Histologic subtypes of breast cancer following radiotherapy for Hodgkin lymphoma.

BACKGROUND: The purpose of the study was to determine whether breast cancers (BCs) that develop in women previously irradiated for Hodgkin lymphoma (HL) are biologically similar to sporadic BC. MATERIALS AND METHODS: We retrospectively reviewed the charts of patients who developed BC after radiotherapy (RT) for HL. Tumors were classified as ductal carcinoma in situ (DCIS) or invasive carcinoma. Invasive carcinomas were further characterized according to the subtype: hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)-, HR+/HER2+, HR-/HER2+, and HR-/HER2-. BCs after HL were compared with four age-matched sporadic, non-breast cancer (BRCA) I or II mutated BCs. RESULTS: One hundred forty-seven HL patients who were treated with RT between 1966 and 1999 and subsequently developed BCs were identified. Of these, 65 patients with 71 BCs had complete pathologic information. The median age at HL diagnosis was 23 (range, 10-48). The median age at BC diagnosis was 44 (range, 28-66). The median time to developing BC was 20 years. Twenty cancers (28%) were DCIS and 51 (72%) were invasive. Of the 51 invasive cancers, 24 (47%) were HR+/HER2-, 2 (4%) were HR+/HER2+, 5 (10%) were HR-/HER2+, and 20 (39%) were HR-/HER2-. There were no differences in BC histologic subtype according to the age at which patients were exposed to RT, the use of chemotherapy for HL treatment, or the time from RT exposure to the development of BC. In a 4 : 1 age-matched comparison to sporadic BCs, BCs after HL were more likely to be HR-/HER2- (39% versus 14%) and less likely to be HR+/HER2- (47% versus 61%) or HR+/HER2+ (4% versus 14%) (P = 0.0003). CONCLUSION(S): BCs arising in previously irradiated breast tissue were more likely to be triple negative compared with age-matched sporadic invasive cancers and less likely to be HR positive. Further studies will be important to determine the molecular pathways of carcinogenesis in breast tissue that is exposed to RT.

Role of beam orientation optimization in intensity-modulated radiation therapy.

PURPOSE: To investigate the role of beam orientation optimization in intensity-modulated radiation therapy (IMRT) and to examine the potential benefits of noncoplanar intensity-modulated beams. METHODS AND MATERIALS: A beam orientation optimization algorithm was implemented. For this purpose, system variables were divided into two groups: beam position (gantry and table angles) and beam profile (beamlet weights). Simulated annealing was used for beam orientation optimization and the simultaneous iterative inverse treatment planning algorithm (SIITP) for beam intensity profile optimization. Three clinical cases were studied: a localized prostate cancer, a nasopharyngeal cancer, and a paraspinal tumor. Nine fields were used for all treatments. For each case, 3 types of treatment plan optimization were performed: (1) beam intensity profiles were optimized for 9 equiangular spaced coplanar beams; (2) orientations and intensity profiles were optimized for 9 coplanar beams; (3) orientations and intensity profiles were optimized for 9 noncoplanar beams. RESULTS: For the localized prostate case, all 3 types of optimization described above resulted in dose distributions of a similar quality. For the nasopharynx case, optimized noncoplanar beams provided a significant gain in the gross tumor volume coverage. For the paraspinal case, orientation optimization using noncoplanar beams resulted in better kidney sparing and improved gross tumor volume coverage. CONCLUSION: The sensitivity of an IMRT treatment plan with respect to the selection of beam orientations varies from site to site. For some cases, the choice of beam orientations is important even when the number of beams is as large as 9. Noncoplanar beams provide an additional degree of freedom for IMRT treatment optimization and may allow for notable improvement in the quality of some complicated plans.

Management of breast cancer after Hodgkin's disease.

