International Journal of Radiation Oncology * Biology * Physics

Issue Highlights

2012-06-01

R. L. Foote A regular feature where senior members of the Red Journal editorial team highlight recent articles related to the scientific literature that they feel are “must reads” for the radiation oncology community. Major articles are summarized and editorial comments are provided. This issue, Senior Editor Robert L. Foote, MD, FASTRO, reviews the best head-and-neck literature. He also explains recent changes to the head-and-neck cancers editorial section.

Oncology Scan – Head and Neck Cancers

Robert L. Foote — 2012-06-01

As senior editor for head-and-neck cancer, I have the pleasure of working with an incredible team of 4 outstanding associate editors. The associate editors read the manuscripts and together we decide whether the manuscript should be sent out for formal review. If there is a consensus by the editors to send the manuscript out for review, the associate editors organize the reviews, read and appraise the reviews, and we all discuss the reviews in the context of the journal's new priorities (see Zietman AL, Receiving the Torch. Int. J. Radiation Oncology Biol. Phys. 2012; 82(1):102). We then make a final decision to be approved by the Editor-in-Chief.

Different Dose Escalation Protocols for Esophageal Primaries: Like Comparing Apples and Oranges? In regard to Welsh et al (Int J Radiat Oncol Biol Phys 2012;82:468–474)

Abhishek Puri — 2012-06-01

To the Editor: The current conventional dose for esophageal primaries is suboptimal, as argued by Welsh et al . Doses can be escalated by either 3-dimensional conformal radiation therapy (3DCRT) or simultaneous integrated boost intensity modulated radiation therapy (SIB-IMRT).

In regard to “Indications for Pelvic Nodal Treatment in Prostate Cancer Should Change. Validation of the Roach Formula in a Large Extended Nodal Dissection Series.” (Int J Radiat Oncol Biol Phys 2012;83:624–629)

James B. Yu — 2012-06-01

To the Editor: I read with interest the article by Dr. Abdollah and colleagues , and I commend them for their efforts. Several issues deserve comment. First, the authors calculate the area under the curve (AUC) of the receiver operating characteristic curve of the Roach formula to be 80.3%, and they use this finding to indicate “overall accuracy.” However, the AUC measures discrimination, not accuracy. Therefore, when any formula (such as the Roach formula) adds multiples of 2 known risk factors for lymph node risk (such as Gleason score and prostate-specific antigen [PSA]), it is almost assured that the AUC will show reasonable discrimination. Therefore, the authors’ claim of accuracy rests solely on descriptive statistics and visual inspection of a calibration plot, without formal statistical testing. Though the calibration plot and Table 2 are encouraging, what remains unanswered is whether the predictive accuracy of the Roach formula is any better than the Gleason score and PSA alone, and whether the predictive ability of the Roach formula can be improved upon.

In regard to Hattangadi et al (Int J Radiat Oncol Biol Phys. Epub Nov 17, 2011): Accelerated Partial Breast Irradiation With Low-Dose-Rate Interstitial Implant Brachytherapy After Wide Local Excision: 12-year Outcomes From a Prospective Trial

Jean-Michel Hannoun-Levi, Csaba Polgar, Erik Van Limbergen — 2012-06-01

To the Editor: The authors presented the updated results of an accelerated partial breast irradiation (APBI) phase I–II dose-escalation study using interstitial low-dose-rate brachytherapy (IB) for early-stage breast cancer . They reported poor cosmetic results and significant toxicity for high doses.

In regard to Zhou et al “Baseline Serum Lactate Dehydrogenase Levels for Patients Treated With Intensity-Modulated Radiotherapy for Nasopharyngeal Carcinoma: A Predictor of Poor Prognosis and Subsequent Liver Metastasis” (Int J Radiat Oncol Biol Phys 2012;82:e359–e365)

Enis Ozyar, Hale Basak Caglar, Banu Atalar — 2012-06-01

To the Editor: We read with great interest the article by Zhou et al , in which they reported that baseline serum lactate dehydrogenase (LDH) levels are a predictor of poor prognosis and subsequent liver metastasis in patients treated with intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC). We very much appreciate that the authors cited our similar retrospective study, which concerned NPC patients treated in the 2-dimensional radiation therapy era.

In regard to RTOG Sarcoma Radiation Oncologists Reach Consensus on Gross Tumor Volume and Clinical Target Volume on Computed Tomographic Images for Preoperative Radiotherapy of Primary Soft Tissue Sarcoma of Extremity in Radiation Therapy Oncology Group Studies: In regard to Wang et al (Int J Radiat Oncol Biol Phys 2011;81:e525–e528)

2012-06-01

To the Editor: We commend the RTOG radiation oncologists who arrived at a consensus for target volume delineation for preoperative sarcoma radiation therapy that generally follows the protocol for their recently completed RTOG 0630 trial , for which we all await local control results. Of interest is the clinical target volume (CTV) definition, which typically entails a 3-cm longitudinal and 1.5-cm radial margin on GTV . Notably however, this longitudinal plane target definition differs from that used in previous prospective trials of pre-operative radiation therapy (RT).

Need for Neck Dissection: A Premature Epitaph for “obsolete paradigm”? In regard to Clavel et al (Int J Radiat Oncol Biol Phys 2012;82:e567–e573)

Abhishek Puri — 2012-06-01

Clavel et al have stoked a controversial debate for neck dissection in complete responders after definitive chemoradiation in head-and-neck cancers, echoed in an accompanying editorial . Although applied radiologic criteria as predictive markers seem robust, at best, imaging is still a supplementary tool in the decision algorithm.

Esophageal Delineation: In regard to Kong et al “Consideration of Dose Limits for Organs at Risk of Thoracic Radiotherapy: Atlas for Lung, Proximal Bronchial Tree, Esophagus, Spinal Cord, Ribs, and Brachial Plexus” (Int J Radiat Oncol Biol Phys 2011;81:1442–1457)

Timothy Zagar, Lawrence Marks — 2012-06-01

To the Editor: We appreciate the effort of Dr. Kong et al to provide some uniformity for normal tissue delineation for thoracic tumors—clearly a worthwhile goal. However, we have one concern regarding the esophagus.

Radiosurgery to the Postoperative Surgical Cavity: Who Needs Evidence?

David Roberge, Ian Parney, Paul D. Brown — 2011-11-17

There is a growing interest in adjuvant radiosurgery after resection of hematogenous brain metastases. This is exemplified by the approximately 1000 cases reported in mainly retrospective series. These cases fall into four paradigms: adjuvant radiosurgery as an alternative to whole-brain radiotherapy (WBRT), radiosurgery neoadjuvant to the surgical resection, radiosurgery as an intensification of adjuvant WBRT, and adjuvant radiosurgery for patients having failed prior WBRT. These procedures seem well tolerated, with an approximate 5% risk of radiation necrosis. Although crude local control rates for each strategy seem improved over surgery alone, multiple biases make comparisons with standard WBRT difficult without prospective data. Because evidence lags behind clinical practice, an upcoming intergroup trial will aim to clarify the value of the most common tumor bed radiosurgery strategy by randomizing oligometastatic patients between adjuvant WBRT and adjuvant radiosurgery.

Role of Postmastectomy Radiation After Neoadjuvant Chemotherapy in Stage II-III Breast Cancer

2012-06-01

Purpose: To identify a cohort of women treated with neoadjuvant chemotherapy and mastectomy for whom postmastectomy radiation therapy (PMRT) may be omitted according to the projected risk of local-regional failure (LRF).Methods and Materials: Seven breast cancer physicians from the University of California cancer centers created 14 hypothetical clinical case scenarios, identified, reviewed, and abstracted the available literature (MEDLINE and Cochrane databases), and formulated evidence tables with endpoints of LRF, disease-free survival, and overall survival. Using the American College of Radiology appropriateness criteria methodology, appropriateness ratings for postmastectomy radiation were assigned for each scenario. Finally, an overall summary risk assessment table was developed.Results: Of 24 sources identified, 23 were retrospective studies from single institutions. Consensus on the appropriateness rating, defined as 80% agreement in a category, was achieved for 86% of the cases. Distinct LRF risk categories emerged. Clinical stage II (T1-2N0-1) patients, aged >40 years, estrogen receptor-positive subtype, with pathologic complete response or 0-3 positive nodes without lymphovascular invasion or extracapsular extension, were identified as having ≤10% risk of LRF without radiation. Limited data support stage IIIA patients with pathologic complete response as being low risk.Conclusions: In the absence of randomized trial results, existing data can be used to guide the use of PMRT in the neoadjuvant chemotherapy setting. Using available studies to inform appropriateness ratings for clinical scenarios, we found a high concordance of treatment recommendations for PMRT and were able to identify a cohort of women with a low risk of LRF without radiation. These low-risk patients will form the basis for future planned studies within the University of California Athena Breast Health Network.

Common Variants of GSTP1, GSTA1, and TGFβ1 are Associated With the Risk of Radiation-Induced Fibrosis in Breast Cancer Patients

2011-11-14

Purpose: To provide new insights into the genetic basis of normal tissue radiosensitivity, we evaluated the association between eight polymorphic variants located in six genes related to DNA repair mechanisms, oxidative stress, and fibroblast proliferation (XRCC1 Arg399Gln, XRCC1 Arg194Trp, TP53 Arg72Pro, GSTP1 Ile105Val, GSTA1 C-69T, eNOS G894T, TGFβ1 C-509T, and TGFβ1 T869C) and the risk of subcutaneous fibrosis in a retrospective series of patients who received radiotherapy after breast-conserving surgery.Methods and Materials: Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue—Subjective Objective Management Analytical scale in 257 breast cancer patients who underwent surgery plus adjuvant radiotherapy. Genotyping was conducted by polymerase chain reaction—restriction fragment length polymorphism analysis on genomic DNA extracted from peripheral blood. The association between genetic variants and the risk of moderate to severe fibrosis was evaluated by binary logistic regression analysis.Results: Two hundred thirty-seven patients were available for the analysis. Among them, 41 patients (17.3%) developed moderate to severe fibrosis (Grade 2–3), and 196 (82.7%) patients displayed no or minimal fibrotic reactions (Grade 0–1). After adjustment of confounding factors, GSTP1 Ile105Val (odds ratio [OR] 2.756; 95% CI, 1.188–6.393; p = 0.018), GSTA1 C-69T (OR 3.223; 95% CI, 1.176–8.826; p = 0.022), and TGFβ1 T869C (OR 0.295; 95% CI, 0.090–0.964; p = 0.043) polymorphisms were found to be significantly associated with the risk of Grade 2–3 radiation-induced fibrosis. In the combined analysis, carriers of three risk genotypes were found to be at higher odds for the development of Grade 2–3 fibrosis than were patients with two risk genotypes (OR 4.415; 95% CI, 1.553–12.551, p = 0.005) or with no or one risk genotype (OR 8.563; 95% CI, 2.671–27.447; p = 0.0003).Conclusions: These results suggest that functional variations in genes involved in oxidative stress response and fibroblast proliferation may modulate the development of radiation-induced fibrosis in breast cancer patients. The results of the combined analysis support the notion that approaches based on the combination of different genetic markers have the potential to predict normal tissue responses.

Factors Associated With Optimal Long-Term Cosmetic Results in Patients Treated With Accelerated Partial Breast Irradiation Using Balloon-Based Brachytherapy

2011-11-14

Purpose: To evaluate factors associated with optimal cosmetic results at 72 months for early-stage breast cancer patients treated with Mammosite balloon-based accelerated partial breast irradiation (APBI).Methods and Materials: A total of 1,440 patients (1,449 cases) with early-stage breast cancer undergoing breast-conserving therapy were treated with balloon-based brachytherapy to deliver APBI (34 Gy in 3.4-Gy fractions). Cosmetic outcome was evaluated at each follow-up visit and dichotomized as excellent/good (E/G) or fair/poor (F/P). Follow-up was evaluated at 36 and 72 months to establish long-term cosmesis, stability of cosmesis, and factors associated with optimal results.Results: The percentage of evaluable patients with excellent/good (E/G) cosmetic results at 36 months and more than 72 months were 93.3% (n = 708/759) and 90.4% (n = 235/260). Factors associated with optimal cosmetic results at 72 months included: larger skin spacing (p = 0.04) and T1 tumors (p = 0.02). Using multiple regression analysis, the only factors predictive of worse cosmetic outcome at 72 months were smaller skin spacing (odds ratio [OR], 0.89; confidence interval [CI], 0.80–0.99) and tumors greater than 2 cm (OR, 4.96, CI, 1.53–16.07). In all, 227 patients had both a 36-month and a 72-month cosmetic evaluation. The number of patients with E/G cosmetic results decreased only slightly from 93.4% at 3 years to 90.8% (p = 0.13) at 6 years, respectively.Conclusions: APBI delivered with balloon-based brachytherapy produced E/G cosmetic results in 90.4% of cases at 6 years. Larger tumors (T2) and smaller skin spacing were found to be the two most important independent predictors of cosmesis.

Is Short-Interval Mammography Necessary After Breast Conservation Surgery and Radiation Treatment in Breast Cancer Patients?

