Robert G. Prosnitz

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.

Combined-Modality Therapy Versus Radiotherapy Alone for Treatment of Early-Stage Hodgkin's Disease: Cure Balanced Against Complications

PURPOSE The treatment of early-stage Hodgkins disease (HD) has evolved from radiotherapy alone (RT) to combined-modality therapy (CMT) because of concerns about late adverse effects from high-dose subtotal nodal irradiation (STNI). However, there is little information regarding the long-term results of CMT programs that substantially reduce the dose and extent of radiation. In addition, lowering the total radiation dose may reduce the complication rate without compromising cure. This retrospective study compares the long-term results of STNI with CMT using modestly reduced RT dose in the treatment of early-stage HD. PATIENTS AND METHODS Between 1982 and 2002, 111 patients with stage IA and IIA HD were treated definitively with RT (mean dose, 37.9 Gy); 70 patients were treated with CMT with low-dose involved-field radiotherapy (LDIFRT; mean dose, 25.5 Gy). Median follow-up was 11.7 years for RT patients and 8.1 years for the CMT group. RESULTS There was a trend toward improved 20-year overall survival with CMT (83% v 70%; P = .405). No second cancers were observed in the CMT group; in the RT group the actuarial frequency of a second cancer was 16% at 20 years. There was no difference in the frequency of cardiac complications (9% v 6%, RT v CMT). CONCLUSION In this retrospective review, CMT with LDIFRT was effective in curing early-stage HD and was not associated with an increase in second malignancies. For RT alone, a moderate dose seemed to reduce cardiac complications but did not lessen second malignancies compared with higher doses used historically.

Radiation-Induced Heart Disease: Vigilance Is Still Required

Radiation therapy (RT) plays an important role in the multimodality management of patients with breast cancer. Trials conducted in the 1970s established that survival is equivalent after either breast conservation (local excision and RT) or mastectomy. Studies performed in the 1980s showed that the addition of RT to lumpectomy significantly reduces the risk of local recurrence and, in a meta-analysis, enhanced survival as well. Finally, trials conducted in the 1980s also demonstrated that RT after mastectomy dramatically decreases locoregional recurrence and significantly improves overall survival in patients with involved axillary nodes or large primary tumors. This silver cloud unfortunately has a black lining. In the late 1980s, data emerged that older radiotherapy (RT) techniques used in the treatment of breast cancer, particularly after mastectomy, resulted in increased rates of both cardiac morbidity and mortality. In a meta-analysis involving 19,582 women with breast cancer enrolled onto 40 randomized trials begun before 1990, the Early Breast Cancer Trialists Collaborative Group found that RT reduced the annual mortality from breast cancer by 13% but increased the annual mortality rate from other causes by 21% and that this increase was due primarily to an excess number of deaths from vascular causes (death rate ratio, 1.3 [SE 0.09]). In a similar meta-analysis, Cuzick et al reviewed individual patient-level data from 7,941 women enrolled onto 10 randomized trials of mastectomy, with or without RT, initiated before 1975 and found that the standardized mortality ratio was significantly higher for patients treated with RT compared with controls (1.11 v 0.69; P .001). Critical factors in the genesis of radiation-induced heart disease are the volume of heart exposed and the radiation dose deposited in that volume. Older methods of delivering postmastectomy RT resulted in relatively large volumes of heart being incidentally exposed to moderate to high doses of radiation. The main culprit was thought to be the use of anterior photons to treat the ipsilateral internal mammary nodes, often as part of a larger L-shaped socalled hockey-stick field that also covered the supraclavicular and sometimes the axillary nodes. Once the adverse effects of RT on the heart were recognized, techniques evolved to irradiate the chest wall and regional nodes while reducing exposure of the heart. The hockey-stick method was abandoned by most radiation oncologists in favor of methods that included the internal mammary nodes (IMNs) within the same tangential RT fields used to irradiate the chest wall (so-called deep or partially wide tangents) or treated the IMNs mostly or entirely with superficially penetrating electrons, rather than deeply penetrating photons. Given the controversy about the necessity of treating the IMNs and the possible increased cardiac risk that came from electively doing so, other radiation oncologists elected to abandon IMN treatment altogether. The safety of irradiating the chest wall was also improved by the development of treatment planning based on computed tomography that enabled better visualization of the heart, leading to the selection of RT fields that minimized cardiac exposure. These heart-sparing RT methods for irradiating the chest wall (with or without the regional nodes), were also applied to the treatment of patients with an intact breast, which rapidly gained in popularity following the publication of the randomized trials comparing mastectomy with breast conservation. For patients with an intact breast, but uninvolved axillary lymph nodes, tangential fields that minimized cardiac exposure were used to treat only the breast itself. Have these modern methods of delivering adjuvant RT following mastectomy or lumpectomy eliminated the risk of cardiac injury? In this issue of the Journal of Clinical Oncology, Patt et al from the M.D. Anderson Cancer Center (Houston, TX) attempt to answer this question. Using data from the Surveillance, Epidemiology, and End Results JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 30 OCTOBER 2

Is there an increased risk of local recurrence under the heart block in patients with left-sided breast cancer?

