.7 (95% CI, 14.5-177.4), and hypertension (HTN) 8.2 (95% CI, 6.4-10.5). RT to the heart increased the likelihood of reporting CHF without doxorubicin (HR6.6, 95% CI, 1.6-28.3), with ≤ 250 mg/m2 (HR13.0, 95% CI, 1.9-89.7), and with > 250 mg/m2 (HR18.3, 95% CI, 3.8-88.2). Doxorubicin without RT did not increase the likelihood of CHF. RT to the contralateral kidney did not increase the likelihood of reporting renal failure or HTN. The prevalence ratio (PR) of adverse health status was significantly different from the sibling group for general overall health (PR 1.7, p=0.001), functional impairment (PR 3.3, p<0.001) and activity limitations (PR 1.9, p<0.001), but not for mental health status (PR 1.2, p=0.09). WT survivors and the siblings showed no differences in self or professional screening for cancer. WT survivors <30 yrs old reported more general medical exams (PR 1.1, p<0.001). Female WT survivors <30 yrs were more likely to report having had a mammogram (PR 1.6, p=0.008). Of female WT survivors who received chest RT, only 13% <30 yrs and 57% ≥30 yrs reported having had a mammogram. Conclusions: Survivors of WT have an excess risk of chronic medical conditions and adverse health status. The health care practices of WT survivors were similar to their siblings, providing opportunity for intervention. No significant financial relationships to disclose.

Chest Radiation Therapy Warrants Early Mammograms and Breast MRIs

An estimated 12% to 20% of women who undergo moderate- or high-dose chest radiation therapy (chest RT) for pediatric malignancies receive breast cancer

Surveillance for Breast Cancer After Childhood Cancer

BREAST CANCER IS A RECOGNIZED COMPLICATION OF chest irradiation for childhood cancer, and surveillance for breast cancer with regular clinical examination and annual screening mammography starting at age 25 years or 8 years after radiation is recommended. However, uptake of screening mammograms in this high-risk group is suboptimal, as shown in the report by Oeffinger and colleagues in this issue of JAMA. The authors examined breast cancer surveillance practices in a survey of 625 female survivors of pediatric cancer who were between 25 and 50 years and participants in the longitudinal Childhood Cancer Survivor Study (CCSS). These survivors were at a significantly increased risk of breast cancer as a result of treatment they received in the form of moderateto high-dose ( 20 Gy) irradiation to the chest for treatment of a childhood cancer (chest RT group). The women in the chest RT group were compared with 639 similarly aged CCSS participants who did not receive chest irradiation and with 712 siblings in the CCSS siblings cohort. Oeffinger et al found that 55% of the women in the chest RT group reported having a screening mammogram within the previous 2 years. Rates of screening mammography varied by age at the time of the survey, with 23.3% of women aged 25 through 39 years and 53.6% of women aged 40 through 50 years reporting a screening mammogram in the previous year. Among women in the younger group, those who reported a physician recommendation for screening were 3 times as likely to have had screening in the previous 2 years when compared with those whose physician did not recommend that they have a mammogram. In light of a recognized increased risk of breast cancer following radiation to the chest, chest irradiation is now used less frequently for the curative treatment of some pediatric cancers, which include different types of childhood cancer including Hodgkin disease, Wilms tumor, neuroblastoma, and non-Hodgkin lymphoma; however, there are an estimated 20 000 to 25 000 adult survivors of pediatric cancer older than 25 years in the United States who are in this risk category. Current Childhood Oncology Group (COG) guidelines for breast cancer surveillance after pediatric cancer in the United States recommend yearly clinical breast examination from the age of puberty until age 25 years, and then every 6 months if the survivor was treated with irradiation of at least20 Gy to mantle, minimantle, mediastinal, chest (thoracic), or axillary fields. In addition, it is recommended that these survivors have annual mammography and an adjunct breast magnetic resonance imaging (MRI) starting at age 25 years or 8 years after radiation, whichever is last. The effectiveness of the standard mammogram in detecting preinvasive and invasive breast cancer is known to be relatively poor in young women due to the density of breast tissue in this age group, increasing the importance of MRI in the detection and diagnosis of breast cancer in younger women with dense breast tissue. The estimated dose of radiation from a standard 2-view screening mammogram is approximately 3.85 mGy per mammogram. Although it is accepted that the additional dose is small compared with the higher therapeutic dose already received, it is not known to what extent repeated exposure to small doses of breast irradiation in women already at an increased risk of breast cancer may result in a significantly increased risk of second primary breast cancer. This is an important question that needs to be addressed in future studies. The generally low uptake rate of screening mammogram in a high-risk population of pediatric cancer survivors has also been highlighted in a previous study of adult survivors. Some factors associated with the uptake of breast screening including age and race/ethnicity, physician recommendation, health beliefs, and personal understanding of breast cancer risk were explored by Oeffinger et al, but economic factors were not. Thus, whether the cost of annual breast cancer screening was a factor in this cohort is not known. In comparison, among a population of 461 Australian women at an increased risk of developing hereditary breast cancer, uptake of breast screening was 89% overall, although it decreased to 77% among those