PURPOSE: To evaluate the incidence, detection, pathology, management, and prognosis of breast cancer occurring after Hodgkin's disease. PATIENTS AND METHODS: Seventy-one cases of breast cancer in 65 survivors of Hodgkin's disease were analyzed. RESULTS: The median age at diagnosis was 24.6 years for Hodgkin's disease and 42.6 years for breast cancer. The relative risk for invasive breast cancer after Hodgkin's disease was 4.7 (95% confidence interval, 3.4 to 6. 0) compared with an age-matched cohort. Cancers were detected by self-examination (63%), mammography (30%), and physician exam (7%). The histologic distribution paralleled that reported in the general population (85% ductal histology) as did other features (27% positive axillary lymph nodes, 63% positive estrogen receptors, and 25% family history). Although 87% of tumors were less than 4 cm, 95% were managed with mastectomy because of prior radiation. Two women underwent lumpectomy with breast irradiation. One of these patients developed tissue necrosis in the region of overlap with the prior mantle field. The incidence of bilateral breast cancer was 10%. Adjuvant systemic therapy was well tolerated; doxorubicin was used infrequently. Ten-year disease-specific survival was as follows: in-situ disease, 100%; stage I, 88%; stage II, 55%; stage III, 60%; and stage IV, zero. CONCLUSION: The risk of breast cancer is increased after Hodgkin's disease. Screening has been successful in detecting early-stage cancers. Pathologic features and prognosis are similar to that reported in the general population. Repeat irradiation of the breast can lead to tissue necrosis, and thus, mastectomy remains the standard of care in most cases.

Fractionated stereotactic radiosurgery and preservation of hearing in patients with vestibular schwannoma: a preliminary report.

OBJECTIVE: Microsurgery and stereotactic radiosurgery (SRS) for vestibular schwannomas are associated with a relatively high incidence of sensorineural hearing loss. A prospective trial of fractionated SRS was undertaken in an attempt to preserve hearing and minimize incidental cranial nerve injury. METHODS: Thirty-three patients with vestibular schwannomas were treated with 2100 cGy in three fractions during a 24-hour period using conventional frame-based linear accelerator radiosurgery. The median tumor diameter was 20 mm (range, 7-42 mm). Baseline and follow-up evaluations included audiometry and contrast-enhanced magnetic resonance imaging. End points were tumor progression, preservation of serviceable hearing, and treatment-related complications. RESULTS: Thirty-one patients (32 tumors) were assessable for tumor progression and treatment-related complications and 21 patients for preservation of serviceable hearing, with a median follow-up interval of 2 years (range, 0.5-4.0 yr). Tumor regression or stabilization was documented in 30 patients (97%) and tumor progression in 1 (3%). The patient with tumor progression remains asymptomatic and has not required surgical intervention. Five patients (16%) developed trigeminal nerve injury at a median of 6 months (range, 4-12 mo) after SRS; two of these patients had preexisting trigeminal neuropathy. One patient (3%) developed facial nerve injury (House-Brackmann Class 3) 7 months after SRS. Preservation of useful hearing (Gardner-Robertson Class 1-2) was 77% at 2 years. All patients with pretreatment Gardner-Robertson Class 1 to 2 hearing maintained serviceable (Class 1-3) hearing as of their last follow-up examination. CONCLUSION: Three-fraction SRS with a conventional stereotactic frame is feasible and well tolerated in the treatment of acoustic neuroma. This study demonstrates a high rate of hearing preservation and few treatment-related complications among a relatively high-risk patient cohort (tumors >15 mm or neurofibromatosis Type 2). Longer follow-up will be required to assess the durability of tumor control.

The Janeway lecture. Hodgkin's disease--finding the balance between cure and late effects.

PURPOSE: The purpose of this review is to summarize the Stanford experience in Hodgkin's disease, the late effects of treatment, and strategies to improve management to maximize cure and decrease late effects in these patients. PATIENTS AND METHODS: Between 1960 and 1999, 2617 consecutive patients with Hodgkin's disease have been seen, treated, and rigorously followed at Stanford. This population includes patients of all ages and stages of disease. The database summarizing this experience serves as the source of survival and mortality data over 4 decades. Two thousand two hundred thirty-two of the population comprise the group evaluated for secondary cardiac disease. Two thousand one hundred sixty-two patients have been evaluated for risk of secondary leukemia, non-Hodgkin's lymphoma, and solid tumors. Eight hundred eighty-five women were evaluated for secondary breast cancer, prompting a subsequent analysis of risk of secondary cancer among 694 pediatric patients. RESULTS: The probability of cure of Hodgkin's disease has dramatically improved over the past 40 years. Today, 94% of patients are expected to survive. Among those who do not survive, approximately half die of Hodgkin's disease, 20% of new cancers, and 14% of cardiovascular complications. Modifications in patient management and treatment have greatly reduced the serious late effects observed from prior therapy. With current combined-modality therapy using moderate doses of involved field of radiation and limited cycles of multiagent, risk adapted chemotherapy, serious cardiac complications and development of secondary cancers are expected to be greatly reduced. The Stanford 25-year pediatric Hodgkin's disease experience reveals that survival in favorable early-stage disease exceeds 95%. Newer protocols for children with advanced-stage disease continue to show these excellent survival rates and promise less late morbidity. Adult protocols using the risk-adapted Stanford V combined-modality program now parallel the pediatric experience, with greater than 90% survival in these patients. DISCUSSION: Thus today the likelihood of cure of Hodgkin's disease greatly exceeds the risk of late effects, a goal both Dr. Henry Janeway and Madame Marie Curie emphasized and taught from first-hand experience.

