Timothy M. Zagar

Hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: A review of the randomised data

Hyperthermia has long been used in combination with radiation for the treatment of superficial malignancies, in part due to its radiosensitising capabilities. Patients who suffer superficial recurrences of breast cancer, be it in their chest wall following mastectomy, or in their breast after breast conservation, typically have poor clinical outcomes. They often develop distant metastatic disease, but one must not overlook the problems associated with an uncontrolled local failure. Morbidity is enormous, and can significantly impair quality of life. There is no accepted standard of care in treating superficial recurrences of breast cancer, particularly in patients that have previously been irradiated. There is a substantial literature regarding the combined use of hyperthermia and radiotherapy for these superficial recurrences. Most of it is retrospective in nature, but there are several larger phase III randomised trials that show an improved rate of clinical complete response in patients treated with both modalities. In this review article, we will highlight the important prospective data that has been published regarding the combined use of hyperthermia and radiation.

Cardiac toxicity after radiotherapy for stage III non-small-cell lung cancer: Pooled analysis of dose-escalation trials delivering 70 to 90 Gy

Purpose The significance of radiotherapy (RT) -associated cardiac injury for stage III non-small-cell lung cancer (NSCLC) is unclear, but higher heart doses were associated with worse overall survival in the Radiation Therapy Oncology Group (RTOG) 0617 study. We assessed the impact of heart dose in patients treated at our institution on several prospective dose-escalation trials. Patients and Methods From 1996 to 2009, 127 patients with stage III NSCLC (Eastern Cooperative Oncology Group performance status, 0 to 1) received dose-escalated RT to 70 to 90 Gy (median, 74 Gy) in six trials. RT plans and cardiac doses were reviewed. Records were reviewed for the primary end point: symptomatic cardiac events (symptomatic pericardial effusion, acute coronary syndrome, pericarditis, significant arrhythmia, and heart failure). Cardiac risk was assessed by noting baseline coronary artery disease and calculating the WHO/International Society of Hypertension score. Competing risks analysis was used. Results In all, 112 patients were analyzed. Median follow-up for surviving patients was 8.8 years. Twenty-six patients (23%) had one or more events at a median of 26 months to first event (effusion [n = 7], myocardial infarction [n = 5], unstable angina [n = 3], pericarditis [n = 2], arrhythmia [n = 12], and heart failure [n = 1]). Heart doses (eg, heart mean dose; hazard ratio, 1.03/Gy; P = .002,), coronary artery disease ( P < .001), and WHO/International Society of Hypertension score ( P = .04) were associated with events on univariable analysis. Heart doses remained significant on multivariable analysis that accounted for baseline risk. Two-year competing risk-adjusted event rates for patients with heart mean dose < 10 Gy, 10 to 20 Gy, or ≥ 20 Gy were 4%, 7%, and 21%, respectively. Heart doses were not associated with overall survival. Conclusion Cardiac events were relatively common after high-dose thoracic RT and were independently associated with both heart dose and baseline cardiac risk. RT-associated cardiac toxicity after treatment of stage III NSCLC may occur earlier than historically understood, and heart doses should be minimized.

Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer

Abstract Purpose: Unresectable chest wall recurrences of breast cancer (CWR) in heavily pretreated patients are especially difficult to treat. We hypothesised that thermally enhanced drug delivery using low temperature liposomal doxorubicin (LTLD), given with mild local hyperthermia (MLHT), will be safe and effective in this population. Patients and methods: This paper combines the results of two similarly designed phase I trials. Eligible CWR patients had progressed on the chest wall after prior hormone therapy, chemotherapy, and radiotherapy. Patients were to get six cycles of LTLD every 21–35 days, followed immediately by chest wall MLHT for 1 hour at 40–42 °C. In the first trial 18 subjects received LTLD at 20, 30, or 40 mg/m2; in the second trial, 11 subjects received LTLD at 40 or 50 mg/m2. Results: The median age of all 29 patients enrolled was 57 years. Thirteen patients (45%) had distant metastases on enrolment. Patients had received a median dose of 256 mg/m2 of prior anthracyclines and a median dose of 61 Gy of prior radiation. The median number of study treatments that subjects completed was four. The maximum tolerated dose was 50 mg/m2, with seven subjects (24%) developing reversible grade 3–4 neutropenia and four (14%) reversible grade 3–4 leucopenia. The rate of overall local response was 48% (14/29, 95% CI: 30–66%), with. five patients (17%) achieving complete local responses and nine patients (31%) having partial local responses. Conclusion: LTLD at 50 mg/m2 and MLHT is safe. This combined therapy produces objective responses in heavily pretreated CWR patients. Future work should test thermally enhanced LTLD delivery in a less advanced patient population.