UNLABELLED Tangential radiotherapy for left-sided breast cancer may be cardiotoxic. Shaping the field with a heart block reduces cardiac exposure but may under-dose the breast and/or chest wall. We compared the incidence and location of local recurrences in patients irradiated with and without a heart block. METHODS AND MATERIALS Between 1994 and 1998, 180 patients irradiated to the left breast and/or chest wall were retrospectively reviewed. The local recurrence rates in patients treated with and without a heart block were compared using a 2-tailed Fisher exact test. An in-depth dosimetric analysis was performed in 23 patients to assess the percentage of breast tissue under-dosed by inclusion of the heart block. RESULTS Overall, the local recurrence rates in patients with or without a heart block were similar. In postlumpectomy patients with inferiorly located tumors, the rates of local recurrence with and without a heart block were 2 of 6 patients versus 0 of 19 patients, respectively. In the dosimetric analysis, the average percentage of breast tissue under-dosed by the inclusion of a heart block was 2.8% (range, 0%-11%). DISCUSSION A heart block is a reasonable method to limit cardiac dose but should be used cautiously following a lumpectomy in patients with inferiorly located tumors. Additional study with larger numbers of patients is warranted.

Quality measures for the use of adjuvant chemotherapy and radiation therapy in patients with colorectal cancer: a systematic review.

Chemotherapy (CT) and radiation therapy (RT) are essential components of adjuvant (preoperative or postoperative) therapy for many patients with colorectal cancer (CRC); however, quality measures (QMs) of these critical aspects of CRC treatment have not been characterized well. Therefore, the authors conducted a systematic review of the literature to determine the available QMs for adjuvant CT and RT in patients with CRC and rated their usefulness for assessing the delivery of quality care.

Late effects of breast radiotherapy in young women.

Radiotherapy (RT) to the breast or chest wall of young women is associated with long-term cardiotoxicity and an increased risk of secondary breast cancers. As many patients with early stage breast cancer and Hodgkins disease are cured of their disease, there is significant concern regarding the long term risks of therapy. Older RT techniques for treating the breast/chest wall and draining lymph nodes for breast cancer resulted in a relatively high dose being delivered to a substantial volume of heart, and convincing evidence exists of excess cardiovascular morbidity and mortality in patients treated with these techniques. While modern RT techniques have reduced radiation exposure to the heart, they have not eliminated it. Many large studies of Hodgkins disease survivors have demonstrated a clear risk of secondary breast cancer development after mantle RT for Hodgkins disease. The risk of developing breast cancer after mantle RT appears to be related to age at time of irradiation, dose delivered to the breast tissue, and whether or not chemotherapy is incorporated into the overall treatment plan. In this article we review late cardiac complications associated with tangential breast RT and the risk of developing a secondary breast cancer after mantle RT for Hodgkins disease.

Screening for Cardiovascular Disease in Survivors of Thoracic Radiation

Background and purpose A solid body of evidence demonstrates that therapeutic thoracic radiotherapy can injure the cardiovascular system. However, there is little consensus on how to screen survivors who received this therapy. This review intends to assess recent evidence on radiotherapy-related cardiac injury with the goal of formulating evidence-based guidelines.

Increased Sectioning of Pathologic Specimens with Ductal Carcinoma In Situ of the Breast: Are There Clinical Consequences?

