International Journal of Radiation Oncology * Biology * Physics

Issue Highlights

2010-02-01

J. J. Caudell, P. E. Schaner, R. A. Desmond, R. F. Meredith, S. A. Spencer, and J. A. Bonner Emerging data suggests that certain anatomical structures may be related to swallowing dysfunction following radiotherapy for head and neck cancers. This report retrospectively examined patients definitively treated for head and neck cancer with intensity modulated radiotherapy and correlated doses received to seven swallowing related structures with three swallowing dysfunction endpoints. Doses to the larynx and inferior pharyngeal constrictor were associated with gastrostomy dependence and aspiration. Doses to the superior and middle pharyngeal constrictor were associated with pharyngoesophageal stricture requiring a dilation procedure. These data may help physicians spare these structures in appropriate patients, possibly resulting in less swallowing toxicity.

American Society for Therapeutic Radiology and Oncology (ASTRO) and American College of Radiology (ACR) Practice Guidelines for Image-Guided Radiation Therapy (IGRT)

2010-02-01

These guidelines are an educational tool designed to assist practitioners in providing appropriate radiologic care for patients. They are not inflexible rules or requirements of practice and are not intended, nor should they be used, to establish a legal standard of care. For these reasons and those set forth below, the American College of Radiology cautions against the use of these guidelines in litigation in which the clinical decisions of a practitioner are called into question.

American Society for Therapeutic Radiology and Oncology (ASTRO) and American College of Radiology (ACR) Practice Guideline for the Performance of Stereotactic Body Radiation Therapy

2010-02-01

Integrating the Healthcare Enterprise in Radiation Oncology Plug and Play—The Future of Radiation Oncology?

2010-02-01

Purpose: To describe the processes and benefits of the integrating healthcare enterprises in radiation oncology (IHE-RO).Methods: The IHE-RO process includes five basic steps. The first step is to identify common interoperability issues encountered in radiation treatment planning and the delivery process. IHE-RO committees partner with vendors to develop solutions (integration profiles) to interoperability problems. The broad application of these integration profiles across a variety of vender platforms is tested annually at the Connectathon event. Demonstration of the seamless integration and transfer of patient data to the potential users are then presented by vendors at the public demonstration event. Users can then integrate these profiles into requests for proposals and vendor contracts by institutions.Results: Incorporation of completed integration profiles into requests for proposals can be done when purchasing new equipment. Vendors can publish IHE integration statements to document the integration profiles supported by their products. As a result, users can reference integration profiles in requests for proposals, simplifying the systems acquisition process. These IHE-RO solutions are now available in many of the commercial radiation oncology-related treatment planning, delivery, and information systems. They are also implemented at cancer care sites around the world.Conclusions: IHE-RO serves an important purpose for the radiation oncology community at large.

Survival Following Radiation and Androgen Suppression Therapy for Prostate Cancer in Healthy Older Men: Implications for Screening Recommendations

2009-04-22

Purpose: The U.S. Preventive Services Task Force has recommended against screening men over 75 for prostate cancer. We examined whether older healthy men could benefit from aggressive prostate cancer treatment.Methods and Materials: 206 men with intermediate to high risk localized prostate cancer randomized to 70 Gy of radiation (RT) or RT plus 6 months of androgen suppression therapy (RT+AST) constituted the study cohort. Within subgroups stratified by Adult Comorbidity Evaluation-27 comorbidity score and age, Cox multivariable analysis was used to determine whether treatment with RT+AST as compared with RT was associated with a decreased risk of death.Results: Among healthy men (i.e., with mild or no comorbidity), 78 were older than the median age of 72.4 years, and in this subgroup, RT+AST was associated with a significantly lower risk of death on multivariable analysis (adjusted hazard ratio = 0.36 (95% CI=0.13-0.98), p = 0.046, with significantly lower 8-year mortality estimates of 16.5% vs. 41.4% (p = 0.011). Conversely, among men with moderate or severe comorbidity, 24 were older than the median age of 73, and in this subgroup, treatment with RT+AST was associated with a higher risk of death (adjusted hazard ratio = 5.2 (1.3-20.2), p = 0.018).Conclusion: In older men with mild or no comorbidity, treatment with RT+AST was associated with improved survival compared with treatment with RT alone, suggesting that healthy older men may derive the same benefits from prostate cancer treatment as younger men. We therefore suggest that prostate cancer screening recommendations should not be based on strict age cutoffs alone but should also take into account comorbidity.

The Rate of Secondary Malignancies After Radical Prostatectomy Versus External Beam Radiation Therapy for Localized Prostate Cancer: A Population-Based Study on 17,845 Patients

2010-02-01

Purpose: External-beam radiation therapy (EBRT) may predispose to secondary malignancies that include bladder cancer (BCa), rectal cancer (RCa), and lung cancer (LCa). We tested this hypothesis in a large French Canadian population-based cohort of prostate cancer patients.Methods and Materials: Overall, 8,455 radical prostatectomy (RP) and 9,390 EBRT patients treated between 1983 and 2003 were assessed with Kaplan-Meier and Cox regression analyses. Three endpoints were examined: (1) diagnosis of secondary BCa, (2) LCa, or (3) RCa. Covariates included age, Charlson comorbidity index, and year of treatment.Results: In multivariable analyses that relied on incident cases diagnosed 60 months or later after RP or EBRT, the rates of BCa (hazard ratio [HR], 1.4; p = 0.02), LCa (HR, 2.0; p = 0.004), and RCa (HR 2.1; p <0.001) were significantly higher in the EBRT group. When incident cases diagnosed 120 months or later after RP or EBRT were considered, only the rates of RCa (hazard ratio 2.2; p = 0.003) were significantly higher in the EBRT group. In both analyses, the absolute differences in incident rates ranged from 0.7 to 5.2% and the number needed to harm (where harm equaled secondary malignancies) ranged from 111 to 19, if EBRT was used instead of RP.Conclusions: EBRT may predispose to clinically meaningfully higher rates of secondary BCa, LCa and RCa. These rates should be included in informed consent consideration.

Natural History of Clinically Staged Low- and Intermediate-Risk Prostate Cancer Treated With Monotherapeutic Permanent Interstitial Brachytherapy

2009-05-20

Purpose: To evaluate the natural history of clinically staged low- and intermediate-risk prostate cancer treated with permanent interstitial seed implants as monotherapy.Methods and Materials: Between April 1995 and May 2005, 463 patients with clinically localized prostate cancer underwent brachytherapy as the sole definitive treatment. Men who received supplemental external beam radiotherapy or androgen deprivation therapy were excluded. Dosimetric implant quality was determined based on the minimum dose that covered 90% of the target volume and the volume of the prostate gland receiving 100% of the prescribed dose. Multiple parameters were evaluated as predictors of treatment outcomes.Results: The 12-year biochemical progression-free survival (bPFS), cause-specific survival, and overall survival rates for the entire cohort were 97.1%, 99.7%, and 75.4%, respectively. Only pretreatment prostate-specific antigen level, percent positive biopsy cores, and minimum dose that covered 90% of the target volume were significant predictors of biochemical recurrence. The bPFS, cause-specific survival, and overall survival rates were 97.4%, 99.6%, and 76.2%, respectively, for low-risk patients and 96.4%, 100%, and 74.0%, respectively, for intermediate-risk patients. The bPFS rate was 98.8% for low-risk patients with high-quality implants versus 92.1% for those with less adequate implants (p < 0.01), and it was 98.3% for intermediate-risk patients with high-quality implants versus 86.4% for those with less adequate implants (p < 0.01).Conclusions: High-quality brachytherapy implants as monotherapy can provide excellent outcomes for men with clinically staged low- and intermediate-risk prostate cancer. For these men, a high-quality implant can achieve results comparable to high-quality surgery in the most favorable pathologically staged patient subgroups.

Local Control Following Permanent Prostate Brachytherapy: Effect of High Biologically Effective Dose on Biopsy Results and Oncologic Outcomes

Nelson N. Stone, Richard G. Stock, Jamie A. Cesaretti, Pam Unger — 2009-07-24

Purpose: To determine factors that influence local control and systemic relapse in patients undergoing permanent prostate brachytherapy (PPB).Methods and Materials: A total of 584 patients receiving PPB alone or PPB with external beam radiation therapy (19.5%) agreed to undergo prostate biopsy (PB) at 2 years postimplantion and yearly if results were positive or if the prostate-specific antigen (PSA) level increased. Short-term hormone therapy was used with 280 (47.9%) patients. Radiation doses were converted to biologically effective doses (BED) (using α/β = 2). Comparisons were made by chi-square analysis and linear regression. Survival was determined by the Kaplan-Meier method.Results: The median PSA concentration was 7.1 ng/ml, and the median follow-up period was 7.1 years. PB results were positive for 48/584 (8.2%) patients. Positive biopsy results by BED group were as follows: 22/121 (18.2%) patients received a BED of ≤150 Gy; 15/244 (6.1%) patients received >150 to 200 Gy; and 6/193 (3.1%; p < 0.001) patients received >200 Gy. Significant associations of positive PB results by risk group were low-risk group BED (p = 0.019), intermediate-risk group hormone therapy (p = 0.011) and BED (p = 0.040), and high-risk group BED (p = 0.004). Biochemical freedom from failure rate at 7 years was 82.7%. Biochemical freedom from failure rate by PB result was 84.7% for negative results vs. 59.2% for positive results (p < 0.001). Cox regression analysis revealed significant associations with BED (p = 0.038) and PB results (p = 0.002) in low-risk patients, with BED (p = 0.003) in intermediate-risk patients, and with Gleason score (p = 0.006), PSA level (p < 0.001), and PB result (p = 0.038) in high-risk patients. Fifty-three (9.1%) patients died, of which eight deaths were due to prostate cancer. Cause-specific survival was 99.2% for negative PB results vs. 87.6% for positive PB results (p < 0.001).Conclusions: Higher radiation doses are required to achieve local control following PPB. A BED of >200 Gy with an α/β ratio of 2 yields 96.9% local control rate. Failure to establish local control impacts survival.