2012-01-16

Purpose: The optimum timing and frequency of mammography in breast cancer patients after breast-conserving therapy (BCT) are controversial. The American Society of Clinical Oncology recommends the first posttreatment mammogram 1 year after diagnosis but no earlier than 6 months after completion of radiotherapy. The National Comprehensive Cancer Network recommends annual mammography. Intermountain Healthcare currently follows a more frequent mammography schedule during the first 2 years in BCT patients. This retrospective study was undertaken to determine the cancer yield mammography during the first 2 years after BCT.Methods and Materials: 1,435 patients received BCT at Intermountain Healthcare between 2003 and 2007, inclusive. Twenty-three patients had bilateral breast cancer (1,458 total breasts). Patients were followed up for 24 months after diagnosis. The 1- and 2-year mammography yields were determined and compared with those of the general screening population.Results: 1,079 breasts had mammography at less than 1 year, and two ipsilateral recurrences (both noninvasive) were identified; 1,219 breasts had mammography during the second year, and nine recurrences (three invasive, six noninvasive) were identified. Of the 11 ipsilateral recurrences during the study, three presented with symptoms and eight were identified by mammography alone. The mammography yield was 1.9 cancers per 1,000 breasts the first year and 4.9 per 1,000 the second year.Conclusions: These data demonstrate that the mammography yield during the first 2 years after BCT is not greater than that in the general population, and they support the policy for initiating followup mammography at 1 year after BCT.

Locoregional Failure in Early-Stage Breast Cancer Patients Treated With Radical Mastectomy and Adjuvant Systemic Therapy: Which Patients Benefit From Postmastectomy Irradiation?

2012-03-05

Purpose: To assess the locoregional failure in patients with Stage I–II breast cancer treated with radical mastectomy and to evaluate whether a subset of these patients might be at sufficiently high risk of locoregional recurrence (LRR) to benefit from postmastectomy irradiation (PMRT).Methods and Materials: Stage I–II breast cancer patients (n = 150) treated with radical mastectomy without adjuvant irradiation between 1999 and 2005 were analyzed. The pattern of LRR was reported. Kaplan-Meier analysis was used to calculate rates of LRR, and Cox proportional hazards methods were used to evaluate potential risk factors.Results: Median follow-up was 75 months. Mean patient age was 56 years. One-hundred forty-three (95%) patients received adjuvant systemic therapy: 85 (57%) hormonal therapy alone, 14 (9%) chemotherapy alone, and 44 (29%) both chemotherapy and hormonal therapy. Statistically significant factors associated with increased risk of LRR were premenopausal status (p = 0.004), estrogen receptor negative cancer (p = 0.02), pathologic grade 3 (p = 0.02), and lymphovascular invasion (p = 0.001). T and N stage were not associated with increased risk of regional recurrence. The 5-year LRR rate for patients with zero or one, two, three, and four risk factors was 1%, 10.3%, 24.2%, and 75%, respectively.Conclusions: A subset of patients with early-stage breast cancer is at high risk of LRR, and therefore PMRT might be beneficial.

Five Year Outcome of 145 Patients With Ductal Carcinoma In Situ (DCIS) After Accelerated Breast Radiotherapy

2012-06-01

Background: Accelerated whole-breast radiotherapy (RT) with tumor bed boost in the treatment of early invasive breast cancer has demonstrated equivalent local control and cosmesis when compared with standard RT. Its efficacy in the treatment of ductal carcinoma in situ (DCIS) remains unknown.Methods and Materials: Patients treated for DCIS with lumpectomy and negative margins were eligible for 2 consecutive hypofractionated whole-breast RT clinical trials. The first trial (New York University [NYU] 01-51) prescribed to the whole breast 42 Gy (2.8 Gy in 15 fractions) and the second trial (NYU 05-181) 40.5 Gy (2.7 Gy in 15 fractions) with an additional daily boost of 0.5 Gy to the surgical cavity.Results: Between 2002 and 2009, 145 DCIS patients accrued, 59 to the first protocol and 86 to the second trial. Median age was 56 years and 65% were postmenopausal at the time of treatment. Based on optimal sparing of normal tissue, 79% of the patients were planned and treated prone and 21% supine. At 5 years' median follow-up (60 months; range 2.6-105.5 months), 6 patients (4.1%) experienced an ipsilateral breast recurrence in all cases of DCIS histology. In 3/6 patients, recurrence occurred at the original site of DCIS and in the remaining 3 cases outside the original tumor bed. New contralateral breast cancers arose in 3 cases (1 DCIS and 2 invasive carcinomas). Cosmetic self-assessment at least 2 years after treatment is available in 125 patients: 91% reported good-to-excellent and 9% reported fair-to-poor outcomes.Conclusions: With a median follow-up of 5 years, the ipsilateral local recurrence rate is 4.1%, comparable to that reported from the NSABP (National Surgical Adjuvant Breast and Bowel Project) trials that employed 50 Gy in 25 fractions of radiotherapy for DCIS. There were no invasive recurrences. These results provide preliminary evidence that accelerated hypofractionated external beam radiotherapy is a viable option for DCIS.

Proposal for a New Prognostic Score for Linac-Based Radiosurgery in Cerebral Arteriovenous Malformations

2011-10-25

Purpose: We evaluate patient-, angioma-, and treatment-specific factors for successful obliteration of cerebral arteriovenous malformations (AVM) to develop a new appropriate score to predict patient outcome after linac-based radiosurgery (RS).Methods and Materials: This analysis in based on 293 patients with cerebral AVM. Mean age at treatment was 38.8 years (4–73 years). AVM classification according Spetzler-Martin was 55 patients Grade I (20.5%), 114 Grade II (42.5%), 79 Grade III (29.5%), 19 Grade IV (7.1%), and 1 Grade V (0.4%). Median maximum AVM diameter was 3.0 cm (range, 0.3–10 cm). Median dose prescribed to the 80% isodose was 18 Gy (range, 12–22 Gy). Eighty-five patients (29.1%) had prior partial embolization; 141 patients (51.9%) experienced intracranial hemorrhage before RS. Median follow-up was 4.2 years.Results: Age at treatment, maximum diameter, nidus volume, and applied dose were significant factors for successful obliteration. Under presumption of proportional hazard in the dose range between 12 and 22 Gy/80% isodose, an increase of obliteration rate of approximately 25% per Gy was seen. On the basis of multivariate analysis, a prediction score was calculated including AVM maximum diameter and age at treatment. The prediction error up to the time point 8 years was 0.173 for the Heidelberg score compared with the Kaplan-Meier value of 0.192. An increase of the score of 1 point results in a decrease of obliteration chance by a factor of 0.447.Conclusion: The proposed score is linac-based radiosurgery–specific and easy to handle to predict patient outcome. Further validation on an independent patient cohort is necessary.

Planned Two-Fraction Proton Beam Stereotactic Radiosurgery for High-Risk Inoperable Cerebral Arteriovenous Malformations

2011-11-17

Purpose: To evaluate patients with high-risk cerebral arteriovenous malformations (AVMs), based on eloquent brain location or large size, who underwent planned two-fraction proton stereotactic radiosurgery (PSRS).Methods and Materials: From 1991 to 2009, 59 patients with high-risk cerebral AVMs received two-fraction PSRS. Median nidus volume was 23 cc (range, 1.4–58.1 cc), 70% of cases had nidus volume ≥14 cc, and 34% were in critical locations (brainstem, basal ganglia). Median AVM score based on age, AVM size, and location was 3.19 (range, 0.9–6.9). Many patients had prior surgery or embolization (40%) or prior PSRS (12%). The most common prescription was 16 Gy radiobiologic equivalent (RBE) in two fractions, prescribed to the 90% isodose.Results: At a median follow-up of 56.1 months, 9 patients (15%) had total and 20 patients (34%) had partial obliteration. Patients with total obliteration received higher total dose than those with partial or no obliteration (mean dose, 17.6 vs. 15.5 Gy (RBE), p = 0.01). Median time to total obliteration was 62 months (range, 23–109 months), and 5-year actuarial rate of partial or total obliteration was 33%. Five-year actuarial rate of hemorrhage was 22% (95% confidence interval, 12.5%–36.8%) and 14% (n = 8) suffered fatal hemorrhage. Lesions with higher AVM scores were more likely to hemorrhage (p = 0.024) and less responsive to radiation (p = 0.026). The most common complication was Grade 1 headache acutely (14%) and long term (12%). One patient developed a Grade 2 generalized seizure disorder, and two had mild neurologic deficits.Conclusions: High-risk AVMs can be safely treated with two-fraction PSRS, although total obliteration rate is low and patients remain at risk for future hemorrhage. Future studies should include higher doses or a multistaged PSRS approach for lesions more resistant to obliteration with radiation.

Challenges in Linear Accelerator Radiotherapy for Chordomas and Chondrosarcomas of the Skull Base: Focus on Complications

2011-12-05

Purpose: Intracranial chordomas and chondrosarcomas are histologically low-grade, locally invasive tumors that infiltrate the skull base. Currently, consensus therapy includes surgical resection and adjuvant radiotherapy. Radiation delivery is typically limited by the proximity of these tumors to critical skull base structures.Methods: This is a retrospective review of 13 cases of chordomas and 2 cases of chondroid chondrosarcomas of the skull based treated with linear accelerator stereotactic radiotherapy (SRT, n = 10) or stereotactic radiosurgery (SRS, n = 5). The average time to the most recent follow-up visit was 4.5 years. The tumor characteristics, treatment details, and outcomes were recorded. Each radiation plan was reviewed, and the dosage received by the brainstem, optic apparatus, and pituitary was calculated.Results: Of the 10 patients treated with SRT, 6 were found to have unchanged or decreased tumor size as determined from radiographic follow-up. Of the 5 patients treated with SRS, 3 were found to have stable or unchanged tumors at follow-up. The complications included 1 SRT patient who developed endocrinopathy, 2 patients (1 treated with SRS and the other with SRT), who developed cranial neuropathy, and 1 SRS patient who developed visual deficits. Additionally, 1 patient who received both SRS and SRT within 2 years for recurrence experienced transient medial temporal lobe radiation changes that resolved.Conclusions: Where proton beam therapy is unavailable, linear accelerator-based SRT or radiosurgery remains a safe option for adjuvant therapy of chordomas and chondrosarcomas of the skull base. The exposure of the optic apparatus, pituitary stalk, and brainstem must be considered during planning to minimize complications. If the optic apparatus is included in the 80% isodose line, it might be best to fractionate therapy. Exposure of the pituitary stalk should be kept to <30 Gy to minimize endocrine dysfunction. Brainstem exposure should be limited to <60 Gy in fractions.

Twenty-Five-Year Experience With Radical Chemoradiation for Anal Cancer

2011-10-24

Purpose: To evaluate the prognostic factors, patterns of failure, and late toxicity in patients treated with chemoradiation (CRT) for anal cancer.Methods and Materials: Consecutive patients with nonmetastatic squamous cell carcinoma of the anus treated by CRT with curative intent between February 1983 and March 2008 were identified through the institutional database. Chart review and telephone follow-up were undertaken to collect demographic data and outcome.Results: Two hundred eighty-four patients (34% male; median age 62 years) were identified. The stages at diagnosis were 23% Stage I, 48% Stage II, 10% Stage IIIA, and 18% Stage IIIB. The median radiotherapy dose to the primary site was 54 Gy. A complete clinical response to CRT was achieved in 89% of patients. With a median follow-up time of 5.3 years, the 5-year rates of locoregional control, distant control, colostomy-free survival, and overall survival were 83% (95% confidence interval [CI] 78–88), 92% (95% CI, 89–96), 73% (95% CI, 68–79), and 82% (95% CI, 77–87), respectively. Higher T stage and male sex predicted for locoregional failure, and higher N stage predicted for distant metastases. Locoregional failure occurred most commonly at the primary site. Omission of elective inguinal irradiation resulted in inguinal failure rates of 1.9% and 12.5% in T1N0 and T2N0 patients, respectively. Pelvic nodal failures were very uncommon. Late vaginal and bone toxicity was observed in addition to gastrointestinal toxicity.Conclusions: CRT is a highly effective approach in anal cancer. However, subgroups of patients fare relatively poorly, and novel approaches are needed. Elective inguinal irradiation can be safely omitted only in patients with Stage I disease. Vaginal toxicity and insufficiency fractures of the hip and pelvis are important late effects that require prospective evaluation.

Concurrent Radiotherapy and Gemcitabine for Unresectable Pancreatic Adenocarcinoma: Impact of Adjuvant Chemotherapy on Survival

2011-10-21

Purpose: To retrospectively analyze results of concurrent chemoradiotherapy (CCRT) using gemcitabine (GEM) for unresectable pancreatic adenocarcinoma.Methods and Materials: Records of 108 patients treated with concurrent external beam radiotherapy (EBRT) and GEM were reviewed. The median dose of EBRT in all 108 patients was 50.4 Gy (range, 3.6–60.8 Gy), usually administered in conventional fractionations (1.8–2 Gy/day). During radiotherapy, most patients received GEM at a dosage of 250 to 350 mg/m2 intravenously weekly for approximately 6 weeks. After CCRT, 59 patients (54.6%) were treated with adjuvant chemotherapy (AC), mainly with GEM. The median follow-up for all 108 patients was 11.0 months (range, 0.4–37.9 months).Results: Initial responses after CCRT for 85 patients were partial response: 26 patients, no change: 51 patients and progressive disease: 8 patients. Local progression was observed in 35 patients (32.4%), and the 2-year local control (LC) rate in all patients was 41.9%. Patients treated with total doses of 50 Gy or more had significantly more favorable LC rates (2-year LC rate, 42.9%) than patients treated with total doses of less than 50 Gy (2-year LC rate, 29.6%). Regional lymph node recurrence was found in only 1 patient, and none of the 57 patients with clinical N0 disease had regional lymph node recurrence. The 2-year overall survival (OS) rate and the median survival time in all patients were 23.5% and 11.6 months, respectively. Patients treated with AC had significantly more favorable OS rates (2-year OS, 31.8%) than those treated without AC (2-year OS, 12.4%; p < 0.0001). On multivariate analysis, AC use and clinical T stage were significant prognostic factors for OS.Conclusions: CCRT using GEM yields a relatively favorable LC rate for unresectable pancreatic adenocarcinoma, and CCRT with AC conferred a survival benefit compared to CCRT without AC.