Radiation therapy for clinically localized prostate cancer: a multi-institutional pooled analysis.

CONTEXT: Prostate-specific antigen (PSA) evaluation leads to the early detection of both prostate cancer and recurrences following primary treatment. Prostate-specific antigen outcome information on patients 5 or more years following treatment is limited and available mainly as single-institution reports. OBJECTIVES: To assess the likelihood and durability of tumor control using PSA evaluation 5 or more years after radical external beam radiation therapy and to identify pretreatment prognostic factors in men with early prostate cancer treated since 1988, the PSA era. DESIGN AND SETTING: Retrospective, nonrandomized, multi-institutional pooled analysis of patients treated with external beam radiation therapy alone between 1988 and 1995 at 6 US medical centers. Follow-up lasted up to a maximum of 9 years. Outcome data were analyzed using Cox regression and recursive partitioning techniques. PATIENTS: A total of 1765 men with stage T1b, T1c, and T2 tumors treated between 1988 and 1995 with external beam radiation. The majority (58%) of patients were older than 70 years and 24.2% had initial PSA values of 20 ng/mL or higher. A minimum of 2 years of subsequent follow-up was required for participation. MAIN OUTCOME MEASURE: Actuarial estimates of freedom from biochemical failure. RESULTS: The 5-year estimates of overall survival, disease-specific survival, and the freedom from biochemical failure are 85.0% (95% confidence interval [CI], 82.5%-87.6%), 95.1% (95% CI, 94.0%-96.2%), and 65.8% (95% CI, 62.8%-68.0%), respectively. The PSA failure-free rates 5 and 7 years after treatment for patients presenting with a PSA of less than 10 ng/mL were 77.8% (95% CI, 74.5%-81.3%), and 72.9% (95% CI, 67.9%-78.2%). Recursive partitioning analysis of initial PSA level, palpation stage, and the Gleason score groupings yielded 4 separate prognostic groups: group 1, included patients with a PSA level of less than 9.2 ng/mL; group 2, PSA level of at least 9.2 but less than 19.7 ng/mL; group 3, PSA level at least 19.7 ng/mL and a Gleason score of 2 to 6; and group 4, PSA level of at least 19.7 ng/mL and a Gleason score of 7 to 10. The estimated rates of survival free of biochemical failure at 5 years are 81 % for group 1, 69% for group 2, 47% for group 3, and 29% for group 4. Of the 302 patients followed up beyond 5 years who were free of biochemical disease, 5.0% relapsed from the fifth to the eighth year. CONCLUSIONS: Estimated PSA control rates in this pooled analysis are similar to those of single institutions. These rates indicate the probability of success for subsets of patients with tumors of several prognostic category groupings. These results represent a multi-institutional benchmark for evidence-based counseling of prostate cancer patients about radiation treatment.

Treatment of cavernous sinus tumors with linear accelerator radiosurgery.