Development of RTOG Consensus Guidelines for the Definition of the Clinical Target Volume for Postoperative Conformal Radiation Therapy for Prostate Cancer

2009-04-24

Purpose: To define a prostate fossa clinical target volume (PF-CTV) for Radiation Therapy Oncology Group (RTOG) trials using postoperative radiotherapy for prostate cancer.Methods and Materials: An RTOG-sponsored meeting was held to define an appropriate PF-CTV after radical prostatectomy. Data were presented describing radiographic failure patterns after surgery. Target volumes used in previous trials were reviewed. Using contours independently submitted by 13 radiation oncologists, a statistical imputation method derived a preliminary “consensus” PF-CTV.Results: Starting from the model-derived CTV, consensus was reached for a CT image–based PF-CTV. The PF-CTV should extend superiorly from the level of the caudal vas deferens remnant to >8–12 mm inferior to vesicourethral anastomosis (VUA). Below the superior border of the pubic symphysis, the anterior border extends to the posterior aspect of the pubis and posteriorly to the rectum, where it may be concave at the level of the VUA. At this level, the lateral border extends to the levator ani. Above the pubic symphysis, the anterior border should encompass the posterior 1–2 cm of the bladder wall; posteriorly, it is bounded by the mesorectal fascia. At this level, the lateral border is the sacrorectogenitopubic fascia. Seminal vesicle remnants, if present, should be included in the CTV if there is pathologic evidence of their involvement.Conclusions: Consensus on postoperative PF-CTV for RT after prostatectomy was reached and is available as a CT image atlas on the RTOG website. This will allow uniformity in defining PF-CTV for clinical trials that include postprostatectomy RT.

Radiographic and Anatomic Basis for Prostate Contouring Errors and Methods to Improve Prostate Contouring Accuracy

Patrick W. McLaughlin, Cheryl Evans, Mary Feng, Vrinda Narayana — 2009-06-09

Purpose: Use of highly conformal radiation for prostate cancer can lead to both overtreatment of surrounding normal tissues and undertreatment of the prostate itself. In this retrospective study we analyzed the radiographic and anatomic basis of common errors in computed tomography (CT) contouring and suggest methods to correct them.Methods and Materials: Three hundred patients with prostate cancer underwent CT and magnetic resonance imaging (MRI). The prostate was delineated independently on the data sets. CT and MRI contours were compared by use of deformable registration. Errors in target delineation were analyzed and methods to avoid such errors detailed.Results: Contouring errors were identified at the prostatic apex, mid gland, and base on CT. At the apex, the genitourinary diaphragm, rectum, and anterior fascia contribute to overestimation. At the mid prostate, the anterior and lateral fasciae contribute to overestimation. At the base, the bladder and anterior fascia contribute to anterior overestimation. Transition zone hypertrophy and bladder neck variability contribute to errors of overestimation and underestimation at the superior base, whereas variable prostate–to–seminal vesicle relationships with prostate hypertrophy contribute to contouring errors at the posterior base.Conclusions: Most CT contouring errors can be detected by (1) inspection of a lateral view of prostate contours to detect projection from the expected globular form and (2) recognition of anatomic structures (genitourinary diaphragm) on the CT scans that are clearly visible on MRI. This study shows that many CT prostate contouring errors can be improved without direct incorporation of MRI data.

Effectiveness of Educational Intervention on the Congruence of Prostate and Rectal Contouring as Compared With a Gold Standard in Three-Dimensional Radiotherapy for Prostate

2009-05-20

Purpose: To examine effects of a teaching intervention on precise delineation of the prostate and rectum during planning of three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer.Methods and Materials: A pretest, posttest, randomized controlled group design was used. During pretest all participants contoured prostate and rectum on planning CT. Afterward, they participated in two types of workshops. The experimental group engaged in an interactive teaching session focused on prostate and rectum MR anatomy compared with CT anatomy. The control group focused on 3D-CRT planning without mention of prostate or rectal contouring. The experimental group practiced on fused MR–CT images, whereas the control group practiced on CT images. All participants completed the posttest.Results: Thirty-one trainees (12 male, 19 female) were randomly assigned to two groups, 17 in the experimental arm, and 14 in the control group. Seventeen felt familiar or very familiar with pelvic organ contouring, 12 somewhat, and 2 had never done it. Thirteen felt confident with organ contouring, 13 somewhat, and 5 not confident. The demographics and composition of groups were analyzed with χ2 and repeated-measures analysis of variance with the two groups (experimental or control) and two tests (pre- or posttest) as factors. Satisfaction with the course and long-term effects of the course on practice were assessed with immediate and delayed surveys. All performance variables showed a similar pattern of results.Conclusions: The training sessions improved the technical performance similarly in both groups. Participants were satisfied with the course content, and the delayed survey reflected that cognitively participants felt more confident with prostate and rectum contouring and would investigate opportunities to learn more about organ contouring.

Phase II Trial of Radiation Dose Escalation With Conformal External Beam Radiotherapy and High-Dose-Rate Brachytherapy Combined With Long-Term Androgen Suppression in Unfavorable Prostate Cancer: Feasibility Report

2009-05-11

Purpose: To determine the feasibility of combined long-term luteinizing hormone-releasing hormone agonist–based androgen suppressive therapy (AST) and dose escalation with high-dose-rate (HDR) brachytherapy for high-risk (HRPC) or very-high-risk prostate cancer (VHRPC).Methods and Materials: Between January 2001 and October 2006, 134 patients (median age, 70 years) with either National Comprehensive Cancer Network criteria–defined HRPC (n = 47, 35.1%) or VHRPC (n = 87, 64.9%) were prospectively enrolled in this Phase II trial. Tumor characteristics included a median pretreatment prostate-specific antigen level of 14.6 ng/mL, a median clinical stage of T2c, and a median Gleason score of 7. Three-dimensional conformal radiotherapy (54 Gy in 30 fractions) was followed by HDR brachytherapy (19 Gy in 4 b.i.d. treatments). Androgen suppressive therapy started 0–3 months before three-dimensional conformal radiotherapy and continued for 2 years.Results: One implant was repositioned with a new procedure (0.7%). Five patients (3.7%) discontinued AST at a median of 13 months (range, 6–18 months) because of disease progression (n = 1), hot flashes (n = 2), fatigue (n = 1), and impotence (n = 1). After a median follow-up of 37.4 months (range, 24–90 months), the highest Radiation Therapy Oncology Group–defined late urinary toxicities were Grade 0 in 47.8%, Grade 1 in 38.1%, Grade 2 in 7.5%, and Grade 3 in 6.7% of patients. Maximal late gastrointestinal toxicities were Grade 0 in 73.1%, Grade 1 in 16.4%, Grade 2 in 7.5%, and Grade 3 in 2.9% of patients. There were no Grade 4 or 5 events.Conclusions: Intermediate-term results show that dose escalation with HDR brachytherapy combined with long-term AST is feasible and has a toxicity profile similar to that reported by previous HDR brachytherapy studies.

Factors Influencing Relapse-Free Survival in Merkel Cell Carcinoma of the Lower Limb—A Review of 60 Cases

Michael Poulsen, Caroline Round, Jacqui Keller, Lee Tripcony, Michael Veness — 2009-06-09

Purpose: Factors affecting relapse-free survival (RFS) in patients with Merkel cell carcinoma (MCC) of the lower limb were reviewed.Methods and Materials: The records of 60 patients from 1986 to 2005 with a diagnosis of MCC of the lower limb or buttock were retrospectively reviewed. The patients were treated with curative intent with surgery, radiation, or chemotherapy.Results: The 5-year overall survival, disease-specific survival, and RFS were 53%, 61%, and 20%, respectively. Factors influencing RFS were analyzed using univariate analysis. It appeared that recurrent disease worsened RFS (p = 0.03) and the addition of any radiotherapy improved RFS (p <0.001), as did radiotherapy to the inguinal nodes (p = 0.01) or primary site and inguinal nodes (p = 0.003). Age, surgical margins, and stage were not statistically significant. On multivariate analysis, the only significant factor was the addition of radiotherapy (hazard ratio = 0.51 p = 0.03).Conclusion: The addition of radiotherapy improves RFS compared with surgery alone. Elective treatment should be given to the inguinal nodes to reduce the risk of relapse.

Organ Preservation With Concurrent Chemoradiation for Advanced Laryngeal Cancer: Are We Succeeding?