Feasibility of Electromagnetic Transponder Use to Monitor Inter- and Intrafractional Motion in Locally Advanced Pancreatic Cancer Patients

2011-11-17

Purpose: The primary objective of this study was to determine the feasibility of electromagnetic transponder implantation in patients with locally advanced unresectable pancreatic cancer. Secondarily, the use of transponders to monitor inter- and intrafractional motion, and the efficacy of breath holding for limiting target motion, were examined.Methods and Materials: During routine screening laparoscopy, 5 patients without metastatic disease were implanted with transponders peri-tumorally. The Calypso System’s localization and tracking modes were used to monitor inter- and intrafractional motion, respectively. Intrafractional motion, with and without breath holding, was also examined using Calypso tracking mode.Results: Transponder implantation was well tolerated in all patients, with minimal migration, aside from 1 patient who expulsed a single transponder. Interfractional motion based on mean shifts from setup using tattoos/orthogonal imaging to transponder based localization from 164 treatments was significant in all dimensions. Mean shift (in millimeters), followed by the standard deviation and p value, were as follows: X-axis: 4.5 mm (1.0, p = 0.01); Y axis: 6.4 mm (1.9, p = 0.03); and Z-axis 3.9 mm (0.6, p = 0.002). Mean intrafractional motion was also found to be significant in all directions: superior, 7.2 mm (0.9, p = 0.01); inferior, 11.9 mm (0.9, p < 0.01); anterior: 4.9 mm (0.5, p = 0.01); posterior, 2.9 mm (0.5, p = 0.02); left, 2.2 mm (0.4, p = 0.02); and right, 3.1 mm (0.6, p = 0.04). Breath holding during treatment significantly decreased tumor motion in all directions.Conclusions: Electromagnetic transponder implantation appears to be safe and effective for monitoring inter- and intrafractional motion. Based on these results a larger clinical trial is underway.

Postoperative Chemotherapy Followed by Conformal Concomitant Chemoradiotherapy in High-Risk Gastric Cancer

2011-11-17

Purpose: To analyze the efficacy, toxicity, and pattern of relapse after adjuvant cisplatin-based chemotherapy followed by three-dimensional irradiation and concomitant LV5FU2 chemotherapy (high-dose leucovorin and 5-fluorouracil bolus plus continuous infusion) in the treatment of completely resected high-risk gastric cancer.Methods and Materials: This was a retrospective analysis of 52 patients with high-risk gastric cancer initially treated by total/partial gastrectomy and lymphadenectomy between January 2002 and June 2007. Median age was 54 years (range, 36–75 years). Postoperative treatment consisted of 5-fluorouracil and cisplatin chemotherapy. Adjuvant chemotherapy was followed by three-dimensional conformal radiotherapy in the tumor bed and regional lymph nodes at 4500 cGy/25 fractions in association with concomitant chemotherapy. Concomitant chemotherapy consisted of a 2-h infusion of leucovorin (200 mg/m²) followed by a bolus of 5-fluorouracil (400 mg/m²) and then a 44-h continuous infusion of 5-fluorouracil (2400–3600 mg/m²) given every 14 days, for three cycles (LV5FU2 protocol).Results: Five-year overall and disease-free survival were 50% and 48%, respectively. Distant metastases and peritoneal spread were the most frequent sites of relapse (37% each). After multivariate analysis, only pathologic nodal status was significantly associated with disease-free and overall survival. Acute toxicities were essentially gastrointestinal and hematologic. One myocardial infarction and one pulmonary embolism were also reported. Eighteen patients had a radiotherapy program interruption because of acute toxicity. All patients but 2 have completed radiotherapy.Conclusion: Postoperative cisplatin-based chemotherapy followed by conformal radiotherapy in association with concurrent 5-fluorouracil seemed to be feasible and resulted in successful locoregional control.

Intensity-Modulated Radiation Therapy With Concurrent Chemotherapy as Preoperative Treatment for Localized Gastric Adenocarcinoma

2011-12-05

Purpose: The goal of this study was to evaluate dosimetric parameters, acute toxicity, pathologic response, and local control in patients treated with preoperative intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy for localized gastric adenocarcinoma.Methods: Between November 2007 and April 2010, 25 patients with localized gastric adenocarcinoma were treated with induction chemotherapy, followed by preoperative IMRT and concurrent chemotherapy and, finally, surgical resection. The median radiation therapy dose was 45 Gy. Concurrent chemotherapy was 5-fluorouracil and oxaliplatin in 18 patients, capecitabine in 3, and other regimens in 4. Subsequently, resection was performed with total gastrectomy in 13 patients, subtotal gastrectomy in 7, and other surgeries in 5.Results: Target coverage, expressed as the ratio of the minimum dose received by 99% of the planning target volume to the prescribed dose, was a median of 0.97 (range, 0.92–1.01). The median V30 (percentage of volume receiving at least 30 Gy) for the liver was 26%; the median V20 (percentage of volume receiving at least 20 Gy) for the right and left kidneys was 14% and 24%, respectively; and the median V40 (percentage of volume receiving at least 40 Gy) for the heart was 18%. Grade 3 acute toxicity developed in 14 patients (56%), including dehydration in 10, nausea in 8, and anorexia in 5. Grade 4 acute toxicity did not develop in any patient. There were no significant differences in the rates of acute toxicity, hospitalization, or feeding tube use in comparison to those in a group of 50 patients treated with preoperative three-dimensional conformal radiation therapy with concurrent chemotherapy. R0 resection was obtained in 20 patients (80%), and pathologic complete response occurred in 5 (20%).Conclusions: Preoperative IMRT for gastric adenocarcinoma was well tolerated, accomplished excellent target coverage and normal structure sparing, and led to appropriate pathologic outcomes.

Four-Week Neoadjuvant Intensity-Modulated Radiation Therapy With Concurrent Capecitabine and Oxaliplatin in Locally Advanced Rectal Cancer Patients: A Validation Phase II Trial

2011-11-14

Purpose: To validate tolerance and pathological complete response rate (pCR) of a 4-week preoperative course of intensity-modulated radiation therapy (IMRT) with concurrent capecitabine and oxaliplatin (CAPOX) in patients with locally advanced rectal cancer.Methods and Materials: Patients with T3 to T4 and/or N+ rectal cancer received preoperative IMRT (47.5 Gy in 19 fractions) with concurrent capecitabine (825 mg/m2 b.i.d., Monday to Friday) and oxaliplatin (60 mg/m2 on Days 1, 8, and 15). Surgery was scheduled 4 to 6 weeks after the completion of chemoradiation. Primary end points were toxicity and pathological response rate. Local control (LC), disease-free survival (DFS), and overall survival (OS) were also analyzed.Results: A total of 100 patients were evaluated. Grade 1 to 2 proctitis was observed in 73 patients (73%). Grade 3 diarrhea occurred in 9% of the patients. Grade 3 proctitis in 18% of the first 50 patients led to reduction of the dose per fraction to 47.5 Gy in 20 treatments. The rate of Grade 3 proctitis decreased to 4% thereafter (odds ratio, 0.27). A total of 99 patients underwent surgery. A pCR was observed in 13% of the patients, major response (96–100% of histological response) in 48%, and pN downstaging in 78%. An R0 resection was performed in 97% of the patients. After a median follow-up of 55 months, the LC, DFS, and OS rates were 100%, 84%, and 87%, respectively.Conclusions: Preoperative CAPOX-IMRT therapy (47.5 Gy in 20 fractions) is feasible and safe, and produces major pathological responses in approximately 50% of patients.

Diffusion-Weighted Magnetic Resonance Imaging in Monitoring Rectal Cancer Response to Neoadjuvant Chemoradiotherapy

2011-11-17

Purpose: To prospectively monitor the response in patients with locally advanced nonmucinous rectal cancer after chemoradiotherapy (CRT) using diffusion-weighted magnetic resonance imaging. The histopathologic finding was the reference standard.Methods and Materials: The institutional review board approved the present study. A total of 62 patients (43 men and 19 women; mean age, 64 years; range, 28–83) provided informed consent. T2- and diffusion-weighted magnetic resonance imaging scans (b value, 0 and 1,000 mm2/s) were acquired before, during (mean 12 days), and 6–8 weeks after CRT. We compared the median apparent diffusion coefficients (ADCs) between responders and nonresponders and examined the associations with the Mandard tumor regression grade (TRG). The postoperative nodal status (ypN) was evaluated. The Mann-Whitney/Wilcoxon two-sample test was used to evaluate the relationships among the pretherapy ADCs, extramural vascular invasion, early percentage of increases in ADCs, and preoperative ADCs.Results: Low pretreatment ADCs (<1.0 × 10−3mm2/s) were correlated with TRG 4 scores (p = .0011) and associated to extramural vascular invasion with ypN+ (85.7% positive predictive value for ypN+). During treatment, the mean percentage of increase in tumor ADC was significantly greater in the responders than in the nonresponders (p < .0001) and a >23% ADC increase had a 96.3% negative predictive value for TRG 4. In 9 of 16 complete responders, CRT-related tumor downsizing prevented ADC evaluations. The preoperative ADCs were significantly different (p = .0012) between the patients with and without downstaging (preoperative ADC ≥1.4 × 10−3mm2/s showed a positive and negative predictive value of 78.9% and 61.8%, respectively, for response assessment). The TRG 1 and TRG 2–4 groups were not significantly different.Conclusion: Diffusion-weighted magnetic resonance imaging seems to be a promising tool for monitoring the response to CRT.

Correlation in Rectal Cancer Between Clinical Tumor Response After Neoadjuvant Radiotherapy and Sphincter or Organ Preservation: 10-Year Results of the Lyon R 96-02 Randomized Trial

Cécile Ortholan, Pascale Romestaing, Olivier Chapet, Jean Pierre Gerard — 2012-06-01

Purpose: To investigate, in rectal cancer, the benefit of a neoadjuvant radiation dose escalation with endocavitary contact radiotherapy (CXRT) in addition to external beam radiotherapy (EBRT). This article provides an update of the Lyon R96-02 Phase III trial.Methods and Materials: A total of 88 patients with T2 to T3 carcinoma of the lower rectum were randomly assigned to neoadjuvant EBRT 39 Gy in 13 fractions (43 patients) vs. the same EBRT with CXRT boost, 85 Gy in three fractions (45 patients). Median follow-up was 132 months.Results: The 10-year cumulated rate of permanent colostomy (CRPC) was 63% in the EBRT group vs. 29% in the EBRT+CXRT group (p < 0.001). The 10-year rate of local recurrence was 15% vs. 10% (p = 0.69); 10-year disease-free survival was 54% vs. 53% (p = 0.99); and 10-year overall survival was 56% vs. 55% (p = 0.85). Data of clinical response (CR) were available for 78 patients (36 in the EBRT group and 42 in the EBRT+CXRT group): 12 patients were in complete CR (1 patient vs. 11 patients), 53 patients had a CR ≥50% (24 patients vs. 29 patients), and 13 patients had a CR <50% (11 patients vs. 2 patients) (p < 0.001). Of the 65 patients with CR ≥50%, 9 had an organ preservation procedure (meaning no rectal resection) taking advantage of major CR. The 10-year CRPC was 17% for patients with complete CR, 42% for patients with CR ≥50%, and 77% for patients with CR <50% (p = 0.014).Conclusion: In cancer of the lower rectum, CXRT increases the complete CR, turning in a significantly higher rate of long-term permanent sphincter and organ preservation.

Chemoradiotherapy of Anal Carcinoma: Survival and Recurrence in an Unselected National Cohort

2012-03-22

Purpose: To evaluate treatment results, elucidate whether national guidelines were followed, and identify areas demanding further treatment optimization.Methods and Material: Between July 2000 and June 2007, 328 patients were treated with curatively intended chemoradiotherapy (CRT) for nonmetastatic squamous cell carcinoma of the anal region, according to national treatment guidelines based on tumor stage.Results: Complete response after CRT was obtained in 87% of patients, rising to 93% after salvage surgery. Chemotherapy, elective irradiation of the groin and salvage surgery were performed to a lesser extent in elderly patients, mainly because of frailty and comorbidity. Recurrence occurred in 24% of the patients, resulting in a 3- and 5-year recurrence-free survival (RFS) of 79% and 74%, respectively. Locoregional recurrences dominated, most commonly in the primary tumor site. Recurrence was treated with curative intent in 45% of the cases. The 3- and 5-year overall survival were 79% and 66%, and cancer-specific survival (CSS) were 84% and 75%, respectively. The risk of adverse outcome increased significantly with more locally advanced tumors and for male gender in multivariable analyses for RFS and CSS.Conclusions: The treatment results are in accordance with similar cohorts. The primary treatment control rate was high, but there was a significant risk of locoregional recurrence in advanced tumors. The loyalty to national guidelines was broad, although individual adjustments occurred. However, caution to avoid toxicity must not lead to inadequate treatment. Male gender seems to have inferior outcome.