Cause-specific mortality and second cancer incidence after non-Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study

AbstractSecond primary malignancies and premature death are a concern for patients surviving treatment for childhood lymphomas. We assessed mortality and second malignant neoplasms (SMNs) among 1082 5-year survivors of non-Hodgkin lymphoma (NHL) in the Childhood Cancer Survivor Study, a multi-institutional North American retrospective cohort study of cancer survivors diagnosed from 1970 to 1986. Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) were calculated using US population rates. Relative risks for death and solid tumor SMNs were calculated based on demographic, clinical, and treatment characteristics using Poisson regression models. There were 87 observed deaths (SMR = 4.2; 95% CI, 1.8-4.1) with elevated rates of death from solid tumors, leukemia, cardiac disease, and pneumonia. Risk for death remained elevated beyond 20 years after NHL. Risk factors for death from causes other than NHL included female sex (rate ratio [RR] = 3.4) and cardiac radiation therapy exposure (RR = 1.9). There were 27 solid tumor SMNs (SIR = 3.9; 95% CI, 2.6-5.7) with 3% cumulative incidence between 5 and 20 years after NHL diagnosis. Risk factors were female sex (RR = 3.1), mediastinal NHL disease (RR = 5.2), and breast irradiation (RR = 4.3). Survivors of childhood NHL, particularly those treated with chest RT, are at continued increased risk of early mortality and solid tumor SMNs.

Initial Evaluation of Treatment-Related Pneumonitis in Advanced-Stage Non–Small-Cell Lung Cancer Patients Treated With Concurrent Chemotherapy and Intensity-Modulated Radiotherapy

To investigate the rate of high-grade treatment-related pneumonitis (TRP) in patients with advanced non-small-cell lung cancer (NSCLC) treated with concurrent chemotherapy and intensity-modulated radiotherapy (IMRT). From August 2002 to August 2005, 151 NSCLC patients were treated with IMRT. We excluded patients who did not receive concurrent chemotherapy or who had early-stage cancers, a history of major lung surgery, prior chest RT, a dose <50 Gy, or IMRT combined with three-dimensional conformal RT (3D-CRT). Toxicities were graded by Common Terminology Criteria for Adverse Events version 3.0. Grade > or = 3 TRP for 68 eligible IMRT patients was compared with TRP among 222 similar patients treated with 3D-CRT. The median follow-up durations for the IMRT and 3D-CRT patients were 8 months (range, 0-27 months) and 9 months (range, 0-56 months), respectively. The median IMRT and 3D-CRT doses were 63 Gy. The median gross tumor volume was 194 mL (range, 21-911 mL) for IMRT, compared with 142 mL (range, 1.5-1,186 mL) for 3D-CRT (p = 0.002). Despite the IMRT group's larger gross tumor volume, the rate of Grade > or = 3 TRP at 12 months was 8% (95% confidence interval 4%-19%), compared with 32% (95% confidence interval 26%-40%) for 3D-CRT (p = 0.002). In advanced NSCLC patients treated with chemoradiation, IMRT resulted in significantly lower levels of Grade > or = 3 TRP compared with 3D-CRT. Clinical, dosimetric, and patient selection factors that may have influenced rates of TRP require continuing investigation. A randomized trial comparing IMRT with 3D-CRT has been initiated.