To assess if there has been increased sectioning of pathologic specimens with ductal carcinoma in situ (DCIS), identify sources of this change, and consider the clinical consequences, pathologic data from patients who underwent initial excisional biopsies at our institution and were referred to the radiation oncology department with DCIS from 1992-2002 were retrospectively reviewed. One hundred forty-four of 480 patients with DCIS were eligible for review. Specimen size was recorded as length, to the nearest 0.1 cm, in 3 dimensions. Specimen volume was approximated by the product of the 3 dimensions of the specimen. The primary endpoint was the number of microscopic sections taken from gross specimens, corrected for specimen size. Other analysis included margin status, use of a previous stereotactic needle biopsy, and whether a subsequent repeat excision was performed. Over time, there was an increase in size of the excisional biopsy specimens (mean of 49 cm3 from 1992 to 1994 and 90 cm3 from 2001 to 2002; P = 0.045). Mean numbers of slides per centimeter of specimen were 2.5, 2.7, 3.9, and 5.8 for the intervals 1992-1994, 1995-1997, 1998-2000, and 2001-2002, respectively (P < 0.001 for 1992-1997 vs. 1998-2002). Adjusting for volume, the increase over time in the number of slides per specimen was statistically significant (parameter significance, P < 0.001). For a given volume, the number of slides increased approximately 9.1% per year, on average, during the study period. The positive margin rates were 52%, 46%, 23%, and 25% from 1992 to 1994, from 1995 to 1997, from 1998 to 2000, and from 2001 to 2002, respectively. The degree of sectioning, corrected for specimen length and volume, increased over time.

TU-EE-A2-05: Challenges in Limiting Kidney Dose When Delivering Total Body Irradiation (TBI) for Patients with Severe Systemic Sclerosis (SSc)

Purpose: To describe challenges in limiting kidney dose when delivering TBI to SSc patients enrolled on a multicenter Phase II/III SCOT (Scleroderma Cyclophosphamide or Transplantation) protocol. Material and Methods: The SCOT protocol uses a preparative regimen of 800 cGy TBI. The kidney dose is limited to 200 cGy. This level of attenuation is atypical for TBI. Hence, the effect of the block thickness and proximity to the spinal cord was investigated with EDR film in an anthropomorphic phantom using 5 cm thick kidney blocks positioned 3, 5, and 8 cm apart. Due to their poor renal function, the kidneys of SSc patients cannot be localized using intravenous contrast. Therefore, methods of kidney‐localization and block‐positioning were devised. Six patients have been treated on the TBI arm of the trial at Duke and information on kidney shape and the shifts from prone to standing position were recorded using diagnostic ultrasound(US).Results: A 10–20% dose inhomogeneity in the lumbar spine region is achievable with a minimum kidney block separation of 4–5 cm (typical width of a vertebral body). Two methods for kidney localization have been proposed. Block design and placement can be accomplished using a combination of CT and US or CT alone. Kidney‐localization based on the combination of CT and US enables more accurate block‐positioning and reduces the superior‐inferior block margins. Kidney shape proved similar among the six patients imaged, leading to a potential use of standard kidney blocks. The US information revealed a wide range of kidney travel, both inferior and superior with a magnitude as large as 3.3 cm. Conclusions: The dose to the kidneys can be attenuated by 75% (per protocol) during TBI while maintaining a 10–20% dose inhomogeneity. The kidneys can be localized more accurately using both CT and US than CT alone.

SU‐FF‐J‐131: Is There a Relationship Between Body Mass Index, Treatment Set‐Up Errors, and the Development of Myocardial Perfusion Defects Following Radiation Therapy for Left‐Sided Breast Cancer?

Purpose: To assess whether body mass index (BMI) affects the rate of “deep” set‐up errors (i.e. those that increase the volume of heart irradiated), resulting in an increased risk of RT‐induced myocardial perfusion defects (PD) 6–60 months post‐RT. Materials and Methods: For 87 patients receiving RT for left‐sided breast cancer,treatment set‐up accuracy was determined by measuring the height of the lung shadow seen at the level of the central axis on simulation and serial medial tangent portal films. SPECT nuclear medicine scans were performed serially pre‐ and post‐RT to assess for cardiac PD. The interaction among BMI, set‐up error frequency, and the rate of PD was compared using a 1‐tailed Fishers Exact Test. Results: The rates of deep set‐up deviations were 9/32 vs. 24/51 in patients with BMI 0% but ⩽1% LV in the field (i.e. patients who are generally predicted to be at very low risk for RT‐induced cardiac dysfunction). The rates of PD in these patients with deep vs. “shallow” set‐up errors (i.e. those that decrease the volume of heart irradiated) were 5/6 vs. 3/10 (p=0.059) (Fig 2). Conclusions: Patients with BMI⩾25 kg/m2 tend to have a higher incidence of deep set‐up errors, causing more heart to be irradiated than intended. In patients with very small volumes of heart in the RT field, those with deep set‐up errors are more likely to have PD post‐RT. Accurate patient set‐up on the treatment machine is critical to minimize the risk of RT‐induced cardiac injury, particularly in overweight and obese patients. Supported by grants 17‐98‐1‐8071 and BC010663 from the DOD.