Radiosensitizing Effect of a Phenylbutyrate-Derived Histone Deacetylase Inhibitor in Hepatocellular Carcinoma

2012-02-29

Purpose: Radiotherapy is integrated into the multimodal treatment of localized hepatocellular carcinoma (HCC) refractory to conventional treatment. Tumor control remains unsatisfactory and the sublethal effect associates with secondary spread. The use of an effective molecularly targeted agent in combination with radiotherapy is a potential therapeutic approach. Our aim was to assess the effect of combining a phenylbutyrate-derived histone deacetylase (HDAC) inhibitor, AR-42, with radiotherapy in in vitro and in vivo models of human HCC.Methods and Materials: Human HCC cell lines (Huh-7 and PLC-5) were used to evaluate the in vitro synergism of combining AR-42 with irradiation. Flow cytometry analyzed the cell cycle changes, whereas Western blot investigated the protein expressions after the combined treatment. Severe combined immunodeficient (SCID) mice bearing ectopic and orthotopic HCC xenografts were treated with AR-42 and/or radiotherapy for the in vivo response.Results: AR-42 significantly enhanced radiation-induced cell death by the inhibition of the DNA end-binding activity of Ku70, a highly versatile regulatory protein for DNA repair, telomere maintenance, and apoptosis. In ectopic xenografts of Huh-7 and PLC-5, pretreatment with AR-42 significantly enhanced the tumor-suppressive effect of radiotherapy by 48% and 66%, respectively. A similar combinatorial effect of AR-42 (10 and 25 mg/kg) and radiotherapy was observed in Huh-7 orthotopic model of tumor growth by 52% and 82%, respectively. This tumor suppression was associated with inhibition of intratumoral Ku70 activity as well as reductions in markers of HDAC activity and proliferation, and increased apoptosis.Conclusion: AR-42 is a potent, orally bioavailable inhibitor of HDAC with therapeutic value as a radiosensitizer of HCC.

PSA Nadir of <0.5 ng/mL Following Brachytherapy for Early-Stage Prostate Adenocarcinoma is Associated With Freedom From Prostate-Specific Antigen Failure

Eric C. Ko, Nelson N. Stone, Richard G. Stock — 2011-10-10

Purpose: Because limited information exists regarding whether the rate or magnitude of PSA decline following brachytherapy predicts long-term clinical outcomes, we evaluated whether achieving a prostate-specific antigen (PSA) nadir (nPSA) <0.5 ng/mL following brachytherapy is associated with decreased PSA failure and/or distant metastasis.Methods and Materials: We retrospectively analyzed our database of early-stage prostate adenocarcinoma patients who underwent brachytherapy, excluding those receiving androgen-deprivation therapy and those with <2 years follow-up. Median and mean pretreatment PSA were 6 ng/mL and 7.16 ng/mL, respectively. By clinical stage, 775 were low risk (≤T2a), 126 were intermediate risk (T2b), and 20 were high risk (>T2b). By Gleason score, 840 were low risk (≤6), 71 were intermediate risk (7), and 10 were high risk (>7). Patients were treated with brachytherapy only (I-125, n = 779, or Pd-103, n = 47), or brachytherapy + external-beam radiation therapy (n = 95). Median follow-up was 6.3 years. We noted whether nPSA <0.5 ng/mL was achieved and the time to achieve this nadir and tested for associations with pretreatment risk factors. We also determined whether this PSA endpoint was associated with decreased PSA failure or distant metastasis.Results: Absence of high-risk factors in clinical stage (≤T2b), Gleason score (≤7), and pretreatment PSA (≤20 ng/mL) was significantly associated with achieving nPSA <0.5 ng/mL. By Kaplan-Meier analysis, patients achieving nPSA <0.5 ng/mL had significantly higher long-term freedom from biochemical failure (FFBF) than nonresponders (5-year FFBF: 95.2 ± 0.8% vs. 71.5 ± 6.7%; p < 0.0005). Among responders, those who achieved nPSA <0.5 ng/mL in ≤5 years had higher FFBF than those requiring >5 years (5-year FFBF: 96.7 ± 0.7% vs. 80.8 ± 4.6%; p < 0.0005). On multivariate analysis, patients who achieved nPSA <0.5 ng/mL in ≤5 years had significantly higher FFBF than other patients.Conclusions: Pretreatment risk factors (clinical tumor stage, Gleason score, pretreatment PSA) strongly predict for patients achieving nPSA <0.5 ng/mL following brachytherapy, and this cohort had significantly higher long-term FFBF.

Inverse Relationship Between Biochemical Outcome and Acute Toxicity After Image-Guided Radiotherapy for Prostate Cancer

2011-11-17

Purpose: Prostate cancer patients exhibit variability in normal tissue reactions and biochemical failure. With the use of image-guided radiotherapy (IGRT), there is a greater likelihood that the differences in normal tissue and tumor response are due to biological rather than physical factors. We tested the hypothesis that prospectively scored acute toxicity is associated with biochemical failure-free rate (BFFR) in prostate cancer patients treated with IGRT.Methods and Materials: We retrospectively analyzed BFFR in 362 patients with localized prostate cancer treated with IGRT. We compared BFFR with prospectively collected Radiation Therapy Oncology Group (RTOG) maximum acute gastrointestinal (GI) and genitourinary (GU) toxicity scores. Median follow-up for all patients was 58.3 months after total radiotherapy doses of 75.6–79.8 Gy.Results: Patients reporting RTOG acute GU or GI toxicity scores of ≥2 were considered “sensitive” (n = 141, 39%) and patients reporting scores <2 were considered “nonsensitive” (n = 221, 61%). When calculating biochemical failure (BF) using the American Society for Therapeutic Radiology and Oncology definition at 5 years, 76% (CI 70–82%) of the “nonsensitive” patients were failure free, compared with only 53% (CI 43–62%) of the “sensitive” patients (log–rank test, p < 0.0001). This difference was also observed using the Phoenix definition; “nonsensitive” 5-year BFFR was 81% (CI 74–86%) vs. “sensitive” BFFR was 68% (CI 58–76%; log–rank test p = 0.0012). The difference in BF between cohorts remained significant when controlled for radiation dose (75.6 vs. 79.8 Gy), prognostic stratification (T category, prostate-specific antigen, and Gleason score), and prostate volume.Conclusions: This study unexpectedly shows that prostate cancer patients who develop ≥Grade 2 RTOG acute toxicity during radiotherapy are less likely to remain BFF at 5 years. These results deserve further study and, if validated in other large IGRT cohorts, additional models would be required to study interaction between normal tissue and tumor biology in prostate cancer patients.

Quality of Life After Hypofractionated Concomitant Intensity-Modulated Radiotherapy Boost for High-Risk Prostate Cancer

2011-11-14

Purpose: To evaluate the change in health-related quality of life (QOL) of patients with high-risk prostate cancer treated using hypofractionated radiotherapy combined with long-term androgen deprivation therapy.Methods and Materials: A prospective Phase I–II study enrolled patients with any of the following: clinical Stage T3 disease, prostate-specific antigen level ≥20 ng/mL, or Gleason score 8–10. Radiotherapy consisted of 45 Gy (1.8 Gy per fraction) to the pelvic lymph nodes with a concomitant 22.5 Gy intensity-modulated radiotherapy boost to the prostate, for a total of 67.5 Gy (2.7 Gy per fraction) in 25 fractions over 5 weeks. Daily image guidance was performed using three gold seed fiducials. Quality of life was measured using the Expanded Prostate Cancer Index Composite (EPIC), a validated tool that assesses four primary domains (urinary, bowel, sexual, and hormonal).Results: From 2004 to 2007, 97 patients were treated. Median follow-up was 39 months. Compared with baseline, at 24 months there was no statistically significant change in the mean urinary domain score (p = 0.99), whereas there were decreases in the bowel (p < 0.01), sexual (p < 0.01), and hormonal (p < 0.01) domains. The proportion of patients reporting a clinically significant difference in EPIC urinary, bowel, sexual, and hormonal scores at 24 months was 27%, 31%, 55%, and 60%, respectively. However, moderate and severe distress related to these symptoms was minimal, with increases of only 3% and 5% in the urinary and bowel domains, respectively.Conclusions: Hypofractionated radiotherapy combined with long-term androgen deprivation therapy was well tolerated. Although there were modest rates of clinically significant patient-reported urinary and bowel toxicity, most of this caused only mild distress, and moderate and severe effects on QOL were limited. Additional follow-up is ongoing to characterize long-term QOL.

Indications for Pelvic Nodal Treatment in Prostate Cancer Should Change. Validation of the Roach Formula in a Large Extended Nodal Dissection Series

2011-11-17

Purpose: Previous studies have criticized the predicting ability of the Roach formula in assessing the risk of lymph node invasion (LNI) in contemporary patients with prostate cancer (PCa) due to a significant overestimation of LNI rates. However, all those studies included patients treated with limited pelvic lymph node dissection (PLND), which is associated with high rates of false negative findings. We hypothesized that the Roach formula is still an accurate tool for LNI predictions if an extended PLND (ePLND) is performed.Methods and Materials: We included 3,115 consecutive patients treated with radical prostatectomy and ePLND between 2000 and 2010 at a single tertiary referral center. Extended PLND consisted of removal of obturator, external iliac, and hypogastric lymph nodes. We externally validated the Roach formula by using the area under the receiver operating characteristics curve and calibration plot method. Moreover, we tested the performance characteristics of different formula-generated cutoff values ranging from 1% to 20%.Results: The accuracy of the Roach formula was 80.3%. The calibration showed only a minor underestimation of the LNI risk in high-risk patients (6.7%). According to the Roach formula, the use of 15% cut off would have allowed 74.2% (2,311/3,115) of patients to avoid nodal irradiation, while up to 32.7% (111/336) of all patients with LNI would have been missed. When the cut off was lowered to 6%, nodal treatment would have been spared in 1,541 (49.5%) patients while missing 41 LNI patients. The sensitivity, specificity, and negative predictive values associated with the 6% cut off were 87.9%, 54%, and 97.3%, respectively.Conclusions: The Roach formula is still accurate and does not overestimate the rate of LNI in contemporary prostate cancer patients if they are treated with ePLND. However, the recommended cut off of 15% would miss approximately one-third of patients with LNI. Based on our results, the cut off should be lowered to 6%.

Intensity-Modulated Radiotherapy Causes Fewer Side Effects than Three-Dimensional Conformal Radiotherapy When Used in Combination With Brachytherapy for the Treatment of Prostate Cancer

Kevin Forsythe, Seth Blacksburg, Nelson Stone, Richard G. Stock — 2011-11-17

Purpose: To measure the benefits of intensity-modulated radiotherapy (IMRT) compared with three-dimensional conformal radiotherapy (3D-CRT) when used in combination with brachytherapy for the treatment of prostate cancer.Methods and Materials: We conducted a retrospective review of all patients with localized prostate cancer who received external-beam radiotherapy (EBRT) in combination with brachytherapy with at least 1 year follow-up (n = 812). Combination therapy consisted of 103Pd or 125I implant, followed by a course of EBRT. From 1993 to March 2003 521 patients were treated with 3D-CRT, and from April 2003 to March 2009 291 patients were treated with IMRT. Urinary symptoms were prospectively measured with the International Prostate Symptom Score questionnaire with a single quality of life (QOL) question; rectal bleeding was assessed per the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring Schema. The Pearson χ2 test was used to compare toxicities experienced by patients who were treated with either IMRT or 3D-CRT. Logistic regression analyses were also performed to rule out possible confounding factors.Results: Within the first 3 months after treatment, patients treated with 3D-CRT scored their urinary symptoms as follows: 19% mild, 44% moderate, and 37% severe; patients treated with IMRT scored their urinary symptoms as follows: 36% mild, 47% moderate, and 17% severe (p < 0.001). The 3D-CRT patients rated their QOL as follows: 35% positive, 20% neutral, and 45% negative; IMRT patients rated their QOL as follows: 51% positive, 18% neutral, and 31% negative (p < 0.001). After 1 year of follow-up there was no longer any difference in urinary morbidity between the two groups. Logistic regression confirmed the differences in International Prostate Symptom Score and QOL in the acute setting (p < 0.001 for both). Grade ≥2 rectal bleeding was reported by 11% of 3D-CRT patients and 7% of IMRT patients (p = 0.046); logistic regression analysis also confirmed this observation (p = 0.040).Conclusions: When used in combination with brachytherapy, IMRT offers less Grade ≥2 rectal bleeding, less acute urinary toxicities, and is associated with a higher QOL compared with 3D-CRT.

Dose-Effect Relationships for Individual Pelvic Floor Muscles and Anorectal Complaints After Prostate Radiotherapy

2011-12-05

Purpose: To delineate the individual pelvic floor muscles considered to be involved in anorectal toxicity and to investigate dose-effect relationships for fecal incontinence-related complaints after prostate radiotherapy (RT).Methods and Materials: In 48 patients treated for localized prostate cancer, the internal anal sphincter (IAS) muscle, the external anal sphincter (EAS) muscle, the puborectalis muscle (PRM), and the levator ani muscles (LAM) in addition to the anal wall (Awall) and rectal wall (Rwall) were retrospectively delineated on planning computed tomography scans. Dose parameters were obtained and compared between patients with and without fecal urgency, incontinence, and frequency. Dose-effect curves were constructed. Finally, the effect of an endorectal balloon, which was applied in 28 patients, was investigated.Results: The total volume of the pelvic floor muscles together was about three times that of the Awall. The PRM was exposed to the highest RT dose, whereas the EAS received the lowest dose. Several anal and rectal dose parameters, as well as doses to all separate pelvic floor muscles, were associated with urgency, while incontinence was associated mainly with doses to the EAS and PRM. Based on the dose-effect curves, the following constraints regarding mean doses could be deduced to reduce the risk of urgency: ≤30 Gy to the IAS; ≤10 Gy to the EAS; ≤50 Gy to the PRM; and ≤40 Gy to the LAM. No dose-effect relationships for frequency were observed. Patients treated with an endorectal balloon reported significantly less urgency and incontinence, while their treatment plans showed significantly lower doses to the Awall, Rwall, and all pelvic floor muscles.Conclusions: Incontinence-related complaints show specific dose-effect relationships to individual pelvic floor muscles. Dose constraints for each muscle can be identified for RT planning. When only the Awall is delineated, substantial components of the continence apparatus are excluded.