Since 1989, 79 patients with benign or malignant cavernous sinus tumors, have been treated at Stanford University with linear accelerator (linac) radiosurgery. Radiosurgery has been used as (1) a planned second-stage procedure for residual tumor following surgery, (2) primary treatment for patients whose medical conditions preclude surgery, (3) palliation of malignant lesions, and (4) definitive treatment for small, well-localized, poorly accessible tumors. Mean patient age was 52 years (range, 18 to 88); there were 28 males and 51 females. Sixty-one patients had benign tumors; 18 had malignant tumors. Mean tumor volume was 6.8 cm(3) (range 0.5 to 22.5 cm(3)) covered with an average of 2.3 isocenter (range, 1 to 5). Radiation dose averaged 17.1 Gy. Mean follow-up was 46 months. Tumor control or shrinkage, or both, varied with pathology. Radiographic tumor improvement was most pronounced in malignant lesions, with greater than 85% showing reduction in tumor size; benign tumors (meningiomas and schwannomas) had a 63% control rate and 37% shrinkage rate, with none enlarging. We concluded that stereotactic radiosurgery is a valuable tool in managing cavernous sinus tumors. There was excellent control and stabilization of benign tumors and palliation of malignant lesions.

Acute hearing loss following fractionated stereotactic radiosurgery for acoustic neuroma. Report of two cases.

Two cases of acute hearing loss are reported following fractionated stereotactic radiosurgery for acoustic neuroma. Both patients had neurofibromatosis type 2 and were treated with a peripheral tumor dose of 21 Gy delivered in three fractions (7 Gy each) with a minimum interfraction interval of 10 hours. One patient who had previously undergone surgical resection of the treated tumor presented with only rudimentary hearing in the treated ear secondary to an abrupt decrease in hearing prior to treatment. That patient reported total loss of hearing before complete delivery of the third fraction. The second patient had moderately impaired hearing prior to treatment; however, within 10 hours after delivery of the final fraction, he lost all hearing. Both patients showed no improvement in response to glucocorticoid therapy. Possible explanations for this phenomenon are presented.

Effect of combined transient androgen deprivation and irradiation following radical prostatectomy for prostatic cancer.

PURPOSE: To evaluate whether transient androgen deprivation improves outcome in patients irradiated after radical prostatectomy for locally advanced disease, persistent or rising postoperative prostate specific antigen (PSA), or local recurrence. METHODS AND MATERIALS: Records of 105 consecutive patients who were treated with pelvic irradiation after radical retropubic prostatectomy between August 1985 and December 1995 were reviewed. Seventy-four patients received radiation alone (mean follow up: 4.6 years), and 31 received transient androgen blockade with a gonadotropin-releasing hormone agonist (4) androgen receptor blocker (1) or both (24) beginning 2 months prior to irradiation (mean follow-up 3.0 years) for a mean duration of 6 months. Two of these patients were excluded from further analysis because they received hormonal therapy for more than 1 year. Patients received a prostatic fossa dose of 60-70 Gy at 2 Gy per fraction; 48 patients also received pelvic nodal irradiation to a median dose of 50 Gy. Survival, freedom from clinical relapse (FFCR), and freedom from biochemical relapse (FFBR) were evaluated by the Kaplan-Meier method. Biochemical relapse was defined as two consecutive PSA measurements exceeding 0.07 ng/ml. RESULTS: At 5 years after irradiation, actuarial survival for all patients was 92%, FFCR was 77%, and FFBR was 34%. FFBR was significantly better among patients who received transient androgen blockade before and during radiotherapy than among those treated with radiation alone (56 vs. 27% at 5 years, p = 0.004). FFCR was also superior for the combined treatment group (100 vs. 70% at 5 years, p = 0.014). Potential clinical prognostic factors before irradiation did not differ significantly between treatment groups, including tumor stage, summed Gleason histologic score, lymph node status, indication for treatment, and PSA levels before surgery or subsequent treatment. Multivariate analysis revealed that transient androgen deprivation was the only significant predictor for biochemical failure. CONCLUSION: This retrospective study of irradiation after radical prostatectomy suggests that transient androgen blockade and irradiation may improve freedom from early biochemical and clinically evident relapse compared to radiotherapy alone, although more prolonged follow-up will be needed to assess durability of impact upon clinical recurrence and survival rates.

Treatment of hemangioblastomas in von Hippel-Lindau disease with linear accelerator-based radiosurgery.