Breast cancer therapy-associated cardiovascular disease

Breast cancer treatments have evolved over the past decades, although several widely used treatments have adverse cardiac effects. Radiotherapy generally improves the survival of women with breast cancer, although its deleterious cardiovascular effects pose competing risks of morbidity and/or mortality. In the past, radiation-associated cardiovascular disease was a phenomenon considered to take more than a decade to manifest, but newer research suggests that this latency is much shorter. Knowledge of coronary anatomy relative to the distribution of the delivered radiation dose has improved over time, and as a result, techniques have enabled this risk to be decreased. Studies continue to be performed to better understand, prevent and mitigate against radiation-associated cardiovascular disease. Treatments such as anthracyclines, which are a mainstay of chemotherapy for breast cancer, and newer targeted agents such as trastuzumab both have established risks of cardiotoxicity, which can limit their effectiveness and result in increased morbidity and/or mortality. Interest in whether β-blockers, statins and/or angiotensin-converting enzyme (ACE)-inhibitors might have therapeutic and/or preventative effects in these patients is currently increasing. This Review summarizes the incidence, risks and effects of treatment-induced cardiovascular disease in patients with breast cancer and describes strategies that might be used to minimize this risk.

Extraosseous Ewing's Sarcoma: 25 Years Later

Timothy M. Zagar, Department of Radiation Oncology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH Timothy J. Triche, Department of Pathology, Los Angeles Children’s Hospital, University of Southern California School of Medicine, Los Angeles, CA Timothy J. Kinsella, Department of Radiation Oncology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH

Changes in Initial Treatment for Prostate Cancer Among Medicare Beneficiaries, 1999–2007

PURPOSE In the absence of evidence from large clinical trials, optimal therapy for localized prostate cancer remains unclear; however, treatment patterns continue to change. We examined changes in the management of patients with prostate cancer in the Medicare population. METHODS AND MATERIALS We conducted a retrospective claims-based analysis of the use of radiation therapy, surgery, and androgen deprivation therapy in the 12 months after diagnosis of prostate cancer in a nationally representative 5% sample of Medicare claims. Patients were Medicare beneficiaries 67 years or older with incident prostate cancer diagnosed between 1999 and 2007. RESULTS There were 20,918 incident cases of prostate cancer between 1999 and 2007. The proportion of patients receiving androgen deprivation therapy decreased from 55% to 36%, and the proportion of patients receiving no active therapy increased from 16% to 23%. Intensity-modulated radiation therapy replaced three-dimensional conformal radiation therapy as the most common method of radiation therapy, accounting for 77% of external beam radiotherapy by 2007. Minimally invasive radical prostatectomy began to replace open surgical approaches, being used in 49% of radical prostatectomies by 2007. CONCLUSIONS Between 2002 and 2007, the use of androgen deprivation therapy decreased, open surgical approaches were largely replaced by minimally invasive radical prostatectomy, and intensity-modulated radiation therapy replaced three-dimensional conformal radiation therapy as the predominant method of radiation therapy in the Medicare population. The aging of the population and the increasing use of newer, higher-cost technologies in the treatment of patients with prostate cancer may have important implications for nationwide health care costs.

The Management of Early-Stage and Metastatic Triple-Negative Breast Cancer: A Review

Triple-negative breast cancer (TNBC), defined as lacking expression of the estrogen receptor, progesterone receptor, and HER2, comprises approximately 15% of incident breast cancers and is over-represented among those with metastatic disease. There are several biologically distinct subtypes within TNBC. Although the incidence of BRCA mutations across all subsets of breast cancer is low, BRCA mutations are more common among those with TNBC and may have therapeutic implications. The general principles guiding the use of chemotherapy and radiation therapy do not differ dramatically between early-stage TNBC and non-TNBC.