Predictors of Metastatic Disease After Prostate Brachytherapy

Kevin Forsythe, Ryan Burri, Nelson Stone, Richard G. Stock — 2011-12-05

Purpose: To identify predictors of metastatic disease after brachytherapy treatment for prostate cancer.Methods and Materials: All patients who received either brachytherapy alone (implant) or brachytherapy in combination with external beam radiation therapy for treatment of localized prostate cancer at The Mount Sinai Hospital between June 1990 and March 2007 with a minimum follow-up of 2 years were included. Univariate and multivariable analyses were performed on the following variables: risk group, Gleason score (GS), clinical T stage, pretreatment prostate-specific antigen level, post-treatment prostate-specific antigen doubling time (PSA-DT), treatment type (implant vs. implant plus external beam radiation therapy), treatment era, total biological effective dose, use of androgen deprivation therapy, age at diagnosis, and race. PSA-DT was analyzed in the following ordinate groups: 0 to 90 days, 91 to 180 days, 180 to 360 days, and greater than 360 days.Results: We included 1,887 patients in this study. Metastases developed in 47 of these patients. The 10-year freedom from distant metastasis (FFDM) rate for the entire population was 95.1%. Median follow-up was 6 years (range, 2–15 years). The only two significant predictors of metastatic disease by multivariable analyses were GS and PSA-DT (p < 0.001 for both variables). Estimated 10-year FFDM rates for GS of 6 or less, GS of 7, and GS of 8 or greater were 97.9%, 94.3%, and 76.1%, respectively (p < 0.001). Estimated FFDM rates for PSA-DT of 0 to 90 days, 91 to 180 days, 181 to 360 days, and greater than 360 days were 17.5%, 67.9%, 74%, and 94.8%, respectively (p < 0.001). Estimated 10-year FFDM rates for the low-, intermediate-, and high-risk groups were 98.6%, 96.2%, and 86.7%, respectively. A demographic shift to patients presenting with higher-grade disease in more recent years was observed.Conclusions: GS and post-treatment PSA-DT are both statistically significant independent predictors of metastatic disease. Patients with a high GS and/or short PSA-DT have a higher likelihood of developing metastatic disease and should be considered for systemic therapy.

A Double-Blind Placebo-Controlled Randomized Clinical Trial With Magnesium Oxide to Reduce Intrafraction Prostate Motion for Prostate Cancer Radiotherapy

2011-11-17

Purpose: To investigate whether magnesium oxide during external-beam radiotherapy for prostate cancer reduces intrafraction prostate motion in a double-blind, placebo-controlled randomized trial.Methods and Materials: At the Department of Radiotherapy, prostate cancer patients scheduled for intensity-modulated radiotherapy (77 Gy in 35 fractions) using fiducial marker–based position verification were randomly assigned to receive magnesium oxide (500 mg twice a day) or placebo during radiotherapy. The primary outcome was the proportion of patients with clinically relevant intrafraction prostate motion, defined as the proportion of patients who demonstrated in ≥50% of the fractions an intrafraction motion outside a range of 2 mm. Secondary outcome measures included quality of life and acute toxicity.Results: In total, 46 patients per treatment arm were enrolled. The primary endpoint did not show a statistically significant difference between the treatment arms with a percentage of patients with clinically relevant intrafraction motion of 83% in the magnesium oxide arm as compared with 80% in the placebo arm (p = 1.00). Concerning the secondary endpoints, exploratory analyses demonstrated a trend towards worsened quality of life and slightly more toxicity in the magnesium oxide arm than in the placebo arm; however, these differences were not statistically significant.Conclusions: Magnesium oxide is not effective in reducing the intrafraction prostate motion during external-beam radiotherapy, and therefore there is no indication to use it in clinical practice for this purpose.

An Endorectal Balloon Reduces Intrafraction Prostate Motion During Radiotherapy

2011-11-17

Purpose: To investigate the effect of endorectal balloons (ERBs) on intrafraction and interfraction prostate motion during radiotherapy.Methods and Materials: Thirty patients were treated with intensity-modulated radiotherapy, to a total dose of 80 Gy in 40 fractions. In 15 patients, a daily-inserted air-filled ERB was applied. Prostate motion was tracked, in real-time, using an electromagnetic tracking system. Interfraction displacements, measured before each treatment, were quantified by calculating the systematic and random deviations of the center of mass of the implanted transponders. Intrafraction motion was analyzed in timeframes of 150 s, and displacements >1 mm, >3 mm, >5 mm, and >7 mm were determined in the anteroposterior, left-right, and superoinferior direction, and for the three-dimensional (3D) vector. Manual table corrections, made during treatment sessions, were retrospectively undone.Results: A total of 576 and 567 tracks have been analyzed in the no-ERB group and ERB group, respectively. Interfraction variation was not significantly different between both groups. After 600 s, 95% and 98% of the treatments were completed in the respective groups. Significantly fewer table corrections were performed during treatment fractions with ERB: 88 vs. 207 (p = 0.02). Intrafraction motion was significantly reduced with ERB. During the first 150 s, only negligible deviations were observed, but after 150 s, intrafraction deviations increased with time. This resulted in cumulative percentages of 3D-vector deviations >1 mm, >3 mm, >5 mm, and >7 mm that were 57.7%, 7.0%, 0.7%, and 0.3% in the ERB-group vs. 70.2%, 18.1%, 4.6%, and 1.4% in the no-ERB group after 600 s. The largest reductions in the ERB group were observed in the AP direction. These data suggest that a 5 mm CTV-to-PTV margin is sufficient to correct for intrafraction prostate movements when using an ERB.Conclusions: ERB significantly reduces intrafraction prostate motion, but not interfraction variation, and may in particular be beneficial for treatment sessions longer than 150 s.

Early Proctoscopy is a Surrogate Endpoint of Late Rectal Toxicity in Prostate Cancer Treated With Radiotherapy

2012-02-23

Purpose: To predict the grade and incidence of late clinical rectal toxicity through short-term (1 year) mucosal alterations.Methods and Materials: Patients with prostate adenocarcinoma treated with curative or adjuvant radiotherapy underwent proctoscopy a year after the course of radiotherapy. Mucosal changes were classified by the Vienna Rectoscopy Score (VRS). Late toxicity data were analyzed according to the Kaplan-Meier method. Comparison between prognosis groups was performed by log-rank analysis.Results: After a median follow-up time of 45 months (range, 18–99), the 3-year incidence of grade ≥2 rectal late toxicity according to the criteria of the European Organization for Research and Treatment of Cancer and the Radiation Therapy Oncology Group was 24%, with all patients (24/24; 100%) experiencing rectal bleeding. The occurrence of grade ≥2 clinical rectal late toxicity was higher in patients with grade ≥2 (32% vs. 15 %, p = 0.02) or grade ≥3 VRS telangiectasia (47% vs. 17%, p ≤ 0.01) and an overall VRS score of ≥2 (31% vs. 16 %, p = 0.04) or ≥3 (48% vs. 17%, p = 0.01) at the 1-year proctoscopy.Conclusions: Early proctoscopy (1 year) predicts late rectal bleeding and therefore can be used as a surrogate endpoint for late rectal toxicity in studies aimed at reducing this frequent complication.

Bladder Preservation for Localized Muscle-Invasive Bladder Cancer: The Survival Impact of Local Utilization Rates of Definitive Radiotherapy

Kevin R. Kozak, Maryam Hamidi, Matthew Manning, John S. Moody — 2012-03-07

Purpose: This study examines the management and outcomes of muscle-invasive bladder cancer in the United States.Methods and Materials: Patients with muscle-invasive bladder cancer diagnosed between 1988 and 2006 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Patients were classified according to three mutually exclusive treatment categories based on the primary initial treatment: no local management, radiotherapy, or surgery. Overall survival was assessed with Kaplan-Meier analysis and Cox models based on multiple factors including treatment utilization patterns.Results: The study population consisted of 26,851 patients. Age, sex, race, tumor grade, histology, and geographic location were associated with differences in treatment (all p < 0.01). Patients receiving definitive radiotherapy tended to be older and have less differentiated tumors than patients undergoing surgery (RT, median age 78 years old and 90.6% grade 3/4 tumors; surgery, median age 71 years old and 77.1% grade 3/4 tumors). No large shifts in treatment were seen over time, with most patients managed with surgical resection (86.3% for overall study population). Significant survival differences were observed according to initial treatment: median survival, 14 months with no definitive local treatment; 17 months with radiotherapy; and 43 months for surgery. On multivariate analysis, differences in local utilization rates of definitive radiotherapy did not demonstrate a significant effect on overall survival (hazard ratio, 1.002; 95% confidence interval, 0.999–1.005).Conclusions: Multiple factors influence the initial treatment strategy for muscle-invasive bladder cancer, but definitive radiotherapy continues to be used infrequently. Although patients who undergo surgery fare better, a multivariable model that accounted for patient and tumor characteristics found no survival detriment to the utilization of definitive radiotherapy. These results support continued research into bladder preservation strategies and suggest that definitive radiotherapy represents a viable initial treatment strategy for those who wish to attempt to preserve their native bladder.

Split-Course, High-Dose Palliative Pelvic Radiotherapy for Locally Progressive Hormone-Refractory Prostate Cancer

2012-02-17

Purpose: Local progression, in patients with hormone-refractory prostate cancer, often causes significant morbidity. Pelvic radiotherapy (RT) provides effective palliation in this setting, with most published studies supporting the use of high-dose regimens. The aim of the present study was to examine the role of split-course hypofractionated RT used at our institution in treating this group of patients.Methods and Materials: A total of 34 men with locoregionally progressive hormone-refractory prostate cancer, treated with a split course of pelvic RT (45–60 Gy in 18–24 fractions) between 2000 and 2008 were analyzed. The primary endpoints were the response rate and actuarial locoregional progression-free survival. Secondary endpoints included overall survival, compliance, and acute and late toxicity.Results: The median age was 71 years (range, 53–88). Treatment resulted in an overall initial response rate of 91%, a median locoregional progression-free survival of 43 months, and median overall survival of 28 months. Compliance was excellent and no significant late toxicity was reported.Conclusions: The split course pelvic RT described has an acceptable toxicity profile, is effective, and compares well with other high-dose palliative regimens that have been previously reported.

Effect of Body Mass Index on Magnitude of Setup Errors in Patients Treated With Adjuvant Radiotherapy for Endometrial Cancer With Daily Image Guidance

Lilie L. Lin, Lauren Hertan, Ramesh Rengan, Boon-Keng Kevin Teo — 2011-12-29

Purpose: To determine the impact of body mass index (BMI) on daily setup variations and frequency of imaging necessary for patients with endometrial cancer treated with adjuvant intensity-modulated radiotherapy (IMRT) with daily image guidance.Methods and Materials: The daily shifts from a total of 782 orthogonal kilovoltage images from 30 patients who received pelvic IMRT between July 2008 and August 2010 were analyzed. The BMI, mean daily shifts, and random and systematic errors in each translational and rotational direction were calculated for each patient. Margin recipes were generated based on BMI. Linear regression and spearman rank correlation analysis were performed. To simulate a less-than-daily IGRT protocol, the average shift of the first five fractions was applied to subsequent setups without IGRT for assessing the impact on setup error and margin requirements.Results: Median BMI was 32.9 (range, 23–62). Of the 30 patients, 16.7% (n = 5) were normal weight (BMI <25); 23.3% (n = 7) were overweight (BMI ≥25 to <30); 26.7% (n = 8) were mildly obese (BMI ≥30 to <35); and 33.3% (n = 10) were moderately to severely obese (BMI ≥ 35). On linear regression, mean absolute vertical, longitudinal, and lateral shifts positively correlated with BMI (p = 0.0127, p = 0.0037, and p < 0.0001, respectively). Systematic errors in the longitudinal and vertical direction were found to be positively correlated with BMI category (p < 0.0001 for both). IGRT for the first five fractions, followed by correction of the mean error for all subsequent fractions, led to a substantial reduction in setup error and resultant margin requirement overall compared with no IGRT.Conclusions: Daily shifts, systematic errors, and margin requirements were greatest in obese patients. For women who are normal or overweight, a planning target margin margin of 7 to 10 mm may be sufficient without IGRT, but for patients who are moderately or severely obese, this is insufficient.