2009-04-24

Purpose: To determine the rates of organ preservation and function in patients with advanced laryngeal and hypopharyngeal carcinomas treated with concurrent chemoradiotherapy (CRT).Methods and Materials: Between April 1999 and September 2005, 82 patients with advanced laryngeal (67%) and hypopharyngeal carcinomas (33%) underwent conventional radiotherapy and concurrent platinum-based chemotherapy with curative intent. Sixty-two patients were male (75.6%). The median age was 59 years. Eighteen patients (22%) were in Stage III and 64 (78%) were in Stage IV. The median radiation dose was 70 Gy. The median potential follow-up was 3.9 years.Results: Overall survival and disease-free survival were respectively 63% and 73% at 3 years. Complete response rate from CRT was 75%. Nineteen patients (23%) experienced significant long-term toxicity after CRT: 6 (7.3%) required a percutaneous endoscopic gastrostomy, 5 (6%) had persistent Grade 2 or 3 dysphagia, 2 (2.4%) had pharyngoesophageal stenosis requiring multiple dilations, 2 (2.4%) had chronic lung aspiration, and 7 (8.5%) required a permanent tracheostomy. Four patients (4.9%) underwent laryngectomy without pathologic evidence of disease. At last follow-up, 5 (6%) patients were still dependent on a gastrostomy. Overall, 42 patients (52%) were alive, in complete response, with a functional larynx and no other major complications.Conclusions: In our institution, CRT for advanced hypopharyngeal and laryngeal carcinoma has provided good overall survival and locoregional control in the majority of patients, but a significant proportion did not benefit from this approach because of either locoregional failure or late complications. Better organ preservation approaches are necessary to improve locoregional control and to reduce long-term toxicities.

Dosimetric Factors Associated With Long-Term Dysphagia After Definitive Radiotherapy for Squamous Cell Carcinoma of the Head and Neck

2009-05-20

Purpose: Intensification of radiotherapy and chemotherapy for head-and-neck cancer may lead to increased rates of dysphagia. Dosimetric predictors of objective findings of long-term dysphagia were sought.Methods and Materials: From an institutional database, 83 patients were identified who underwent definitive intensity-modulated radiotherapy for squamous cell carcinoma of the head and neck, after exclusion of those who were treated for a second or recurrent head-and-neck primary lesion, had locoregional recurrence at any time, had less than 12 months of follow-up, or had postoperative radiotherapy. Dosimetric parameters were analyzed relative to three objective endpoints as a surrogate for severe long-term dysphagia: percutaneous endoscopic gastrostomy (PEG) tube dependence at 12 months, aspiration on modified barium swallow, or pharyngoesophageal stricture requiring dilation.Results: Mean dose greater than 41 Gy and volume receiving 60 Gy (V60) greater than 24% to the larynx were significantly associated with PEG tube dependence and aspiration. V60 greater than 12% to the inferior pharyngeal constrictor was also significantly associated with increased PEG tube dependence and aspiration. V65 greater than 33% to the superior pharyngeal constrictor or greater than 75% to the middle pharyngeal constrictor was associated with pharyngoesophageal stricture requiring dilation.Conclusions: Doses to the larynx and pharyngeal constrictors predicted long-term swallowing complications, even when controlled for other clinical factors. The addition of these structures to intensity-modulated radiotherapy optimization may reduce the incidence of dysphagia, although cautious clinical validation is necessary.

Concurrent Chemoradiation With Carboplatin–5-Fluorouracil Versus Cisplatin in Locally Advanced Oropharyngeal Cancers: Is More Always Better?

2009-05-11

Purpose: The optimal chemotherapy regimen remains undefined in the treatment of locally advanced oropharyngeal cancer by concomitant chemoradiation. This article compares two platinum-based chemotherapy regimens.Methods and Materials: In this retrospective study, we reviewed all consecutive patients treated for Stage III or IVA–B oropharyngeal cancer using either a combination of carboplatin and 5-fluorouracil (5FU) every 3 weeks or high-dose cisplatin every 3 weeks concomitant with definitive radiation therapy.Results: A total of 200 patients were treated with carboplatin-5FU and 53 patients with cisplatin. Median potential follow-up was 43 months. The 3-year overall survival rates for carboplatin-5FU and cisplatin respectively were 79.1% and 74.9% (p = 0.628), the 3-year disease-free survival rates were 76.0% and 71.3% (p = 0.799), and the 3-year locoregional control rates were 88.4% and 94.2% (p = 0.244).Conclusions: We could not demonstrate differences between these two regimens, which both proved efficacious. Polychemotherapy and monochemotherapy therefore seem comparable in this retrospective analysis.

Weekly Low-Dose Docetaxel–Based Chemoradiotherapy for Locally Advanced Oropharyngeal or Hypopharyngeal Carcinoma: A Retrospective, Single-Institution Study

2009-04-30

Purpose: To retrospectively assess the efficacy, toxicity, and prognostic factors of weekly low-dose docetaxel–based chemoradiotherapy for Stage III/IV oropharyngeal or hypopharyngeal carcinoma.Methods and Materials: Between 2001 and 2005, 72 consecutive patients with locally advanced oropharyngeal or hypopharyngeal carcinoma were treated with concurrent chemoradiotherapy (CCR; radiation at 60 Gy plus weekly docetaxel [10 mg/m2]). Thirty of these patients also received neoadjuvant chemotherapy (NAC; docetaxel, cisplatin, and 5-fluorouracil) before concurrent chemoradiotherapy. Survival was calculated according to the Kaplan-Meier method. The prognostic factors were evaluated by univariate and multivariate analyses.Results: The median follow-up was 33 months, with overall survival, disease-free survival, and locoregional control rates at 3 years of 59%, 45%, and 52%, respectively. Thirty-six patients (50%) experienced more than one Grade 3 to 4 acute toxicity. Grade 3 mucositis occurred in 32 patients (44%), Grade 4 laryngeal edema in 1 (1%). Grade ≥3 severe hematologic toxicity was observed in only 2 patients (3%). Grade 3 dysphagia occurred as a late complication in 2 patients (3%). Multivariate analyses identified age, T stage, hemoglobin level, and completion of weekly docetaxel, but not NAC, as significant factors determining disease-free survival.Conclusions: Docetaxel is an active agent used in both concurrent and sequential chemoradiotherapy regimens. Mucositis was the major acute toxicity, but this was well tolerated in most subjects. Anemia was the most significant prognostic factor determining survival. Further studies are warranted to investigate the optimal protocol for integrating docetaxel into first-line chemoradiotherapy regimens, as well as the potential additive impact of NAC.

Radiation-Induced Reductions in Regional Lung Perfusion: 0.1–12 Year Data From a Prospective Clinical Study

2009-07-24

Purpose: To assess the time and regional dependence of radiation therapy (RT)-induced reductions in regional lung perfusion 0.1–12 years post-RT, as measured by single photon emission computed tomography (SPECT) lung perfusion.Materials/Methods: Between 1991 and 2005, 123 evaluable patients receiving RT for tumors in/around the thorax underwent SPECT lung perfusion scans before and serially post-RT (0.1–12 years). Registration of pre- and post-RT SPECT images with the treatment planning computed tomography, and hence the three-dimensional RT dose distribution, allowed changes in regional SPECT-defined perfusion to be related to regional RT dose. Post-RT follow-up scans were evaluated at multiple time points to determine the time course of RT-induced regional perfusion changes. Population dose response curves (DRC) for all patients at different time points, different regions, and subvolumes (e.g., whole lungs, cranial/caudal, ipsilateral/contralateral) were generated by combining data from multiple patients at similar follow-up times. Each DRC was fit to a linear model, and differences statistically analyzed.Results: In the overall groups, dose-dependent reductions in perfusion were seen at each time post-RT. The slope of the DRC increased over time up to 18 months post-RT, and plateaued thereafter. Regional differences in DRCs were only observed between the ipsilateral and contralateral lungs, and appeared due to tumor-associated changes in regional perfusion.Conclusions: Thoracic RT causes dose-dependent reductions in regional lung perfusion that progress up to ∼18 months post-RT and persists thereafter. Tumor shrinkage appears to confound the observed dose-response relations. There appears to be similar dose response for healthy parts of the lungs at different locations.

Postoperative Radiotherapy in the Management of Resected Non–Small-Cell Lung Carcinoma: 10 Years' Experience in a Single Institute

2009-04-21

Purpose: This study reports the long term outcomes of postoperative radiotherapy in patients with resection for non–small-cell lung cancer (NSCLC).Methods and Materials: A total of 98 patients with resected NSCLC who received postoperative radiotherapy (PORT) between January 1994 and December 2004 were retrospectively analyzed. The most frequently performed surgical procedure was lobectomy (59 patients), followed by pneumonectomy (25), wedge resection (8), and bilobectomy (6). Postoperative radiotherapy was delivered as an adjuvant treatment in 71 patients, after a wedge resection in 8 patients, and after an R1 resection in 19 patients. The PORT was administered using a Co-60 source in 86 patients and 6-MV photons in 12 patients. A Kaplan-Meier estimate of overall survival, locoregional control, and distant metastasis-free survival were calculated.Results: Stages included I (n =13), II (n = 50), IIIA (n = 29), and IIIB (n = 6). After a median follow-up of 52 months median survival was 61 months. The 5-year overall survival, locoregional control, and distant metastasis-free survival rates for the whole group were 50%, 78%, and 55% respectively. The RT dose, Karnofsky performance status, age, lateralization of the tumor, and pneumonectomy were independent prognostic factors for OAS; anemia and the number of involved lymph nodes were independent prognostic factors for LC.Conclusions: Doses of PORT of greater than 54 Gy were associated with higher death rate in patients with left-sided tumor, which may indicate a risk of radiation-induced cardiac mortality.