OBJECTIVE: Stereotactic radiosurgery is increasingly being used to treat hemangioblastomas, particularly those that are in surgically inaccessible locations or that are multiple, as is common in von Hippel-Lindau disease. The purpose of this study was to retrospectively evaluate the effectiveness of radiosurgery in the treatment of hemangioblastomas. METHODS: From 1989 to 1996, 29 hemangioblastomas in 13 patients with von Hippel-Lindau disease were treated with linear accelerator-based radiosurgery. The mean patient age was 40 years (range, 31-57 yr). The radiation dose to the tumor periphery averaged 23.2 Gy (range, 18-40 Gy). The mean tumor volume was 1.6 cm3 (range, 0.07-65.4 cm3). Tumor response was evaluated in serial, contrast-enhanced, computed tomographic and magnetic resonance imaging scans. The mean follow-up period was 43 months (range, 11-84 mo). RESULTS: Only one (3%) of the treated hemangioblastomas progressed. Five tumors (17%) disappeared, 16 (55%) regressed, and 7 (24%) remained unchanged in size. Five of nine patients with symptoms referable to treated hemangioblastomas experienced symptomatic improvement. During the follow-up period, one patient died as a result of progression of untreated hemangioblastomas in the cervical spine. Three patients developed radiation necrosis, two of whom were symptomatic. CONCLUSION: Although follow-up monitoring is limited, stereotactic radiosurgery provides a high likelihood of local control of hemangioblastomas and is an attractive alternative to multiple surgical procedures for patients with von Hippel-Lindau disease.

Clinical uses of radiosurgery.

Radiosurgery uses stereotactic targeting methods to precisely deliver highly focused, large doses of radiation to small intracranial tumors and arteriovenous malformations (AVMs). This article reviews the most common clinical applications of radiosurgery and the clinical results reported from a number of series using either a cobalt-60 gamma knife or linear accelerator as radiation sources. Radiosurgery is used to treat malignant tumors, such as selected cases of brain metastases and malignant gliomas (for which stereotactic radiosurgical boosts are utilized in conjunction with fractionated radiation therapy), as well as benign tumors, such as meningiomas, acoustic neuromas, and pituitary adenomas. Treatment of small AVMs is also highly effective. Although radiosurgery has the potential to produce complications, the majority of patients experience clinical improvement with less morbidity than occurs with surgical resection.

Clinical experience with image-guided robotic radiosurgery (the Cyberknife) in the treatment of brain and spinal cord tumors.

The Cyberknife is an image-guided "frameless" dedicated radiosurgical device. This instrument has several distinct advantages over frame-based systems, including improved patient comfort, increased treatment degrees of freedom, and the potential to target extracranial lesions. Clinical results thus far with respect to the treatment of malignant intracranial tumors has been promising. Additionally, the Cyberknife will likely revolutionize the application of radiosurgery to extracranial sites. A description of the components, treatment planning, and clinical results of the Cyberknife will be reviewed.

Stanford-Kaiser Permanente G1 study for clinical stage I to IIA Hodgkin's disease: subtotal lymphoid irradiation versus vinblastine, methotrexate, and bleomycin chemotherapy and regional irradiation.

PURPOSE: We have demonstrated that a relatively mild chemotherapy regimen, vinblastine, methotrexate, and bleomycin (VBM), and involved-field radiotherapy (IFRT) could substitute for extended-field radiotherapy in patients with favorable Hodgkin's disease (HD) who have been laparotomy-staged. The purpose of this study is to determine if VBM and regional radiotherapy can substitute for extended-field radiotherapy in favorable clinical stage (CS) I and II HD. PATIENTS AND METHODS: Seventy-eight patients with favorable CS I to II HD were randomly assigned to subtotal lymphoid irradiation (STLI) or VBM chemotherapy and regional radiotherapy. Randomization was stratified on the basis of age, sex, number of Ann Arbor sites, histology, and institution. Patients were evaluated for freedom from progressive HD, survival, and toxicity. Results were compared with the predecessor trial in pathologically staged patients. RESULTS: With a median follow-up period of 4 years, the rate of freedom from progressive HD was 92% (95% confidence interval [CI], 88% to 96%) for patients treated with STLI and 87% (95% CI, 81% to 93%) for patients treated with VBM and regional radiotherapy. Six of seven patients who relapsed are alive and in remission following successful second-line therapy. CONCLUSION: Given the caveat of a small number of patients, the results of extended-field radiotherapy and VBM and regional radiotherapy are comparable with a median follow-up period of 4 years. VBM serves as a paradigm to reduce late effects in favorable early-stage HD. We do not advocate its routine use in clinical practice, but instead encourage participation in clinical trials with the objective of maintaining efficacy while reducing toxicity in CS I and II HD.