Breast Cancer Radiotherapy and Coronary Artery Stenosis: Location, Location, Location

Radiation therapy (RT) plays an integral role in the treatment of breast cancer. Lumpectomy followed by whole breast RT provides equivalent outcomes to mastectomy. In a meta-analysis of nearly 42,000 women who were treated within clinical trials, the use of RT after mastectomy or lumpectomy improved local control, breast cancer–specific survival, and overall survival. Unfortunately, the use of RT also has a dark side. In that same Oxford meta-analysis, the hazard ratio for death secondary to heart disease, presumably radiation related, was 1.27. Although the incidence of cardiac events was low in the first 5 years of follow-up, it increased over time and persisted after year 15. In the article that accompanies this editorial, Nilsson et al provide the oncology community with another useful and elegantly performed study that addresses radiation-associated heart disease. Previous studies from this group and others have suggested that RT for breast cancer can clearly increase the risk of cardiovascular disease, including pericarditis, coronary artery disease (CAD), conduction abnormalities, congestive heart failure, and valvular disease. In addition, essentially all of the increased risk of clinically meaningful cardiac events is not manifest until more than 10 years after RT. Given this long latency, prospective studies with clinical end points have been difficult; therefore, much of the current data is derived from population-based studies and a few clinical trials with long follow-up. Additionally clouding the issue is that RT techniques have been improved during the last several decades and much of the cardiac toxicity data come from older series. RT is also associated with reductions in regional perfusion as assessed by single photon emission computed tomography (SPECT) scans, in a manner consistent with microvascular injury, relatively soon after RT (eg, 6 months to 5 years). These perfusion defects seem to largely persist with longer follow-up, but their clinical relevance is not yet known. Previous studies have not clearly defined the anatomic distribution of RT-associated CAD. One would reasonably hypothesize that the increasedriskofCADwouldbedosedependentandwouldmanifest largely in the coronary arteries that are directly within the radiation portal. In the few studies that have considered a dose response, doses are typically described as those received by the entire heart, left ventricle, and/or left anterior descending artery (LAD). Doses to the individual branches/portions of the coronary arteries are not typically considered. Nilsson et al took a meaningful step to address this lack of data in a systematic and logical manner. They examined a Swedish cohort of patients with breast cancer who were identified through their national registry and who had been treated between 1970 and 2003. They then cross referenced this with their coronary angiography registry and found 199 women who were treated for breast cancer and who went on to have coronary angiography at some point after their treatment. A comparison group of patients who were not treated for breast cancer was also identified. A radiologist who was blinded to the radiation information reviewed the angiographies and scored the degree of coronary artery stenosis within 18 segments of the major coronary arteries. Because detailed, three-dimensional dose data were not available for the patients, the authors defined coronary subsegments that were most likely to be directly included within the RT beams for the patients with leftversus right-sided disease, and for the different RT techniques (eg, with or without a separate anterior internal mammary nodal [IMN] field). Among all of the women who received RT, those with left-sided breast cancer had a statistically significant increased rate of stenosis in the coronaryarterybranchesontheleft-anteriorsurfaceoftheheart(themid, distal, and distal diagonal branch of the LAD) when compared with those with right-sided cancer. This makes perfect sense given the location of typical RT fields. Interestingly, there was not an increased risk of stenosis in the left main coronary artery or in the proximal LAD, likely because of their relatively posterior locations. This is illustrated nicely in Figure 2A of the article by Nilsson et al. The rate of stenosis in the proximal right coronary artery is (nonstatistically significantly) slightly higher in the patients with rightversus left-sided disease—again, a logical finding given thelocationoftheproximalrightcoronaryarteryrelativetothetypicalRT fields. The lack of a more dramatic difference may be a result of the frequent use of an anterior IMN field in patients for whom the right and left-sided arteries are both at risk. The patients who received RT were additionally subdivided into those who received high-risk (as termed by the authors) versus low-risk RTbeams,onthebasisofthelocationofthebeamsrelativetothecoronary arteries at risk. High-risk beams included any anterior IMN field or leftsidedtangents.Amongthepatientswithcoronarylesions, thedistribution of lesions was similar in the reference subjects (no breast cancer and no RT) to the patients with breast cancer who either received no RT or received RT using low-risk beams. Conversely, in the patients who were treated with high-risk beams, the distribution of coronary lesions differed from that of the reference subjects. There was a marked increase in rightmain disease in those patients who were treated with a right IMN field, andtherewasasomewhatmoresubtle increase inmidanddistal leftmain and distal diagonal disease in the patients with left-sided disease who received RT using high-risk beams. Again, the RT seems to alter the distribution of coronary lesions. There are several shortcomings that might limit the interpretation of the data. For example, there may have been biases with respect to which patients were sent for an angiogram, on the basis of their Editorials