Intensity-Modulated Radiation Therapy in the Salvage of Locally Recurrent Nasopharyngeal Carcinoma

Sufang Qiu, Shaojun Lin, Ivan W.K. Tham, Jianji Pan, Jun Lu, Jiade J. Lu — 2011-10-24

Purpose: Local recurrences of nasopharyngeal carcinoma (NPC) may be salvaged by reirradiation with conventional techniques, but with significant morbidity. Intensity-modulated radiation therapy (IMRT) may improve the therapeutic ratio by reducing doses to normal tissue. The aim of this study was to address the efficacy and toxicity profile of IMRT for a cohort of patients with locally recurrent NPC.Methods and Materials: Between August 2003 and June 2009, 70 patients with radiologic or pathologically proven locally recurrent NPC were treated with IMRT. The median time to recurrence was 30 months after the completion of conventional radiation to definitive dose. Fifty-seven percent of the tumors were classified asrT3–4. The minimum planned doses were 59.4 to 60 Gy in 1.8- to 2-Gy fractions per day to the gross disease with margins, with or without chemotherapy.Results: The median dose to the recurrent tumor was 70 Gy (range, 50–77.4 Gy). Sixty-five patients received the planned radiation therapy; 5 patients received between 50 and 60 Gy because of acute side effects. With a median follow-up time of 25 months, the rates of 2-year locoregional recurrence-free survival, disease-free survival, and overall survival were 65.8%, 65.8%, and 67.4%, respectively. Moderate to severe late toxicities were noted in 25 patients (35.7%). Eleven patients (15.7%) had posterior nasal space ulceration, 17 (24.3%) experienced cranial nerve palsies, 12 (17.1%) had trismus, and 12 (17.1%) experienced deafness. Extended disease-free interval (relative risk 2.049) and advanced T classification (relative risk 3.895) at presentation were adverse prognostic factors.Conclusion: Reirradiation with IMRT provides reasonable long-term control in patients with locally recurrent NPC.

Distant Metastases in Head-and-Neck Squamous Cell Carcinoma Treated With Intensity-Modulated Radiotherapy

2011-12-13

Purpose: To determine the pattern and risk factors for distant metastases in head-and-neck squamous cell carcinoma (HNSCC) after curative treatment with intensity-modulated radiotherapy (IMRT).Methods and Materials: This was a retrospective study of 284 HNSCC patients treated in a single institution with IMRT. Sites included were oropharynx (125), oral cavity (70), larynx (55), hypopharynx (17), and unknown primary (17). American Joint Committee on Cancer stage distribution includes I (3), II (19), III (42), and IV (203). There were 224 males and 60 females with a median age of 57. One hundred eighty-six patients were treated with definitive IMRT and 98 postoperative IMRT. One hundred forty-nine patients also received concurrent cisplatin-based chemotherapy.Results: The median follow-up for all patients was 22.8 months (range, 0.07–77.3 months) and 29.5 months (4.23–77.3 months) for living patients. The 3-year local recurrence-free survival, regional recurrence-free survival, locoregional recurrence-free survival, distant metastasis-free survival, and overall survival were 94.6%, 96.4%, 92.5%, 84.1%, and 68.95%, respectively. There were 45 patients with distant metastasis. In multivariate analysis, distant metastasis was strongly associated with N stage (p = 0.046), T stage (p < 0.0001), and pretreatment maximum standardized uptake value of the lymph node (p = 0.006), but not associated with age, gender, disease sites, pretreatment standardized uptake value of the primary tumor, or locoregional control. The freedom from distant metastasis at 3 years was 98.1% for no factors, 88.6% for one factor, 68.3% for two factors, and 41.7% for three factors (p < 0.0001 by log–rank test).Conclusion: With advanced radiation techniques and concurrent chemotherapy, the failure pattern has changed with more patients failing distantly. The majority of patients with distant metastases had no local or regional failures, indicating that these patients might have microscopic distant disease before treatment. The clinical factors identified here should be incorporated in future clinical trials.

Continuous-Course Reirradiation With Concurrent Carboplatin and Paclitaxel for Locally Recurrent, Nonmetastatic Squamous Cell Carcinoma of the Head-and-Neck

2011-11-22

Purpose: To examine the efficacy and toxicity of continuous-course, conformal reirradiation with weekly paclitaxel and carboplatin for the treatment of locally recurrent, nonmetastatic squamous cell carcinoma of the head and neck (SCCHN) in a previously irradiated field.Methods and Materials: Patients treated with continuous course-reirradiation with concurrent carboplatin and paclitaxel at the Medical College of Wisconsin and the Clement J. Zablocki VA from 2001 through 2009 were retrospectively reviewed. Patients included in the analysis had prior radiation at the site of recurrence of at least 45 Gy. The analysis included patients who received either intensity-modulated radiotherapy (RT) or three-dimensional conformal RT techniques. All patients received weekly concurrent carboplatin (AUC2) and paclitaxel (30–50 mg/m2).Results: Thirty-eight patients with nonmetastatic SCCHN met the entry criteria for analysis. The primary sites at initial diagnosis were oropharyngeal or laryngeal in most patients (66%). Median reirradiation dose was 60 Gy (range, 54–70 Gy). Acute toxicity included Grade 2 neutropenia (5%), Grade 3 neutropenia (15%), and Grade 1/2 thrombocytopenia (8%). No deaths occurred from hematologic toxicity. Chemotherapy doses held (50%) was more prevalent than radiation treatment break (8%). Sixty-eight percent of patients required a gastrostomy tube in follow-up. Significant late toxicity was experienced in 6 patients (16%): 1 tracheoesophageal fistula, 1 pharyngocutaneous fistula, 3 with osteoradionecrosis, and 1 patient with a lingual artery bleed. Patients treated with three-dimensional conformal RT had more frequent significant late toxicites than patients treated with intensity-modulated RT (44% and 7% respectively, p < 0.05). The median time to progression was 7 months and progression-free rates at 1, 2, and 5 years was 44%, 34%, and 29% respectively. The median overall survival was 16 months. Overall survival at 1, 3, and 5 years was 54%, 31%, and 20% respectively.Conclusions: Continuous-course, conformal reirradiation with weekly paclitaxel and carboplatin has an acceptable toxicity profile and offers a potentially curative option in a subset of patients with few other options.

Evaluation of Deformable Image Coregistration in Adaptive Dose Painting by Numbers for Head-and-Neck Cancer

2011-12-06

Purpose: To assess the accuracy of contour deformation and feasibility of dose summation applying deformable image coregistration in adaptive dose painting by numbers (DPBN) for head and neck cancer.Methods and Materials: Data of 12 head-and-neck-cancer patients treated within a Phase I trial on adaptive 18F-FDG positron emission tomography (PET)–guided DPBN were used. Each patient had two DPBN treatment plans: the initial plan was based on a pretreatment PET/CT scan; the second adapted plan was based on a PET/CT scan acquired after 8 fractions. The median prescription dose to the dose-painted volume was 30 Gy for both DPBN plans. To obtain deformed contours and dose distributions, pretreatment CT was deformed to per-treatment CT using deformable image coregistration. Deformed contours of regions of interest (ROIdef) were visually inspected and, if necessary, adjusted (ROIdef_ad) and both compared with manually redrawn ROIs (ROIm) using Jaccard (JI) and overlap indices (OI). Dose summation was done on the ROIm, ROIdef_ad, or their unions with the ROIdef.Results: Almost all deformed ROIs were adjusted. The largest adjustment was made in patients with substantially regressing tumors: ROIdef = 11.8 ± 10.9 cm3 vs. ROIdef_ad = 5.9 ± 7.8 cm3 vs. ROIm = 7.7 ± 7.2 cm3 (p = 0.57). The swallowing structures were the most frequently adjusted ROIs with the lowest indices for the upper esophageal sphincter: JI = 0.3 (ROIdef) and 0.4 (ROIdef_ad); OI = 0.5 (both ROIs). The mandible needed the least adjustment with the highest indices: JI = 0.8 (both ROIs), OI = 0.9 (ROIdef), and 1.0 (ROIdef_ad). Summed doses differed non-significantly. There was a trend of higher doses in the targets and lower doses in the spinal cord when doses were summed on unions.Conclusion: Visual inspection and adjustment were necessary for most ROIs. Fast automatic ROI propagation followed by user-driven adjustment appears to be more efficient than labor-intensive de novo drawing. Dose summation using deformable image coregistration was feasible. Biological uncertainties of dose summation strategies warrant further investigation.

Outcome of T4 (International Union Against Cancer Staging System, 7th edition) or Recurrent Nasal Cavity and Paranasal Sinus Carcinoma Treated With Proton Beam

2011-11-17

Purpose: To investigate the clinical features, prognostic factors, and toxicity of treatment for unresectable carcinomas of the nasal cavity and paranasal sinus (NCPS) treated with proton beam therapy (PBT).Methods and Materials: Seventeen patients (13 men, 4 women) with unresectable carcinomas of the NCPS who underwent PBT at the University of Tsukuba between 2001 and 2007 were analyzed. The patients' median age was 62 years (range, 30–83 years). The tumors were located in the nasal cavity in 3 patients, the frontal sinus in 1, the ethmoid sinus in 9, and the maxillary sinus in 4. The clinical stage was Stage IVA in 5 cases, IVB in 10, and recurrent in 2. The tumors were deemed unresectable for medical reasons in 16 patients and because of refusal at a previous hospital 4 months earlier in 1 patient. All the patients received PBT irradiation dose of 22–82.5 GyE and a total of 72.4–89.6 GyE over 30–64 fractions (median 78 GyE over 36 fractions) with X-ray, with attention not exceeding the delivery of 50 GyE to the optic chiasm and brainstem.Results: The overall survival rate was 47.1% at 2 years and 15.7% at 5 years, and the local control rate was 35.0% at 2 years and 17.5% at 5 years. Invasion of the frontal or sphenoid sinus was a prognostic factor for overall survival or local control. Late toxicity of more than Grade 3 was found in 2 patients (brain necrosis in 1 and ipsilateral blindness in 1); however, no mortal adverse effects were observed.Conclusion: Proton beam therapy enabled a reduced irradiation dose to the optic chiasm and brainstem, enabling the safe treatment of unresectable carcinomas in the NCPS. Superior or posterior extension of the tumor influenced patient outcome.

Image Guidance During Head-and-Neck Cancer Radiation Therapy: Analysis of Alignment Trends With In-Room Cone-Beam Computed Tomography Scans

2011-11-17

Purpose: On-board cone-beam computed tomography (CBCT) is currently available for alignment of patients with head-and-neck cancer before radiotherapy. However, daily CBCT is time intensive and increases the overall radiation dose. We assessed the feasibility of using the average couch shifts from the first several CBCTs to estimate and correct for the presumed systematic setup error.Methods and Materials: 56 patients with head-and-neck cancer who received daily CBCT before intensity-modulated radiation therapy had recorded shift values in the medial–lateral, superior–inferior, and anterior–posterior dimensions. The average displacements in each direction were calculated for each patient based on the first five or 10 CBCT shifts and were presumed to represent the systematic setup error. The residual error after this correction was determined by subtracting the calculated shifts from the shifts obtained using daily CBCT.Results: The magnitude of the average daily residual three-dimensional (3D) error was 4.8 ± 1.4 mm, 3.9 ± 1.3 mm, and 3.7 ± 1.1 mm for uncorrected, five CBCT corrected, and 10 CBCT corrected protocols, respectively. With no image guidance, 40.8% of fractions would have been >5 mm off target. Using the first five CBCT shifts to correct subsequent fractions, this percentage decreased to 19.0% of all fractions delivered and decreased the percentage of patients with average daily 3D errors >5 mm from 35.7% to 14.3% vs. no image guidance. Using an average of the first 10 CBCT shifts did not significantly improve this outcome.Conclusions: Using the first five CBCT shift measurements as an estimation of the systematic setup error improves daily setup accuracy for a subset of patients with head-and-neck cancer receiving intensity-modulated radiation therapy and primarily benefited those with large 3D correction vectors (>5 mm). Daily CBCT is still necessary until methods are developed that more accurately determine which patients may benefit from alternative imaging strategies.

Can Intensity-Modulated Radiotherapy Preserve Oral Health-Related Quality of Life of Nasopharyngeal Carcinoma Patients?

2012-03-05

Purpose: To investigate the changes in salivary function and oral health-related quality of life for patients with nasopharyngeal carcinoma treated by intensity-modulated radiotherapy (IMRT).Methods and Materials: A total of 57 patients with early-stage nasopharyngeal carcinoma received IMRT. The parotid and whole saliva flow was measured, and the Medical Outcomes Study 36-item short form, European Organization for Research and Treatment of Cancer Quality of Life questionnaire-C30, European Organization for Research and Treatment of Cancer Quality of Life questionnaire 35-item head-and-neck module, and Oral Health Impact Profile questionnaires were completed at baseline and 2, 6, 12, 18, and 24 months after IMRT.Results: Parotid saliva flow recovered fully after 1 year and maintained. Whole saliva flow recovered partially to 40% of baseline. A general trend of deterioration in most quality of life scales was observed after IMRT, followed by gradual recovery. Persistent oral-related symptoms were found 2 years after treatment.Conclusion: IMRT for early-stage nasopharyngeal carcinoma could only partially preserve the whole salivary function and oral health-related quality of life.