Postoperative Radiotherapy After Surgical Resection of Thymoma: Differing Roles in Localized and Regional Disease

2009-05-11

Purpose: To analyze the Surveillance, Epidemiology and End Results (SEER) registry data to determine the impact of postoperative radiotherapy (PORT) for thymoma and thymic carcinoma (T/TC).Methods and Materials: Patients with surgically resected localized (LOC) or regional (REG) malignant T/TC with or without PORT were analyzed for overall survival (OS) and cause-specific survival (CSS) by querying the SEER database from 1973–2005. Patients dying within the first 3 months after surgery were excluded. Kaplan-Meier and multivariate analyses with Cox proportional hazards were performed.Results: A total of 901 T/TC patients were identified (275 with LOC disease and 626 with REG disease). For all patients with LOC disease, PORT had no benefit and may adversely impact the 5-year CSS rate (91% vs. 98%, p = 0.03). For patients with REG disease, the 5-year OS rate was significantly improved by adding PORT (76% vs. 66% for surgery alone, p = 0.01), but the 5-year CSS rate was no better (91% vs. 86%, p = 0.12). No benefit was noted for PORT in REG disease after extirpative surgery (defined as radical or total thymectomy). On multivariate OS and CSS analysis, stage and age were independently correlated with survival. For multivariate CSS analysis, the outcome of PORT is significantly better for REG disease than for LOC disease (hazard ratio, 0.167; p = 0.001).Conclusions: Our results from SEER show that PORT for T/TC had no advantage in patients with LOC disease (Masaoka Stage I), but a possible OS benefit of PORT in patients with REG disease (Masaoka Stage II–III) was found, especially after non-extirpative surgery. The role of PORT in T/TC needs further evaluation.

Three-Dimensional Conformal Radiation Therapy for Esophageal Squamous Cell Carcinoma: Is Elective Nodal Irradiation Necessary?

Kuai-le Zhao, Jin-bo Ma, Guang Liu, Kai-liang Wu, Xue-hui Shi, Guo-liang Jiang — 2009-12-09

Purpose: To evaluate the local control, survival, and toxicity associated with three-dimensional conformal radiotherapy (3D-CRT) for squamous cell carcinoma (SCC) of the esophagus, to determine the appropriate target volumes, and to determine whether elective nodal irradiation is necessary in these patients.Methods and Materials: A prospective study of 3D-CRT was undertaken in patients with esophageal SCC without distant metastases. Patients received 68.4 Gy in 41 fractions over 44 days using late-course accelerated hyperfractionated 3D-CRT. Only the primary tumor and positive lymph nodes were irradiated. Isolated out-of-field regional nodal recurrence was defined as a recurrence in an initially uninvolved regional lymph node.Results: All 53 patients who made up the study population tolerated the irradiation well. No acute or late Grade 4 or 5 toxicity was observed. The median survival time was 30 months (95% confidence interval, 17.7–41.8). The overall survival rate at 1, 2, and 3 years was 77%, 56%, and 41%, respectively. The local control rate at 1, 2, and 3 years was 83%, 74%, and 62%, respectively. Thirty-nine of the 53 patients (74%) showed treatment failure. Seventeen of the 39 (44%) developed an in-field recurrence, 18 (46%) distant metastasis with or without regional failure, and 3 (8%) an isolated out-of-field nodal recurrence only. One patient died of disease in an unknown location.Conclusions: In patients treated with 3D-CRT for esophageal SCC, the omission of elective nodal irradiation was not associated with a significant amount of failure in lymph node regions not included in the planning target volume. Local failure and distant metastases remained the predominant problems.

Usefulness of Intraluminal Brachytherapy Combined With External Beam Radiation Therapy for Submucosal Esophageal Cancer: Long-Term Follow-Up Results

2009-05-05

Purpose: To assess the efficacy of radiation therapy (RT) by using intraluminal brachytherapy (IBT) combined with external beam RT (EBRT) for submucosal esophageal cancer.Methods and Materials: Between 1991 and 2005, 59 consecutive patients received definitive RT without chemotherapy. IBT was performed after patients completed EBRT as a booster therapy for 17 patients, using low-dose-rate Cs-137 sources until 1997, and for 19 patients, using high-dose-rate Ir-192 sources thereafter. The long-term outcomes were investigated with a median follow-up time of 61 months.Results: Logoregional recurrences and distant metastases were observed in 14 patients and in 2 patients in the lung, respectively, and 5 patients were rescued by salvage treatments. The 5-year logoregional control and cause-specific survival rates were 75% and 76%, respectively. The 5-year cause-specific survival rate in the EBRT group was 62%, whereas the corresponding rate in the IBT group was 86% (p = 0.04). Multivariate analysis revealed that IBT was the most powerful predictor of survival but did not reach a significant level (p = 0.07). There were five esophageal ulcers in the IBT group, but no ulcers developed with small fractions of 3 Gy. Grade 2 or higher cardiorespiratory complications developed in 2 patients (5.6%) in the IBT group and in 3 patients (13.0%) in the EBRT group.Conclusions: Combining IBT with EBRT is suggested to be one of the preferable treatment modalities for medically inoperable submucosal esophageal cancer because of its preferable local control and survival probabilities, with appreciably less morbidity.

Proton Beam Therapy for Large Hepatocellular Carcinoma

2009-05-08

Purpose: To investigate the safety and efficacy of proton beam therapy (PBT) in patients with large hepatocellular carcinoma (HCC).Methods and Materials: Twenty-two patients with HCC larger than 10 cm were treated with proton beam therapy at our institution between 1985 and 2006. Twenty-one of the 22 patients were not surgical candidates because of advanced HCC, intercurrent disease, or old age. Median tumor size was 11 cm (range, 10–14cm), and median clinical target volume was 567 cm3 (range, 335–1,398 cm3). Hepatocellular carcinoma was solitary in 18 patients and multifocal in 4 patients. Tumor types were nodular and diffuse in 18 and 4 patients, respectively. Portal vein tumor thrombosis was present in 11 patients. Median total dose delivered was 72.6 GyE in 22 fractions (range, 47.3–89.1 GyE in 10–35 fractions).Results: The median follow-up period was 13.4 months (range, 1.5–85 months). Tumor control rate at 2 years was 87%. One-year overall and progression-free survival rates were 64% and 62%, respectively. Two-year overall and progression-free survival rates were 36% and 24%, respectively. The predominant tumor progression pattern was new hepatic tumor development outside the irradiated field. No late treatment-related toxicity of Grade 3 or higher was observed.Conclusions: The Bragg peak properties of PBT allow for improved conformality of the treatment field. As such, large tumor volumes can be irradiated to high doses without significant dose exposure to surrounding normal tissue. Proton beam therapy therefore represents a promising modality for the treatment of large-volume HCC. Our study shows that PBT is an effective and safe method for the treatment of patients with large HCC.

Impact Factors for Microinvasion in Patients With Hepatocellular Carcinoma: Possible Application to the Definition of Clinical Tumor Volume

2009-04-29

Purpose: To evaluate the degree of invasion of hepatocellular carcinoma (HCC) microscopically that will provide a potential application for gross tumor volume to clinical tumor volume (GTV-to-CTV) expansion.Methods and Materials: From January 2002 to January 2006, 149 HCC patients were selected from those who had undergone surgical resection. Pathology slides and clinical data of all patients were reviewed, including platelet counts, serum α-fetoprotein (AFP) levels, degree of liver cirrhosis, tumor size, capsular status, portal vein invasion, TNM stage, and histologic tumor grade. The distance between the tumor margin (or fibrous capsule) and the invasive lesions was measured by senior pathologists.Results: Of these 149 patients, 79 (53.0%) patients presented with tumor microinvasion between 0.5 and 4 mm. This degree of microinvasion was inversely correlated with lower platelet counts and positively correlated with higher AFP levels, larger tumor sizes, portal vein invasion, and advanced TNM stage. Microinvasion distances less than or equal to 2 mm were found in 96.1% of patients (74/77) with tumor dimensions less than or equal to 5 cm and in 94.5% of patients (85/90) with AFP levels less than 400 μg/l.Conclusions: Based on our study findings, GTV-to-CTV expansions of 4 mm for HCC are required to conceal the gross tumor and any microscopic disease with 100% accuracy. Tumor size and AFP levels are the simplest indicators for determining the GTV-to-CTV distance for HCC.

A Prospective Randomized Trial to Study the Impact of Pretreatment FDG-PET for Cervical Cancer Patients With MRI-Detected Positive Pelvic but Negative Para-Aortic Lymphadenopathy

2009-05-22

Purpose: This prospective randomized study was undertaken to determine the possible impact of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) on extrapelvic metastasis detection, radiation field design, and survival outcome for cervical cancer patients with enlarged pelvic nodes on MRI image.Methods and Materials: Inclusion criteria were patients with newly diagnosed Stage I–IVA cervical cancer and with positive pelvic but negative para-aortic lymph nodes (PALN) as detected by magnetic resonance image and good performance status for concurrent chemoradiotherapy. Eligible patients were randomized to receive either pretreatment FDG-PET (study group) or not (control group). Whole pelvis was the standard irradiation field for the control group and those with no extrapelvic findings on PET. The radiation fields for the rest of the study group were extended to include the PALN region or were modified according to the extrapelvic PET finding.Results: From January 2002 to April 2006, 129 patients were included, and 66 of them were randomized to receive FDG-PET. PET detected seven extrapelvic metastases (11%, 6 PALN and 1 omental node), and four of them remained disease-free after treatment modification. For patients who underwent PET compared with those who did not, there were no differences in the 4-year rates of overall survival (79% vs. 85%, p = 0.65), disease-free survival (75 % vs. 77%, p = 0.64), and distant metastasis-free survival (82% vs. 78%, p = 0.83).Conclusions: Pretreatment FDG-PET in conjunction with magnetic resonance imaging can improve the detection of extrapelvic metastasis, mainly PALN, and help select patients for extended-field radiotherapy. However, the addition of FDG-PET may not translate into survival benefit, even though PALN relapses are reduced.