Durable palliation of breast cancer chest wall recurrence with radiation therapy, hyperthermia, and chemotherapy

BACKGROUND AND PURPOSE Chest wall recurrences of breast cancer are a therapeutic challenge and durable local control is difficult to achieve. Our objective was to determine the local progression free survival (LPFS) and toxicity of thermochemoradiotherapy (ThChRT) for chest wall recurrence. METHODS Twenty-seven patients received ThChRT for chest wall failure from 2/1995 to 6/2007 and make up this retrospective series. All received concurrent superficial hyperthermia twice weekly (median 8 sessions), chemotherapy (capecitabine in 21, vinorelbine in 2, and paclitaxel in 4), and radiation (median 45 Gy). Patients were followed up every 1.5-3 months and responses were graded with RECIST criteria and toxicities with the NCI CTC v4.0. RESULTS Twenty-three (85%) patients were previously irradiated (median 60.4 Gy) and 22 (81%) patients received prior chemotherapy. Median follow-up was 11 months. Complete response (CR) was achieved in 16/20 (80%) of patients with follow-up data, and 1 year LPFS was 76%. Overall survival was 23 months for patients with CR, and 5.4 months in patients achieving a partial response (PR) (p=0.01). Twenty-two patients experienced acute grade 1/2 treatment related toxicities, primarily moist desquamation. Two patients experienced 3rd degree burns; all resolved with conservative measures. CONCLUSIONS ThChRT offers durable palliation and prolonged LPFS with tolerable acute toxicity, especially if CR is achieved.

Clinical experience with 3-dimensional surface matching-based deep inspiration breath hold for left-sided breast cancer radiation therapy

PURPOSE Three-dimensional (3D) surface matching is a novel method to administer deep inspiration breath-hold (DIBH) radiation therapy for left-sided breast cancer to reduce cardiac exposure. We analyzed port (x-ray) films to assess patient setup accuracy and treatment times to assess the practical workflow of this system. METHODS AND MATERIALS The data from 50 left-sided breast cancer patients treated with DIBH were studied. AlignRT (London, UK) was used. The distance between the field edge and the anterior pericardial shadow as seen on the routine port films (dPORT), and the corresponding distance seen on the digitally reconstructed radiographs (DRR) from the planning (dDRR) were compared as a quantitative measure of setup accuracy. Variations of dPORT - dDRR over the treatment course were assessed. In a subset of 21 patients treated with tangential beams alone, the daily treatment durations were analyzed to assess the practical workflow of this system. RESULTS Considering all 50 patients, the mean absolute systematic uncertainty between dPORT and dDRR was 0.20 cm (range, 0 to 1.22 cm), the mean systematic uncertainty was -0.07 cm (range, -1.22 to 0.67 cm), and their mean random uncertainty was 0.19 cm (range, 0 to 0.84 cm). There was no significant change in dPORT - dDRR during the course of treatment. The mean patient treatment duration for the 21 patients studied was 11 minutes 48 seconds. On intrapatient assessments, 15/21 had nonsignificant trends toward reduced treatment durations during their course of therapy. On interpatient comparisons, the mean treatment times declined as we gained more experience with this technique. CONCLUSIONS The DIBH patient setup appears to provide a fairly reproducible degree of cardiac sparing with random uncertainties of ≈ 0.2 cm. The treatment durations are clinically acceptable and appear not to change significantly over time on an intrapatient basis, and to improve over time on an interpatient basis.