Phase II Study to Assess the Efficacy of Hypofractionated Stereotactic Radiotherapy in Patients With Large Cavernous Sinus Hemangiomas

Xin Wang, Xiaoxia Liu, Guanghai Mei, Jiazhong Dai, Li Pan, Enmin Wang — 2012-02-23

Purpose: Cavernous sinus hemangioma is a rare vascular tumor. The direct microsurgical approach usually results in massive hemorrhage. Although radiosurgery plays an important role in managing cavernous sinus hemangiomas as a treatment alternative to microsurgery, the potential for increased toxicity with single-session treatment of large tumors is a concern. The purpose of this study was to assess the efficacy of hypofractionated stereotactic radiotherapy in patients with large cavernous sinus hemangiomas.Methods: Fourteen patients with large (volume >20 cm3) cavernous sinus hemangiomas were enrolled in a prospective Phase II study between December 2007 and December 2010. The hypofractionated stereotactic radiotherapy dose was 21 Gy delivered in 3 fractions.Results: After a mean follow-up of 15 months (range, 6–36 months), the magnetic resonance images showed a mean of 77% tumor volume reduction (range, 44–99%). Among the 6 patients with cranial nerve impairments before hypofractionated stereotactic radiotherapy, 1 achieved symptomatic complete resolution and 5 had improvement. No radiotherapy-related complications were observed during follow-up.Conclusion: Our current experience, though preliminary, substantiates the role of hypofractionated stereotactic radiotherapy for large cavernous sinus hemangiomas. Although a longer and more extensive follow-up is needed, hypofractionated stereotactic radiotherapy of 21 Gy delivered in 3 fractions is effective in reducing the tumor volume without causing any new deficits and can be considered as a treatment modality for large cavernous sinus hemangiomas.

Local Control With Reduced-Dose Radiotherapy for Low-Risk Rhabdomyosarcoma: A Report From the Children’s Oncology Group D9602 Study

2011-11-21

Purpose: To analyze the effect of reduced-dose radiotherapy on local control in children with low-risk rhabdomyosarcoma (RMS) treated in the Children’s Oncology Group D9602 study.Methods and Materials: Patients with low-risk RMS were nonrandomly assigned to receive radiotherapy doses dependent on the completeness of surgical resection of the primary tumor (clinical group) and the presence of involved regional lymph nodes. After resection, most patients with microscopic residual and uninvolved nodes received 36 Gy, those with involved nodes received 41.4 to 50.4 Gy, and those with orbital primary tumors received 45 Gy. All patients received vincristine and dactinomycin, with cyclophosphamide added for patient subsets with a higher risk of relapse in Intergroup Rhabdomyosarcoma Study Group III and IV studies.Results: Three hundred forty-two patients were eligible for analysis; 172 received radiotherapy as part of their treatment. The cumulative incidence of local/regional failure was 15% in patients with microscopic involved margins when cyclophosphamide was not part of the treatment regimen and 0% when cyclophosphamide was included. The cumulative incidence of local/regional failure was 14% in patients with orbital tumors. Protocol-specified omission of radiotherapy in girls with Group IIA vaginal tumors (n = 5) resulted in three failures for this group.Conclusions: In comparison with Intergroup Rhabdomyosarcoma Study Group III and IV results, reduced-dose radiotherapy does not compromise local control for patients with microscopic tumor after surgical resection or with orbital primary tumors when cyclophosphamide is added to the treatment program. Girls with unresected nonbladder genitourinary tumors require radiotherapy for postsurgical residual tumor for optimal local control to be achieved.

Local Failure in Resected N1 Lung Cancer: Implications for Adjuvant Therapy

2011-12-29

Purpose: To evaluate actuarial rates of local failure in patients with pathologic N1 non–small-cell lung cancer and to identify clinical and pathologic factors associated with an increased risk of local failure after resection.Methods and Materials: All patients who underwent surgery for non–small-cell lung cancer with pathologically confirmed N1 disease at Duke University Medical Center from 1995–2008 were identified. Patients receiving any preoperative therapy or postoperative radiotherapy or with positive surgical margins were excluded. Local failure was defined as disease recurrence within the ipsilateral hilum, mediastinum, or bronchial stump/staple line. Actuarial rates of local failure were calculated with the Kaplan-Meier method. A Cox multivariate analysis was used to identify factors independently associated with a higher risk of local recurrence.Results: Among 1,559 patients who underwent surgery during the time interval, 198 met the inclusion criteria. Of these patients, 50 (25%) received adjuvant chemotherapy. Actuarial (5-year) rates of local failure, distant failure, and overall survival were 40%, 55%, and 33%, respectively. On multivariate analysis, factors associated with an increased risk of local failure included a video-assisted thoracoscopic surgery approach (hazard ratio [HR], 2.5; p = 0.01), visceral pleural invasion (HR, 2.1; p = 0.04), and increasing number of positive N1 lymph nodes (HR, 1.3 per involved lymph node; p = 0.02). Chemotherapy was associated with a trend toward decreased risk of local failure that was not statistically significant (HR, 0.61; p = 0.2).Conclusions: Actuarial rates of local failure in pN1 disease are high. Further investigation of conformal postoperative radiotherapy may be warranted.

Long-Term Results of Conformal Radiotherapy for Progressive Airway Amyloidosis

2012-01-23

Purpose: To evaluate the efficacy of conformal external beam radiotherapy (RT) for local control of progressive airway amyloidosis.Methods and Materials: We conducted a retrospective review of patients with biopsy-proven progressive airway amyloidosis treated with conformal RT between 2000 and 2006 at Boston Medical Center. The patients were evaluated for performance status and pulmonary function, with computed tomography and endoscopy after RT compared with the pretreatment studies. Local control was defined as the lack of progression of airway wall thickening on computed tomography imaging and stable endobronchial deposits by endoscopy.Results: A total of 10 symptomatic airway amyloidosis patients (3 laryngeal and 7 tracheobronchial) received RT to a median total dose of 20 Gy in 10 fractions within 2 weeks. At a median follow-up of 6.7 years (range, 1.5–10.3), 8 of the 10 patients had local control. The remaining 2 patients underwent repeat RT 6 and 8.4 months after initial RT, 1 for persistent bronchial obstruction and 1 for progression of subglottic amyloid disease with subsequent disease control. The Eastern Cooperative Oncology Group performance status improved at a median of 18 months after RT compared with the baseline values, from a median score of 2 to a median of 1 (p = .035). Airflow (forced expiratory volume in 1 second) measurements increased compared with the baseline values at each follow-up evaluation, reaching a 10.7% increase (p = .087) at the last testing (median duration, 64.8 months). Acute toxicity was limited to Grade 1-2 esophagitis, occurring in 40% of patients. No late toxicity was observed.Conclusions: RT prevented progressive amyloid deposition in 8 of 10 patients, resulting in a marginally increased forced expiratory volume in 1 second, and improved functional capacity, without late morbidity.

Celiac Node Failure Patterns After Definitive Chemoradiation for Esophageal Cancer in the Modern Era

2012-03-22

Purpose: The celiac lymph node axis acts as a gateway for metastatic systemic spread. The need for prophylactic celiac nodal coverage in chemoradiation therapy for esophageal cancer is controversial. Given the improved ability to evaluate lymph node status before treatment via positron emission tomography (PET) and endoscopic ultrasound, we hypothesized that prophylactic celiac node irradiation may not be needed for patients with localized esophageal carcinoma.Methods and Materials: We reviewed the radiation treatment volumes for 131 patients who underwent definitive chemoradiation for esophageal cancer. Patients with celiac lymph node involvement at baseline were excluded. Median radiation dose was 50.4 Gy. The location of all celiac node failures was compared with the radiation treatment plan to determine whether the failures occurred within or outside the radiation treatment field.Results: At a median follow-up time of 52.6 months (95% CI 46.1–56.7 months), 6 of 60 patients (10%) without celiac node coverage had celiac nodal failure; in 5 of these patients, the failures represented the first site of recurrence. Of the 71 patients who had celiac coverage, only 5 patients (7%) had celiac region relapse. In multivariate analyses, having a pretreatment-to-post-treatment change in standardized uptake value on PET >52% (odds ratio [OR] 0.198, p = 0.0327) and having failure in the clinical target volume (OR 10.72, p = 0.001) were associated with risk of celiac region relapse. Of those without celiac coverage, the 6 patients that later developed celiac failure had a worse median overall survival time compared with the other 54 patients who did not fail (median overall survival time: 16.5 months vs. 31.5 months, p = 0.041). Acute and late toxicities were similar in both groups.Conclusions: Although celiac lymph node failures occur in approximately 1 of 10 patients, the lack of effective salvage treatments and subsequent low morbidity may justify prophylactic treatment in distal esophageal cancer patients.

Oxidative Stress Mediates Radiation Lung Injury by Inducing Apoptosis

Yu Zhang, Xiuwu Zhang, Zahid N. Rabbani, Isabel L. Jackson, Zeljko Vujaskovic — 2012-01-23

Purpose: Apoptosis in irradiated normal lung tissue has been observed several weeks after radiation. However, the signaling pathway propagating cell death after radiation remains unknown.Methods and Materials: C57BL/6J mice were irradiated with 15 Gy to the whole thorax. Pro-apoptotic signaling was evaluated 6 weeks after radiation with or without administration of AEOL10150, a potent catalytic scavenger of reactive oxygen and nitrogen species.Results: Apoptosis was observed primarily in type I and type II pneumocytes and endothelium. Apoptosis correlated with increased PTEN expression, inhibition of downstream PI3K/AKT signaling, and increased p53 and Bax protein levels. Transforming growth factor-β1, Nox4, and oxidative stress were also increased 6 weeks after radiation. Therapeutic administration of AEOL10150 suppressed pro-apoptotic signaling and dramatically reduced the number of apoptotic cells.Conclusion: Increased PTEN signaling after radiation results in apoptosis of lung parenchymal cells. We hypothesize that upregulation of PTEN is influenced by Nox4-derived oxidative stress. To our knowledge, this is the first study to highlight the role of PTEN in radiation-induced pulmonary toxicity.

Live-Cell Imaging Visualizes Frequent Mitotic Skipping During Senescence-Like Growth Arrest in Mammary Carcinoma Cells Exposed to Ionizing Radiation

2012-02-27

Purpose: Senescence-like growth arrest in human solid carcinomas is now recognized as the major outcome of radiotherapy. This study was designed to analyze cell cycle during the process of senescence-like growth arrest in mammary carcinoma cells exposed to X-rays.Methods and Materials: Fluorescent ubiquitination-based cell cycle indicators were introduced into the human mammary carcinoma cell line MCF-7. Cell cycle was sequentially monitored by live-cell imaging for up to 5 days after exposure to 10 Gy of X-rays.Results: Live-cell imaging revealed that cell cycle transition from G2 to G1 phase without mitosis, so-called mitotic skipping, was observed in 17.1% and 69.8% of G1- and G2-irradiated cells, respectively. Entry to G1 phase was confirmed by the nuclear accumulation of mKO2-hCdt1 as well as cyclin E, which was inversely correlated to the accumulation of G2-specific markers such as mAG-hGeminin and CENP-F. More than 90% of cells skipping mitosis were persistently arrested in G1 phase and showed positive staining for the senescent biochemical marker, which is senescence-associated ß-galactosidase, indicating induction of senescence-like growth arrest accompanied by mitotic skipping. While G2 irradiation with higher doses of X-rays induced mitotic skipping in approximately 80% of cells, transduction of short hairpin RNA (shRNA) for p53 significantly suppressed mitotic skipping, suggesting that ionizing radiation-induced mitotic skipping is associated with p53 function.Conclusions: The present study found the pathway of senescence-like growth arrest in G1 phase without mitotic entry following G2-irradiation.

Early Changes in Apparent Diffusion Coefficient From Diffusion-Weighted MR Imaging During Radiotherapy for Prostate Cancer

2011-12-12

Purpose: To investigate the feasibility of diffusion-weighted MRI (DWI) as an early and reproducible change indicator in patients receiving radiotherapy for prostate cancer (PC).Methods and Materials: Eight consecutive patients with biopsy-proven PC underwent DWI at 3T. All patients who received external-beam radiotherapy had four serial MR scans, as follows: before therapy (PreTx); after 1 week of therapy (PostT1); after 3 weeks of therapy (PostT2); and 1 month after the completion of therapy (PostT3). At each time, the apparent diffusion coefficient (ADC) was measured in tumors and normal tissues. For reproducibility of the ADC measurement, five patients also had two separate pretreatment DWI scans at an interval of <2 weeks. Serum prostate-specific antigen (PSA) levels were evaluated at the same time as MR scans.Results: Thirteen tumors (peripheral zone = 10; transition zone = 3) were found. The mean ADC values for the tumors from PreTx to PostT3 were 0.86, 1.03, 1.15, and 1.26 × 10−3 mm2/s in sequence, respectively. Compared with PreTx, PostT1 (p = 0.005), PostT2 (p = 0.003), and PostT3 (p < 0.001) showed a significant increase in ADC values. The mean ADC values of the benign tissues from PreTx to PostT3 were 1.60, 1.58, 1.47, and 1.46 × 10−3 mm2/s in sequence, respectively. Reproducibility of ADC measurements was confirmed with a mean difference in ADC of –0.04 in peripheral zone and –0.017 in transition zone between two separate pretreatment MR scans. The mean PSA levels from PreTx to PostT3 were 9.05, 9.18, 9.25, and 4.11 ng/mL in sequence, respectively.Conclusions: DWI, as a reproducible biomarker, has the potential to evaluate the early therapeutic changes of PC to radiotherapy.