Effects of Bladder Distension on Organs at Risk in 3D Image-Based Planning of Intracavitary Brachytherapy for Cervical Cancer

Robert Y. Kim, Sui Shen, Hui-Yi Lin, Sharon A. Spencer, Jennifer De Los Santos — 2009-05-20

Purpose: To investigate the effects of bladder distension on organs at risk (OARs) in the image-based planning of intracavitary brachytherapy for cervical cancer.Methods and Materials: Thirteen patients with cancer of the cervix were treated with high-dose radiation brachytherapy (800 cGy/fraction for 3 fractions). For the three-dimensional (3D) analysis, pelvic CT scans were obtained from patients with indwelling catheters in place (defined as empty bladder) and from patients who received 180-cc injections of sterile water in their bladders (defined as full bladder). To compare the International Commission on Radiation Units and Measurements (ICRU) point doses with 3D-volume doses, the volume dose was defined by using two different criteria, D2cc (the minimum dose value in a 2.0-cm3 volume receiving the highest dose) and D50% (the dose received by 50% of the volume of the OAR) for OARs.Results: The bladder D2cc was located more cranially in the bladder base and was distributed in multiple spots in 46% of patients. The rectal D2cc was located in the area of the ICRU point as a single “hot spot.” For patients with a full bladder, the mean bladder D2cc increased from 634 to 799 cGy (28.8%, p = 0.002). However, the bowel D2cc decreased from 475 to 261 cGy (45.0%, p < 0.001). There were no substantial differences in rectal and sigmoid D2cc values. However, the mean D50% values of both the bladder and the bowel decreased from 108 to 80 cGy (23.7%, p < 0.001) and from 282 to 221 cGy (19.7%, p = 0.004) with a full bladder, respectively.Conclusions: An increase in bladder volume resulted in a significant reduction in bowel D2cc values at the expense of an increase in bladder D2cc values. Treatment with a distended bladder is preferable to protect the bowel.

Factors for Predicting Rectal Dose of High-Dose-Rate Intracavitary Brachytherapy After Pelvic Irradiation in Patients With Cervical Cancer: A Retrospective Study With Radiography-Based Dosimetry

2009-05-20

Purpose: To evaluate the predictive factors for rectal dose of the first fraction of high-dose-rate intracavitary brachytherapy (HDR-ICBT) in patients with cervical cancer.Methods and Materials: From March 1993 through February 2008, 946 patients undergoing pelvic irradiation and HDR-ICBT were analyzed. Examination under anesthesia (EUA) at the first implantation of the applicator was usually performed in the early period. Rectal point was determined radiographically according to the 38th Report of the International Commission of Radiation Units and Measurements (ICRU). The ICRU rectal dose (PRD) as a percentage of point A dose was calculated; multiple linear regression models were used to predict PRD.Results: Factors influencing successful rectal dose calculation were EUA (p < 0.001) and absence of diabetes (p = 0.047). Age (p < 0.001), body weight (p = 0.002), diabetes (p = 0.020), and EUA (p < 0.001) were independent factors for the PRD. The predictive equation derived from the regression model was PRD (%) = 57.002 + 0.443 × age (years) − 0.257 × body weight (kg) + 6.028 × diabetes (no: 0; yes: 1) − 8.325 × EUA (no: 0; yes: 1)Conclusion: Rectal dose at the first fraction of HDR-ICBT is positively influenced by age and diabetes, and negatively correlated with EUA and body weight. A small fraction size at point A may be considered in patients with a potentially high rectal dose to reduce the biologically effective dose if the ICRU rectal dose has not been immediately obtained in the first fraction of HDR-ICBT.

Factors Associated With Neurological Recovery of Brainstem Function Following Postoperative Conformal Radiation Therapy for Infratentorial Ependymoma

2009-05-22

Purpose: To identify risk factors associated with incomplete neurological recovery in pediatric patients with infratentorial ependymoma treated with postoperative conformal radiation therapy (CRT).Methods: The study included 68 patients (median age ± standard deviation of 2.6 ± 3.8 years) who were followed for 5 years after receiving CRT (54–59.4 Gy) and were assessed for function of cranial nerves V to VII and IX to XII, motor weakness, and dysmetria. The mean (± standard deviation) brainstem dose was 5,487 (±464) cGy. Patients were divided into four groups representing those with normal baseline and follow-up, those with abnormal baseline and full recovery, those with abnormal baseline and partial or no recovery, and those with progressive deficits at 12 (n = 62 patients), 24 (n = 57 patients), and 60 (n = 50 patients) months. Grouping was correlated with clinical and treatment factors.Results: Risk factors (overall risk [OR], p value) associated with incomplete recovery included gender (male vs. female, OR = 3.97, p = 0.036) and gross tumor volume (GTV) (OR/ml = 1.23, p = 0.005) at 12 months, the number of resections (>1 vs. 1; OR = 23.7, p = 0.003) and patient age (OR/year = 0.77, p = 0.029) at 24 months, and cerebrospinal fluid (CSF) shunting (Yes vs. No; OR = 21.9, p = 0.001) and GTV volume (OR/ml = 1.18, p = 0.008) at 60 months. An increase in GTV correlated with an increase in the number of resections (p = 0.001) and CSF shunting (p = 0.035); the number of resections correlated with CSF shunting (p < 0.0001), and male patients were more likely to undergo multiple tumor resections (p = 0.003). Age correlated with brainstem volume (p < 0.0001). There were no differences in outcome based on the absolute or relative volume of the brainstem that received more than 54 Gy.Conclusions: Incomplete recovery of brainstem function after CRT for infratentorial ependymoma is related to surgical morbidity and the volume and the extent of tumor.

Intracranial Metastatic Disease Spares the Limbic Circuit: A Review of 697 Metastatic Lesions in 107 Patients

2010-02-01

Purpose: We report the incidence of metastatic involvement of the limbic circuit in a retrospective review of patients treated at our institution. This review was performed to assess the feasibility of selectively sparing the limbic system during whole-brain radiotherapy and prophylactic cranial irradiation.Methods and Materials: We identified 697 intracranial metastases in 107 patients after reviewing contrast-enhanced CT and/or MR image sets for each patient. Lesions were localized to the limbic circuit or to the rest of the brain/brain stem. Patients were categorized by tumor histology (e.g., non-small-cell lung cancer, small-cell lung cancer, breast cancer, and other) and by total number of intracranial metastases (1-3, oligometastatic; 4 or more, nonoligometastatic).Results: Thirty-six limbic metastases (5.2% of all metastases) were identified in 22 patients who had a median of 16.5 metastases/patient (limbic metastases accounted for 9.9% of their lesions). Sixteen metastases (2.29%) involved the hippocampus, and 20 (2.86%) involved the rest of the limbic circuit; 86.2% of limbic metastases occurred in nonoligometastatic patients, and 13.8% occurred in oligometastatic patients. The incidence of limbic metastases by histologic subtype was similar. The incidence of limbic metastases in oligometastatic patients was 4.9% (5/103): 0.97%, hippocampus; 3.9%, remainder of the limbic circuit. One of 53 oligometastatic patients (1.9%) had hippocampal metastases, while 4/53 (7.5%) had other limbic metastases.Conclusions: Metastatic involvement of the limbic circuit is uncommon and limited primarily to patients with nonoligometastatic disease, supporting our hypothesis that it is reasonable to selectively exclude or reduce the dose to the limbic circuit when treating patients with prophylactic cranial irradiation or whole-brain radiotherapy for oligometastatic disease not involving these structures.

Gamma Knife Radiosurgery as a Therapeutic Strategy for Intracranial Sarcomatous Metastases

2009-05-20

Purpose: To determine the indication and outcomes for Gamma Knife stereotactic radiosurgery (GKSRS) in the care of patients with intracranial sarcomatous metastases.Methods and Materials: Data from 21 patients who underwent radiosurgery for 60 sarcomatous intracranial metastases (54 parenchymal and 6 dural-based) were studied. Nine patients had radiosurgery for solitary tumors and 12 for multiple tumors. The primary pathology was metastatic leiomyosarcoma (4 patients), osteosarcoma (3 patients), soft-tissue sarcoma (5 patients), chondrosarcoma (2 patients), alveolar soft part sarcoma (2 patients), and rhabdomyosarcoma, Ewing's sarcoma, liposarcoma, neurofibrosarcoma, and synovial sarcoma (1 patient each). Twenty patients received multimodality management for their primary tumor, and 1 patient had no evidence of systemic disease. The mean tumor volume was 6.2 cm3 (range, 0.07–40.9 cm3), and a median margin dose of 16 Gy was administered. Three patients had progressive intracranial disease despite fractionated whole-brain radiotherapy before SRS.Results: A local tumor control rate of 88% was achieved (including patients receiving boost, up-front, and salvage SRS). New remote brain metastases developed in 7 patients (33%). The median survival after diagnosis of intracranial metastasis was 16 months, and the 1-year survival rate was 61%.Conclusions: Gamma Knife radiosurgery was a well-tolerated and initially effective therapy in the management of patients with sarcomatous intracranial metastases. However, many patients, including those who also received fractionated whole-brain radiotherapy, developed progressive new brain disease.