Gastrointestinal cancer after treatment of Hodgkin's disease.

PURPOSE: This study aimed to quantify the risk of gastrointestinal cancer following Hodgkin's disease treatment according to age at treatment, type of treatment, and anatomic sites. METHODS AND MATERIALS: Cases were identified from the records of 2,441 patients treated for Hodgkin's disease between 1961 and 1994. Follow-up averaged 10.9 years, representing 26,590 person-years of observation. Relative risks (RR) for gastrointestinal cancer incidence and mortality were computed by comparison with expected annualized rates for a general population matched for age, sex, and race. RESULTS: Gastrointestinal cancers developed in 25 patients. The incidence RR was 2.5 [95% confidence interval (CI), 1.5-3.5] and mortality RR was 3.8 (CI, 2.4-4.7). Sites associated with significantly increased risks included the stomach [RR 7.3 (CI, 3.4-13.8)], small intestine [RR 11.6 (CI, 1.9-38.3)], and pancreas [RR 3.5 (CI, 1.1-8.5)]. Risk was significantly elevated after combined modality therapy, RR 3.9 (CI, 2.2-5.6). The risk after radiotherapy alone was 2.0 (CI, 1.0-3.4), not a statistically significant elevation. The RR for gastrointestinal cancer was greatest after treatment at young age and decreased with advancing age. It was significantly elevated within 10 years after treatment [RR 2.0 (CI, 1.1-3.5)] and increased further after 20 years [RR 6.1 (CI, 2.5-12.7)]. Risk assessed by attained age paralleled risk according to age at treatment. Fifteen cases of gastrointestinal cancers arose within the irradiation fields. CONCLUSION: Patients treated for Hodgkin's disease are at modestly increased risk for secondary gastrointestinal cancer, especially after combined modality therapy and treatment at a young age. Risk was highest more than 20 years after treatment, but was significantly elevated within 10 years. Gastrointestinal sites with increased risk included the stomach, pancreas, and small intestine.

The Cyberknife: a frameless robotic system for radiosurgery.

The Cyberknife is a unique instrument for performing frameless stereotactic radiosurgery. Rather than using rigid immobilization, the Cyberknife relies on an image-to-image correlation algorithm for target localization. Furthermore, the system utilizes a novel, light-weight, high-energy radiation source. The authors describe the technical specifications of the Cyberknife and summarize the initial clinical experience.

Linear accelerator-based stereotaxic radiosurgery for brain metastases:the influence of number of lesions on survival.

PURPOSE: To evaluate the influence of the number of brain metastases on survival after stereotaxic radiosurgery and factors that affect the risk of delayed radiation necrosis after treatment. MATERIALS AND METHODS: Between March 1989 and December 1993, 120 consecutive patients underwent linear accelerator-based stereotaxic radiosurgery for brain metastases identified by computed tomography (CT) or magnetic resonance imaging (MRI) scans. The influence of various clinical factors on outcome was assessed using Kaplan-Meier plots of survival from the date of radiosurgery, and univariate and multivariate analyses. RESULTS: The median survival time was 32 weeks. Progressive brain metastases, both local and regional, caused 25 of 104 deaths. Patients with two metastases (n = 30) or a solitary metastasis (n = 70) had equivalent actuarial survival times (P = .07; median, 37 weeks; maximum, 211+ weeks). Patients treated to three or more metastases (n = 20) had significantly shorter survival times (P < .002; median, 14 weeks; maximum, 63 weeks). Prognostic factors associated with prolonged survival included a pretreatment Karnofsky performance status > or = 70% and fewer than three metastases. Delayed radiation necrosis at the treated site developed in 20 patients and correlated with prior or concurrent delivery of whole-brain irradiation and the logarithm of the tumor volume. CONCLUSION: Survival duration is equivalent for patients with one or two brain metastases and is similar to that reported for patients with a solitary metastasis managed by surgical resection and whole-brain irradiation. Survival after radiosurgery for three or more metastases was similar to that reported for whole-brain irradiation.