Left ventricular wall motion analysis using real-time three-dimensional ultrasound

This study tested the ability of real-time 3-D (RT 3-D) echocardiography to detect and delineate regions of abnormal contraction (akinesia or dyskinesia) in a canine model of regional myocardial injury and to develop methods to simplify injury assessments. Closed chest RT 3-D scans were obtained and regional left ventricular (LV) contractile function was assessed in nine animals at baseline and after myocardial cryoinjury with a 1-cm cryoprobe. Evaluation of contractile function was based on radial shortening of LV chamber cross-sections at multiple levels. Radial length changes were analyzed using color-coded circumferential maps of the LV. Seven sets of motion maps demonstrated new areas of poorly contracting myocardium in the cryoinjured region relative to baseline. Two sets of data were excluded due to insufficient LV visualization. Motion maps derived from RT 3-D echo have the ability to detect and localize regions of abnormal LV wall motion. (E-mail: johhny.kuo@duke.edu)

A phase II study of paclitaxel, carboplatin, and hyperfractionated radiation therapy for locally advanced inoperable non–small-cell lung cancer (a Vanderbilt cancer center affiliate network study)

Purpose: We conducted a prospective phase II study to determine the response rate, toxicity, and survival rate of concurrent weekly paclitaxel, carboplatin, and hyperfractionated radiation therapy (paclitaxel/carboplatin/HFX RT) followed by 2 cycles of paclitaxel and carboplatin for locally advanced unresectable non-small cell lung cancer (NSCLC). The weekly paclitaxel and carboplatin regimen was designed to optimize the radiosensitizing properties of paclitaxel during the concurrent phase of treatment. Methods and Materials: Forty-three patients with unresectable stage IIIA and IIIB NSCLC from the Vanderbilt Cancer Center and Affiliate Network (VCCAN) institutions were entered onto the study from June 1996 until May 1997. Weekly intravenous (IV) paclitaxel (50 mg/m 2/l-hour) and weekly carboplatin (AUC 2) plus concurrent hyperfractionated chest RT (1.2 Gy/BID/69.6 Gy) were delivered for 6 weeks followed by 2 cycles of paclitaxel (200 mg/m 2) and carboplatin (AUC 6). Results: Forty-two patients were evaluable for response and toxicities. Three patients achieved a complete response (7.2%) and 30 patients achieved a partial response (71.4%), for an overall response rate of 78.6% [95% C.I. (66.2%–91.0%)]. The 1- and 2-year overall and progression-free survival rates of all 43 patients were 61.6% and 35% respectively, with a median survival time of 14.3 months. The median follow-up time was 14 months. Esophagitis was the principal toxicity. Grade 3 or 4 esophagitis occurred in 11 patients (26%). There was an incidence of 7% grade 3 and 9.5% grade 4 pulmonary toxicities. Conclusions: Weekly paclitaxel, carboplatin, plus concurrent hyperfractionated RT is a well-tolerated outpatient regimen. The response rate from this regimen is encouraging and appears to be at least equivalent to the more toxic chemoradiation trials. These findings warrant further clinical evaluation of weekly paclitaxel/carboplatin/HFX RT in a phase III study.

Phase II Study of Concurrent Chemotherapy with Etoposide and Cisplatin (EP) and Radiation Therapy for Unresectable Stage III Non-small Cell Lung Cancer

Background : Various combinations of treatment modalities have been reported in stage III non-small cell lung cancer (NSCLC). however, the standard treatment modality has not established yet. Recently, the efficacy of concurrent chemotherapy and radiation therapy has been reported in locally advanced lung cancer. We evaluate the response rate, toxicity, and survival of concurrent chemotherapy with etoposide and cisplatin(EP) and radiation therapy for unresectable stage III NSCLC. Method : Between October 1995 and December 1996, 32 patients with histologically proven unresectable stage III NSCLC without malignant pleural effusion were entered into this study. Twenty-nine patients were eligible for the response, survival, and toxicity analysis. Induction was two cycles of chemotherapy with etoposide and cisplatin plus concurrent chest RT to 4500cGy. Resection was attempted if the clinical response offered surgical resectability. Boost radiation therapy upto 5940cGy and one cycle of EP were performed if the disease were stable or responsive but still unresectable. Results : Of 29 eligible patients, 22(75.9%) showed partial response(PR). The progression free interval was 6.3months(range 1.1 to 19.5months). Surgical resection was performed in one patient. The median survival was 12.1months and one-year survival rate was 50.6%. The major toxicity was leukopenia( grade 3, 46%). Thrombocytopenia over grade 3 was found in 11%. Radiation pneumonitis occurred in 13 patients(46%). Conclusion : Concurrent chemotherapy(EP) plus radiotherapy was effective and tolerable in the treatment of unresectable stage III NSCLC.