Repeat Stereotactic Radiosurgery for Acoustic Neuromas

2009-09-23

Purpose: To evaluate the outcome of repeat stereotactic radiosurgery (SRS) for acoustic neuromas, we assessed tumor control, clinical outcomes, and the risk of adverse radiation effects in patients whose tumors progressed after initial management.Methods and Materials: During a 21-year experience at our center, 1,352 patients underwent SRS as management for their acoustic neuromas. We retrospectively identified 6 patients who underwent SRS twice for the same tumor. The median patient age was 47 years (range, 35–71 years). All patients had imaging evidence of tumor progression despite initial SRS. One patient also had incomplete surgical resection after initial SRS. All patients were deaf at the time of the second SRS. The median radiosurgery target volume at the time of the initial SRS was 0.5 cc and was 2.1 cc at the time of the second SRS. The median margin dose at the time of the initial SRS was 13 Gy and was 11 Gy at the time of the second SRS. The median interval between initial SRS and repeat SRS was 63 months (range, 25–169 months).Results: At a median follow-up of 29 months after the second SRS (range, 13–71 months), tumor control or regression was achieved in all 6 patients. No patient developed symptomatic adverse radiation effects or new neurological symptoms after the second SRS.Conclusions: With this limited experience, we found that repeat SRS for a persistently enlarging acoustic neuroma can be performed safely and effectively.

Clinical Experience With Image-Guided Radiotherapy in an Accelerated Partial Breast Intensity-Modulated Radiotherapy Protocol

2009-05-20

Purpose: To explore the feasibility of fiducial markers for the use of image-guided radiotherapy (IGRT) in an accelerated partial breast intensity modulated radiotherapy protocol.Methods and Materials: Nineteen patients consented to an institutional review board approved protocol of accelerated partial breast intensity-modulated radiotherapy with fiducial marker placement and treatment with IGRT. Patients (1 patient with bilateral breast cancer; 20 total breasts) underwent ultrasound guided implantation of three 1.2- × 3-mm gold markers placed around the surgical cavity. For each patient, table shifts (inferior/superior, right/left lateral, and anterior/posterior) and minimum, maximum, mean error with standard deviation were recorded for each of the 10 BID treatments. The dose contribution of daily orthogonal films was also examined.Results: All IGRT patients underwent successful marker placement. In all, 200 IGRT treatment sessions were performed. The average vector displacement was 4 mm (range, 2–7 mm). The average superior/inferior shift was 2 mm (range, 0–5 mm), the average lateral shift was 2 mm (range, 1–4 mm), and the average anterior/posterior shift was 3 mm (range, 1 5 mm).Conclusions: This study shows that the use of IGRT can be successfully used in an accelerated partial breast intensity-modulated radiotherapy protocol. The authors believe that this technique has increased daily treatment accuracy and permitted reduction in the margin added to the clinical target volume to form the planning target volume.

Low-Dose Hyperradiosensitivity: Is There a Place for Future Investigation in Clinical Settings?

2009-06-19

Background and Purpose: In vitro radiation doses of below 0.5 Gy have been shown to be more effective than higher doses per unit dose in killing clonogenic cells of many epithelial tumor cell lines. This phenomenon is known as low-dose hyperradiosensitivity. Preclinical studies have now suggested that there is synergism between chemotherapy and low-dose fractionated radiotherapy (LD-FRT). To test the clinical efficacy of this approach, we prospectively evaluated concurrent palliative chemotherapy and LD-FRT in patients with various types of epithelial tumors.Methods and Materials: Patients suffering from relapses or metastases of epithelial tumors were scheduled to receive concurrent LD-FRT (two fractions of 0.4 Gy per day) and chemotherapy. Radiologic assessments were performed after three cycles of chemotherapy plus LD-FRT.Results: Between June 2006 and October 2007, 12 patients with lung cancer, 7 patients with head-and-neck tumors, 2 patients with breast cancer, and 1 patient with esophageal carcinoma, for a total patient population of 22, underwent concomitant LD-FRT and chemotherapy. All patients but 3 (86%) had received previous treatments for their cancer. The median total dose of LD-FRT delivered was 800 cGy (range, 320–1280 cGy). The overall response rate was 45% (42% in previously treated patients). Grade 3–4 hematologic toxicities (Radiation Therapy Oncology Group ratings) were observed in 2 patients. At a median follow-up of 6.5 months, however, no local toxicity was observed.Conclusion: In our experience, concurrent LD-FRT and chemotherapy was well tolerated. Because the response rate seems promising, prospective Phase II studies of the strategy are now under way.

Radiation-Associated Breast Tumors Display a Distinct Gene Expression Profile

2010-02-01

Purpose: Women who received irradiation for Hodgkin's lymphoma have a strong increased risk for developing breast cancer. Approximately 90% of the breast cancers in these patients can be attributed to their radiation treatment, rendering such series extremely useful to determine whether a common radiation-associated cause underlies the carcinogenic process.Methods and Materials: In this study we used gene expression profiling technology to assess gene expression changes in radiation-associated breast tumors compared with a set of control breast tumors of women unexposed to radiation, diagnosed at the same age. RNA was obtained from fresh frozen tissue samples from 22 patients who developed breast cancer after Hodgkin's lymphoma (BfHL) and from 20 control breast tumors.Results: Unsupervised hierarchical clustering of the profile data resulted in a clustering of the radiation-associated tumors separate from the control tumors (p < 0.001). Using a supervised class prediction tool, a nearest centroid classifier of 198 probes was identified. The BfHL tumors were often of the intrinsic basal breast tumor subtype, and they showed a chromosomal instability profile and a higher expression of the proliferation marker Ki-67.Conclusion: These results indicate that radiation-associated tumors are different from other breast tumors on the basis of their expression profile and that they are mainly of one specific cause that is characterized by high proliferation and a more aggressive tumor type.

Quantifying Local Radiation-Induced Lung Damage From Computed Tomography

2010-02-01

Purpose: Optimal implementation of new radiotherapy techniques requires accurate predictive models for normal tissue complications. Since clinically used dose distributions are nonuniform, local tissue damage needs to be measured and related to local tissue dose. In lung, radiation-induced damage results in density changes that have been measured by computed tomography (CT) imaging noninvasively, but not yet on a localized scale. Therefore, the aim of the present study was to develop a method for quantification of local radiation-induced lung tissue damage using CT.Methods and Materials: CT images of the thorax were made 8 and 26 weeks after irradiation of 100%, 75%, 50%, and 25% lung volume of rats. Local lung tissue structure (SL) was quantified from local mean and local standard deviation of the CT density in Hounsfield units in 1-mm3 subvolumes. The relation of changes in SL (ΔSL) to histologic changes and breathing rate was investigated. Feasibility for clinical application was tested by applying the method to CT images of a patient with non–small-cell lung carcinoma and investigating the local dose–effect relationship of ΔSL.Results: In rats, a clear dose–response relationship of ΔSL was observed at different time points after radiation. Furthermore, ΔSL correlated strongly to histologic endpoints (infiltrates and inflammatory cells) and breathing rate. In the patient, progressive local dose-dependent increases in ΔSL were observed.Conclusion: We developed a method to quantify local radiation-induced tissue damage in the lung using CT. This method can be used in the development of more accurate predictive models for normal tissue complications.

A New Class of Molecular Targeted Radioprotectors: GSK-3β Inhibitors

2010-02-01

Purpose: Development of new treatments is critical to effective protection against radiation-induced injury. We investigate the potential of developing small-molecule inhibitors of glycogen synthase kinase 3β (GSK-3β)—SB216763 or SB415286—as radioprotective agents to attenuate intestinal injury.Methods and Materials: A survival study was done by use of C57BL/6J mice to evaluate the radioprotective effect of GSK-3β inhibitors. Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay and immunohistochemical staining for Bax and Bcl-2 were used to assess apoptosis in the small intestines of the treated mice. A clonogenic survival study, apoptosis assays (staining with annexin V or 4′,6-diamidino-2-phenylindole), and immunoblot analysis of β-catenin, Bcl-2, Bax, and caspase 3 were done by use of Rat intestinal epithelial cell line IEC-6 cells.Results: Pretreatment with SB415286 significantly improved survival of mice irradiated with 8 and 12 Gy. Mice pretreated with SB216763 or SB415286 showed a significant reduction in TUNEL- and Bax-positive cells and an increase in Bcl-2–positive cells in intestinal crypts at 4 and/or 12 h after radiation with 4 and/or 8 Gy compared with radiation alone. Pretreatment of irradiated IEC-6 cells with GSK-3β inhibitors significantly increased clonogenic survival compared with cells treated with radiation alone. This increase was due to the attenuation of radiation-induced apoptosis, as shown by annexin V and 4′,6-diamidino-2-phenylindole assays, as well as immunoblot analysis of Bcl-2, Bax, and caspase 3.Conclusions: Glycogen synthase kinase 3β small-molecule inhibitors protect mouse intestine from radiation-induced damage in cell culture and in vivo and improve survival of mice. Molecular mechanisms of this protection involve attenuated radiation-induced apoptosis regulated by Bcl-2, Bax, and caspase 3. Therefore GSK-3β inhibitors reduce deleterious consequences of intestinal irradiation and thereby improve quality of life during radiation therapy.

Suberoylanilide Hydroxyamic Acid Modification of Chromatin Architecture Affects DNA Break Formation and Repair

Sheetal Singh, Hongan Le, Shyh-Jen Shih, Bay Ho, Andrew T. Vaughan — 2010-02-01

Purpose: Chromatin-modifying compounds that inhibit the activity of histone deacetylases have shown potency as radiosensitizers, but the action of these drugs at a molecular level is not clear. Here we investigated the effect of suberoylanilide hydroxyamic acid (SAHA) on DNA breaks and their repair and induction of rearrangements.Methods and Materials: The effect of SAHA on both clonogenic survival and repair was assessed using cell lines SCC-25, MCF7, and TK6. In order to study unique DNA double-strand breaks, anti-CD95 antibody was employed to introduce a DNA double-strand break at a known location within the 11q23 region. The effects of SAHA on DNA cleavage and rearrangements were analyzed by ligation-mediated PCR and inverse PCR, respectively.Results: SAHA acts as radiosensitizer at 1 μM, with dose enhancement factors (DEFs) at 10% survival of: SCC-25 - 1.24 ± 0.05; MCF7 - 1.16 ± 0.09 and TK6 - 1.17 ± 0.05, and it reduced the capacity of SCC-25 cells to repair radiation induced lesions. Additionally, SAHA treatment diffused site-specific fragmentation over at least 1 kbp in TK6 cells. Chromosomal rearrangements produced in TK6 cells exposed to SAHA showed a reduction in microhomology at the breakpoint between 11q23 and partner chromosomes.Conclusions: SAHA shows efficacy as a radiosensitizer at clinically obtainable levels. In its presence, targeted DNA strand breaks occur over an expanded region, indicating increased chromatin access. The rejoining of such breaks is degraded by SAHA when measured as rearrangements at the molecular level and rejoining that contributes to cell survival.

Irradiation-Induced Regulation of Plasminogen Activator Inhibitor Type-1 and Vascular Endothelial Growth Factor in Six Human Squamous Cell Carcinoma Lines of the Head and Neck

2010-02-01

Purpose: It has been shown that plasminogen activator inhibitor type–1 (PAI-1) and vascular endothelial growth factor (VEGF) are involved in neo-angiogenesis. The aim of this study was to investigate the irradiation-induced regulation of PAI-1 and VEGF in squamous cell carcinomas of the head and neck (SCCHN) cell lines of varying radiation sensitivity.Methods and Materials: Six cell lines derived from SCCHN were investigated in vitro. The colorimetric AlamarBlue assay was used to detect metabolic activity of cell lines during irradiation as a surrogate marker for radiation sensitivity. PAI-1 and VEGF secretion levels were measured by enzyme-linked immunosorbent assay 24, 48, and 72 h after irradiation with 0, 2, 6, and 10 Gy. The direct radioprotective effect of exogenous PAI-1 was measured using the clonogenic assay. For regulation studies, transforming growth factor–β1 (TGF-β1), hypoxia-inducible factor-1α (HIF-1α), hypoxia-inducible factor-2α (HIF-2α), or both HIF-1α and HIF-2α were downregulated using siRNA.Results: Although baseline levels varied greatly, irradiation led to a comparable dose-dependent increase in PAI-1 and VEGF secretion in all six cell lines. Addition of exogenous stable PAI-1 to the low PAI-1–expressing cell lines, XF354 and FaDu, did not lead to a radioprotective effect. Downregulation of TGF-β1 significantly decreased VEGF secretion in radiation-sensitive XF354 cells, and downregulation of HIF-1α and HIF-2α reduced PAI-1 and VEGF secretion in radiation-resistant SAS cells.Conclusions: Irradiation dose-dependently increased PAI-1 and VEGF secretion in all SCCHN cell lines tested regardless of their basal levels and radiation sensitivity. In addition, TGF-β1 and HIF-1α could be partly responsible for VEGF and PAI-1 upregulation after irradiation.

Results of a Multi-Institution Deformable Registration Accuracy Study (MIDRAS)

Kristy K. Brock, Deformable Registration Accuracy Consortium — 2009-11-11

Purpose: To assess the accuracy, reproducibility, and computational performance of deformable image registration algorithms under development at multiple institutions on common datasets.Methods and Materials: Datasets from a lung patient (four-dimensional computed tomography [4D-CT]), a liver patient (4D-CT and magnetic resonance imaging [MRI] at exhale), and a prostate patient (repeat MRI) were obtained. Radiation oncologists localized anatomic structures for accuracy assessment. Algorithm accuracy was determined by comparing the computer-predicted displacement at each bifurcation point with the displacement computed from the oncologists' annotations. Thirty-seven academic institutions and medical device manufacturers with published evidence of active deformable image registration capabilities were invited to participate.Results: Twenty-seven groups agreed to participate; 6 did not return results. Sixteen completed the liver 4D-CT, 12 the lung 4D-CT, 3 the prostate MRI, and 3 the liver MRI-CT. The range of average absolute error for the lung 4D-CT was 0.6–1.2 mm (left–right [LR]), 0.5–1.8 mm (anterior–posterior [AP]), and 0.7–2.0 mm (superior–inferior [SI]); the liver 4D-CT was 0.8–1.5 mm (LR), 1.0–5.2 mm (AP), and 1.0–5.9 mm (SI); the liver MRI-CT was 1.1–2.6 mm (LR), 2.0–5.0 mm (AP), and 2.2–2.6 mm (SI); and the repeat prostate MRI prostate datasets was 0.5–6.2 mm (LR), 3.1–3.7 mm (AP), and 0.4–2.0 mm (SI).Conclusions: An infrastructure was developed to assess multi-institution deformable registration accuracy. The results indicate large discrepancies in reported shifts, although the majority of deformable registration algorithms performed at an accuracy equivalent to the voxel size, promising to improve treatment planning, delivery, and assessment.

Use of Respiratory-Correlated Four-Dimensional Computed Tomography to Determine Acceptable Treatment Margins for Locally Advanced Pancreatic Adenocarcinoma

2009-10-15

Purpose: Respiratory-induced excursions of locally advanced pancreatic adenocarcinoma could affect dose delivery. This study quantified tumor motion and evaluated standard treatment margins.Methods and Materials: Respiratory-correlated four-dimensional computed tomography images were obtained on 30 patients with locally advanced pancreatic adenocarcinoma; 15 of whom underwent repeat scanning before cone-down treatment. Treatment planning software was used to contour the gross tumor volume (GTV), bilateral kidneys, and biliary stent. Excursions were calculated according to the centroid of the contoured volumes.Results: The mean ± standard deviation GTV excursion in the superoinferior (SI) direction was 0.55 ± 0.23 cm; an expansion of 1.0 cm adequately accounted for the GTV motion in 97% of locally advanced pancreatic adenocarcinoma patients. Motion GTVs were generated and resulted in a 25% average volume increase compared with the static GTV. Of the 30 patients, 17 had biliary stents. The mean SI stent excursion was 0.84 ± 0.32 cm, significantly greater than the GTV motion. The xiphoid process moved an average of 0.35 ± 0.12 cm, significantly less than the GTV. The mean SI motion of the left and right kidneys was 0.65 ± 0.27 cm and 0.77 ± 0.30 cm, respectively. At repeat scanning, no significant changes were seen in the mean GTV size (p = .8) or excursion (p = .3).Conclusion: These data suggest that an asymmetric expansion of 1.0, 0.7, and 0.6 cm along the respective SI, anteroposterior, and medial–lateral directions is recommended if a respiratory-correlated four-dimensional computed tomography scan is not available to evaluate the tumor motion during treatment planning. Surrogates of tumor motion, such as biliary stents or external markers, should be used with caution.

Interfractional Uncertainty in the Treatment of Pancreatic Cancer With Radiation

2009-10-30

Purpose: To compare the interfractional variation in pancreatic tumor position using bony anatomy and implanted fiducial markers.Methods and Materials: Five consecutively treated patients with pancreatic adenocarcinoma who received definitive intensity-modulated radiation therapy at Stanford University (Stanford, CA) underwent fiducial seed placement and treatment on the Varian Trilogy system (Varian, Palo Alto, CA) with respiratory gating. Daily orthogonal kilovoltage imaging was performed to verify patient positioning, and isocenter shifts were made initially to match bony anatomy. Next, a final shift to the fiducial seeds was made under fluoroscopic guidance to confirm the location of the pancreatic tumor during the respiratory gated phase. All shifts were measured along three axes, left (+)–right (−), anterior (−)–posterior (+), and superior (+)–inferior (−), and the overall interfractional tumor movement was calculated based on these values.Results: A total of 140 fractions were analyzed. The mean absolute shift to fiducial markers after shifting to bony anatomy was 1.6 mm (95th percentile, 7 mm; range, 0–9 mm), 1.8 mm (95th percentile, 7 mm; range, 0–13 mm), and 4.1 mm (95th percentile, 12 mm; range, 0–19 mm) in the anterior–posterior, left–right, and superior–inferior directions, respectively. The mean interfractional vector shift distance was 5.5 mm (95th percentile, 14.5 mm; range, 0–19.3 mm). In 28 of 140 fractions (20%) no fiducial shift was required after alignment to bony anatomy.Conclusions: There is substantial residual uncertainty after alignment to bony anatomy when radiating pancreatic tumors using respiratory gating. Bony anatomy matched tumor position in only 20% of the radiation treatments. If bony alignment is used in conjunction with respiratory gating without implanted fiducials, treatment margins need to account for this uncertainty.

Intensity-Modulated and 3D-Conformal Radiotherapy for Whole-Ventricular Irradiation as Compared With Conventional Whole-Brain Irradiation in the Management of Localized Central Nervous System Germ Cell Tumors

2009-10-30

Purpose: To compare the sparing potential of cerebral hemispheres with intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) for whole-ventricular irradiation (WVI) and conventional whole-brain irradiation (WBI) in the management of localized central nervous system germ cell tumors (CNSGCTs).Methods and Materials: Ten cases of patients with localized CNSGCTs and submitted to WVI by use of IMRT with or without a “boost” to the primary lesion were selected. For comparison purposes, similar treatment plans were produced by use of 3D-CRT (WVI with or without boost) and WBI (opposed lateral fields with or without boost), and cerebral hemisphere sparing was evaluated at dose levels ranging from 2 Gy to 40 Gy.Results: The median prescription dose for WVI was 30.6 Gy (range, 25.2–37.5 Gy), and that for the boost was 16.5 Gy (range, 0–23.4 Gy). Mean irradiated cerebral hemisphere volumes were lower for WVI with IMRT than for 3D-CRT and were lower for WVI with 3D-CRT than for WBI. Intensity-modulated radiotherapy was associated with the lowest irradiated volumes, with reductions of 7.5%, 12.2%, and 9.0% at dose levels of 20, 30, and 40 Gy, respectively, compared with 3D-CRT. Intensity-modulated radiotherapy provided statistically significant reductions of median irradiated volumes at all dose levels (p = 0.002 or less). However, estimated radiation doses to peripheral areas of the body were 1.9 times higher with IMRT than with 3D-CRT.Conclusions: Although IMRT is associated with increased radiation doses to peripheral areas of the body, its use can spare a significant amount of normal central nervous system tissue compared with 3D-CRT or WBI in the setting of CNSGCT treatment.

Biological in situ Dose Painting for Image-Guided Radiation Therapy Using Drug-Loaded Implantable Devices

2009-10-30

Purpose: Implantable devices routinely used for increasing spatial accuracy in modern image-guided radiation treatments (IGRT), such as fiducials or brachytherapy spacers, encompass the potential for in situ release of biologically active drugs, providing an opportunity to enhance the therapeutic ratio. We model this new approach for two types of treatment.Methods and Materials: Radiopaque fiducials used in IGRT, or prostate brachytherapy spacers (“eluters”), were assumed to be loaded with radiosensitizer for in situ drug slow release. An analytic function describing the concentration of radiosensitizer versus distance from eluters, depending on diffusion–elimination properties of the drug in tissue, was developed. Tumor coverage by the drug was modeled for tumors typical of lung stereotactic body radiation therapy treatments for various eluter dimensions and drug properties. Six prostate 125I brachytherapy cases were analyzed by assuming implantation of drug-loaded spacers. Radiosensitizer-induced subvolume boost was simulated from which biologically effective doses for typical radiosensitizers were calculated in one example.Results: Drug distributions from three-dimensional arrangements of drug eluters versus eluter size and drug properties were tabulated. Four radiosensitizer-loaded fiducials provide adequate radiosensitization for ∼4-cm-diameter lung tumors, thus potentially boosting biologically equivalent doses in centrally located stereotactic body treated lesions. Similarly, multiple drug-loaded spacers provide prostate brachytherapy with flexible shaping of “biologically equivalent doses” to fit requirements difficult to meet by using radiation alone, e.g., boosting a high-risk region juxtaposed to the urethra while respecting normal tissue tolerance of both the urethra and the rectum.Conclusions: Drug loading of implantable devices routinely used in IGRT provides new opportunities for therapy modulation via biological in situ dose painting.

A Case Study in Proton Pencil-Beam Scanning Delivery

2010-02-01

Purpose: We completed an implementation of pencil-beam scanning (PBS), a technology whereby a focused beam of protons, of variable intensity and energy, is scanned over a plane perpendicular to the beam axis and in depth. The aim of radiotherapy is to improve the target to healthy tissue dose differential. We illustrate how PBS achieves this aim in a patient with a bulky tumor.Methods and Materials: Our first deployment of PBS uses “broad” pencil-beams ranging from 20 to 35 mm (full-width-half-maximum) over the range interval from 32 to 7 g/cm2. Such beam-brushes offer a unique opportunity for treating bulky tumors. We present a case study of a large (4,295 cc clinical target volume) retroperitoneal sarcoma treated to 50.4 Gy relative biological effectiveness (RBE) (presurgery) using a course of photons and protons to the clinical target volume and a course of protons to the gross target volume.Results: We describe our system and present the dosimetry for all courses and provide an interdosimetric comparison.Discussion: The use of PBS for bulky targets reduces the complexity of treatment planning and delivery compared with collimated proton fields. In addition, PBS obviates, especially for cases as presented here, the significant cost incurred in the construction of field-specific hardware. PBS offers improved dose distributions, reduced treatment time, and reduced cost of treatment.

Computer Modeling of Yttrium-90–Microsphere Transport in the Hepatic Arterial Tree to Improve Clinical Outcomes

2009-11-11

Purpose: Radioembolization (RE) via yttrium-90 (90Y) microspheres is an effective and safe treatment for unresectable liver malignancies. However, no data are available regarding the impact of local blood flow dynamics on 90Y-microsphere transport and distribution in the human hepatic arterial system.Methods and Materials: A three-dimensional (3-D) computer model was developed to analyze and simulate blood-microsphere flow dynamics in the hepatic arterial system with tumor. Supplemental geometric and flow data sets from patients undergoing RE were also available to validate the accuracy of the computer simulation model. Specifically, vessel diameters, curvatures, and branching patterns, as well as blood flow velocities/pressures and microsphere characteristics (i.e., diameter and specific gravity), were measured. Three-dimensional computer-aided design software was used to create the vessel geometries. Initial trials, with 10,000 noninteracting microspheres released into the hepatic artery, used resin spheres 32-μm in diameter with a density twice that of blood.Results: Simulations of blood flow subject to different branch-outlet pressures as well as blood-microsphere transport were successfully carried out, allowing testing of two types of microsphere release distributions in the inlet plane of the main hepatic artery. If the inlet distribution of microspheres was uniform (evenly spaced particles), a greater percentage would exit into the vessel branch feeding the tumor. Conversely, a parabolic inlet distribution of microspheres (more particles around the vessel center) showed a high percentage of microspheres exiting the branch vessel leading to the normal liver.Conclusions: Computer simulations of both blood flow patterns and microsphere dynamics have the potential to provide valuable insight on how to optimize 90Y-microsphere implantation into hepatic tumors while sparing normal tissue.

Consensus Statement: APBI From ASTRO (Int J Radiat Oncol Biol Phys 2009;74:987–1001)

Kathryn Beal, Beryl McCormick — 2010-02-01

To the Editor: The American Society for Therapeutic Radiology and Oncology (ASTRO) consensus statement is timely and provides much needed guidance for accelerated partial breast radiation (APBI) treatment, until the results of the NSABP B-39/RTOG 0413 Phase III trial are available. We congratulate the task force members and remind the reader that this trial remains open to accrual.

In Reply to Dr. Beal et al

2010-02-01

To the Editor: We thank Drs. Beal and McCormick for sharing their experience regarding magnetic resonance imaging in the preoperative evaluation of women age ≥60 years with clinical Stage I invasive ductal breast carcinoma. Their finding of a lack of benefit derived from breast magnetic resonance imaging in their single-institution experience is consistent with our conclusion that “insufficient data are available to justify routine use of breast magnetic resonance imaging (MRI) in patients selected for APBI [accelerated partial breast irradiation].” Larger, prospective studies are still needed to define the role, if any, of breast magnetic resonance imaging in selecting patients for accelerated partial breast irradiation.

In Regards to Dr. Eisbruch A et al. (Int J Radiat Oncol Biol Phys 2009. Electronic Publication, June 17, 2009.)

Geoffrey S. Ibbott, Andrea Molineu, David S. Followill — 2010-02-01

To the Editor: Eisbruch et al. recently published the results of a Radiation Therapy Oncology Group (RTOG) trial of oropharyngeal cancer. This was a significant study for a number of reasons, among them that this was the first use of intensity-modulated radiation therapy (IMRT) in a prospective multi-institutional trial and also that it was the first trial to require participants to undergo IMRT credentialing tests before registering patients.

Response to Letter by Dr. Ibott et al.

2010-02-01

To the Editor: We appreciate the correction by Dr. Ibott et al. to the identification of the contributors to the centralized QA and credentialing programs employed in the RTOG 00-22 study . We would like to express our appreciation of the Radiologic Physics Center, the RTOG Dosimetry Group, and the Image Guided Therapy Center's role in conducting the preapproval procedures and phantom work, which were crucial to the success of the study.

Meetings

2010-02-01

February 11-12, 2010 School of Breast Brachytherapy & Brachytherapy Physics

ASTRO News

2010-02-01

The Current State of the Art Techniques for IMRT, IGRT and SBRT symposium is scheduled for May 14-16, 2010, at the Fairmont hotel in Dallas. Attendees will receive the latest information on techniques used in the adaptation of IMRT, IGRT and SBRT that the successful clinician needs to review and decide on criteria, such as patient selection, immobilization options, setup uncertainties, multimodality imaging, image registration, motion evaluation and management, quality assurance, and correction strategies. For registration and housing information visit http://www.astro.org/Meetings/UpcomingMeetings/IGRTSymposium.