Optimizing Normal Tissue Sparing in Ion Therapy Using Calculated Isoeffective Dose for Ion Selection

Nicholas B. Remmes, Michael G. Herman, Jon J. Kruse — 2012-03-20

Purpose: To investigate how the selection of ion type affects the calculated isoeffective dose to the surrounding normal tissue as a function of both normal tissue and target tissue α/β ratios.Methods and Materials: A microdosimetric biologic dose model was incorporated into a Geant4 simulation of parallel opposed beams of protons, helium, lithium, beryllium, carbon, and neon ions. The beams were constructed to give a homogeneous isoeffective dose to a volume in the center of a water phantom for target tissues covering a range of cobalt equivalent α/β ratios of 1–20 Gy. Concomitant normal tissue isoeffective doses in the plateau of the ion beam were then compared for different ions across the range of normal tissue and target tissue radiosensitivities for a fixed isoeffective dose to the target tissue.Results: The ion type yielding the optimal normal tissue sparing was highly dependent on the α/β ratio of both the normal and the target tissue. For carbon ions, the calculated isoeffective dose to normal tissue at a 5-cm depth varied by almost a factor of 5, depending on the α/β ratios of the normal and target tissue. This ranges from a factor of 2 less than the isoeffective dose of a similar proton treatment to a factor of 2 greater.Conclusions: No single ion is optimal for all treatment scenarios. The heavier ions are superior in cases in which the α/β ratio of the target tissue is low and the α/β ratio of normal tissue is high, and protons are superior in the opposite circumstances. Lithium and beryllium appear to offer dose advantages similar to carbon, with a considerably lower normal tissue dose when the α/β ratio in the target tissue is high and the α/β ratio in the normal tissue is low.

Dosimetric Impact of Breathing Motion in Lung Stereotactic Body Radiotherapy Treatment Using Image-Modulated Radiotherapy and Volumetric Modulated Arc Therapy

2012-02-27

Purpose: The objective of this study was to investigate the influence of tumor motion on dose delivery in stereotactic body radiotherapy (SBRT) for lung cancer, using fixed field intensity- modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT).Methods and Materials: For each of 10 patients with stage I/II non-small-cell pulmonary tumors, a respiration-correlated four-dimensional computed tomography (4DCT) study was carried out. The internal target volume was delineated on the maximum intensity projection CT, which was reconstructed from the 4DCT dataset. A 5-mm margin was used for generation of the planning target volume. VMAT and five-field IMRT plans were generated using Pinnacle3 SmartArc and direct machine parameter optimization, respectively. All plans were generated for an Elekta Synergy linear accelerator using 6-MV photons. Simulation was performed to study the interplay between multileaf collimator (MLC) sequences and target movement during the delivery of VMAT and IMRT. For each plan, 4D dose was calculated using deformable image registration of the 4DCT images. Target volume coverage and doses to critical structures calculated using 4D methodology were compared with those calculated using 3D methodology.Results: For all patients included in this study, the interplay effect was found to present limited impact (less than 1% of prescription) on the target dose distribution, especially for SBRT, in which fewer fractions (three fractions) are delivered. Dose to the gross tumor volume (GTV) was, on average, slightly decreased (1% of prescription) in the 4D calculation compared with the 3D calculation. The motion impact on target dose homogeneity was patient-dependent and relatively small.Conclusions: Both VMAT and IMRT plans experienced negligible interplay effects between MLC sequence and tumor motion. For the most part, the 3D doses to the GTV and critical structures provided good approximations of the 4D dose calculations.

Localization of a Portion of an Endorectal Balloon for Prostate Image-Guided Radiation Therapy Using Cone-Beam Tomosynthesis: A Feasibility Study

2012-03-07

Purpose: To assess the feasibility of using cone-beam tomosynthesis (CBTS) to localize the air–tissue interface for the application of prostate image-guided radiation therapy using an endorectal balloon for immobilization and localization.Methods and Materials: A Feldkamp-David-Kress-based CBTS reconstruction was applied to selected sets of cone-beam computed tomography (CBCT) projection data to simulate volumetric imaging achievable from tomosynthesis for a limited range of scan angles. Projection data were calculated from planning CT images of 10 prostate cancer patients treated with an endorectal balloon, as were experimental CBCT projections for a pelvic phantom in two patients. More than 50 points at the air–tissue interface were objectively identified by an intensity-based interface-finding algorithm. Using three-dimensional point sets extracted from CBTS images compared with points extracted from corresponding CBCT images, the relative shift resulting from a reduced scan angle was determined. Because the CBCT and CBTS images were generated from the same projection data set, shift identified was presumed to be due to distortions introduced by the tomosynthesis technique.Results: Scans of ≥60° were shown to be able to localize an air–tissue interface near the isocenter with accuracy on the order of a millimeter. The accuracy was quantified in terms of the mean discrepancy as a function of reconstruction angle.Conclusion: This work provides an understanding of the effect of scan angle used in localization of a portion of an endorectal balloon by means of CBTS. CBTS with relatively small scan angles is capable of accurately localizing an extended interface near the isocenter and may provide clinically relevant measurements to guide IGRT treatments while reducing imaging radiation to the patient.

Image-Based Dynamic Multileaf Collimator Tracking of Moving Targets During Intensity-Modulated Arc Therapy

Per Rugaard Poulsen, Walther Fledelius, Byungchul Cho, Paul Keall — 2012-03-07

Purpose: Intensity-modulated arc therapy (IMAT) enables efficient and highly conformal dose delivery. However, intrafraction motion may compromise the delivered target dose distribution. Dynamic multileaf collimator (DMLC) tracking can potentially mitigate the impact of target motion on the dose. The purpose of this study was to use a single kV imager for DMLC tracking during IMAT and to investigate the ability of this tracking to maintain the dose distribution.Methods: A motion phantom carrying a two-dimensional (2D) ion chamber array and buildup material with an embedded gold marker reproduced eight representative tumor trajectories (four lung tumors, four prostate). For each trajectory, a low and high IMAT plan were delivered with and without DMLC tracking. The three-dimensional (3D) real-time target position signal for tracking was provided by fluoroscopic kV images acquired immediately before and during treatment. For each image, the 3D position of the embedded marker was estimated from the imaged 2D position by a probability-based method. The MLC leaves were continuously refitted to the estimated 3D position. For lung, prediction was used to compensate for the tracking latency. The delivered 2D dose distributions were measured with the ion chamber array and compared with a reference dose distribution delivered without target motion using a 3%/3 mm γ-test.Results: For lung tumor motion, tracking reduced the mean γ-failure rate from 38% to 0.7% for low-modulation IMAT plans and from 44% to 2.8% for high-modulation plans. For prostate, the γ-failure rate reduction was from 19% to 0% (low modulation) and from 20% to 2.7% (high modulation). The dominant contributor to the residual γ-failures during tracking was target localization errors for most lung cases and leaf fitting errors for most prostate cases.Conclusion: Image-based tracking for IMAT was demonstrated for the first time. The tracking greatly improved the dose distributions to moving targets.

Quantifying the Interfractional Displacement of the Gastroesophageal Junction During Radiation Therapy for Esophageal Cancer

2012-03-22

Purpose: Accounting for interfractional changes in tumor location improves the accuracy of radiation treatment delivery. The purpose of this study was to quantify the interfractional displacement of the gastroesophageal junction (GEJ) based on standard treatment setup in patients with esophageal cancer undergoing radiation therapy.Methods and Materials: Free-breathing four-dimensional computed tomography (4D-CT) datasets were acquired weekly from 22 patients during treatment for esophageal adenocarcinoma. Scans were registered to baseline (simulation) 4D-CT scans by using bony landmarks. The distance between the center of the GEJ contour on the simulation scan and the mean location of GEJ centers on subsequent scans was used to assess changes in GEJ location between fractions; displacement was also correlated with clinical and respiratory variables.Results: The mean absolute random error was 1.69 mm (range, 0.11–4.11 mm) in the lateral direction, 1.87 mm (range, 0.51–4.09 mm) in the anterior–posterior (AP) direction, and 3.09 mm (range, 0.99–6.16 mm) in the superior–inferior (SI) direction. The mean absolute systemic GEJ displacement between fractions was 2.88 mm lateral (≥5 mm in 14%), mostly leftward; 2.90 mm (≥5 mm in 14%) AP, mostly anterior; and 6.77 mm (≥1 cm in 18%) SI, mostly inferior. Variations in tidal volume and diaphragmatic excursion during treatment correlated strongly with systematic SI GEJ displacement (r = 0.964, p < 0.0001; and r = 0.944, p < 0.0001, respectively) and moderately with systematic AP GEJ displacement (r = 0.678, p = 0.0005; r = 0.758, p < 0.0001, respectively). Systematic displacement in the inferior direction resulted in higher-than-intended doses (≥60 Gy) to the GEJ, with increased hot-spot to the adjacent stomach and lung base.Conclusion: We found large (>1-cm) interfractional displacements in the GEJ in the SI (especially inferior) direction that was not accounted for when skeletal alignment alone was used for patient positioning. Because systematic displacement in the SI direction had dosimetric impact and correlated with tidal volume, better accounting for depth of breathing is needed to reduce interfractional variability.

Surface Dose Investigation of the Flattening Filter-Free Photon Beams

Yuenan Wang, Mohammad K. Khan, Joseph Y. Ting, Stephen B. Easterling — 2012-03-12

Purpose: Flattening filter-free (FFF) x-rays can provide more efficient use of photons and a significant increase of dose rate compared with conventional flattened x-rays, features that are especially beneficial for stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT). The available data on the entrance doses of the FFF photon beams remain limited. The purpose of this study was to investigate the entrance dose of FFF photons in the buildup region and to compare it with that of conventional flattened photons.Methods and Materials: A Varian TrueBeam linear accelerator has been in full clinical operation with 6-MV and 10-MV FFF and flattened x-ray photons. Entrance dose at the surface was measured using a parallel plate ionization chamber in a solid water phantom with buildup depth = 0∼15 mm for 6X and 0∼25 mm for 10X. Different field size (FS) patterns were created in the Eclipse Treatment Planning System by multileaf collimator (MLC) rather than jaws (FS = 2 × 2, 3 × 3, 4 × 4, 6 × 6, and 10 × 10 cm2 by MLC and jaw size = 2.2 × 2.2, 3.2 × 3.2, 4.2 × 4.2, 6 × 6, and 10 × 10 cm2). The smallest FS was about four times larger than the ion chamber dimension. All buildup dose measurements were normalized to FS = 10 × 10 cm2 at the depth of dose maximum (dmax).Results: Good repeatability was demonstrated and surface dose increased linearly with FS for both flattened and FFF photons. The entrance dose of the FFF photons was modestly larger than that of the corresponding flattened photons for both 6X and 10X for different FS ranging from 2 × 2 cm2 to 10 × 10 cm2.Conclusions: The FFF photons have a higher entrance dose than that of the corresponding flattened photons for FS smaller than 10 × 10 cm2. However, the difference is not substantial and may be clinically insignificant.

An Innovative Tool for Intraoperative Electron Beam Radiotherapy Simulation and Planning: Description and Initial Evaluation by Radiation Oncologists

2012-03-07

Purpose: Intraoperative electron beam radiation therapy (IOERT) involves a modified strategy of conventional radiation therapy and surgery. The lack of specific planning tools limits the spread of this technique. The purpose of the present study is to describe a new simulation and planning tool and its initial evaluation by clinical users.Methods and Materials: The tool works on a preoperative computed tomography scan. A physician contours regions to be treated and protected and simulates applicator positioning, calculating isodoses and the corresponding dose–volume histograms depending on the selected electron energy. Three radiation oncologists evaluated data from 15 IOERT patients, including different tumor locations. Segmentation masks, applicator positions, and treatment parameters were compared.Results: High parameter agreement was found in the following cases: three breast and three rectal cancer, retroperitoneal sarcoma, and rectal and ovary monotopic recurrences. All radiation oncologists performed similar segmentations of tumors and high-risk areas. The average applicator position difference was 1.2 ± 0.95 cm. The remaining cancer sites showed higher deviations because of differences in the criteria for segmenting high-risk areas (one rectal, one pancreas) and different surgical access simulated (two rectal, one Ewing sarcoma).Conclusions: The results show that this new tool can be used to simulate IOERT cases involving different anatomic locations, and that preplanning has to be carried out with specialized surgical input.

Clinical Application of a Novel Hybrid Intensity-Modulated Radiotherapy Technique for Stage III Lung Cancer and Dosimetric Comparison With Four Other Techniques

2012-06-01

Purpose: In large stage III lung tumors, planning delivery of doses exceeding 60 Gy can be challenging and time consuming. Intensity modulated radiation therapy (IMRT) can improve target coverage but may increase volumes receiving low-dose irradiation. We clinically implemented a novel hybrid IMRT (h-IMRT) technique that allowed plans to be produced quickly, and compared these plans with 4 other techniques.Methods and Materials: h-IMRT was used to treat 14 consecutive patients with planning target volumes (PTVs) exceeding 500 cm3 (average, 779 cm3) with concurrent chemo-radiation therapy to 66 Gy. h-IMRT plans consisted of 2 components: an anterior-posterior/posterior-anterior/posterior-anterior (AP-PA-PA) oblique, open-field technique delivering an average dose of 58 Gy, plus a 3-field IMRT component optimized to achieve a final homogeneous dose of 66 Gy. Total lung V20 and contralateral lung V5 were kept as low as possible but preferably less than 35% and less than 50%, respectively. All plans were retrospectively replanned using a 5- to 9-field 3-dimensional conformal technique, full RapidArc, 6-field full IMRT, and a hybrid RapidArc (h-RapidArc) technique similar to the h-IMRT.Results: The h-IMRT, h-RapidArc, and full RapidArc plans could be generated in less than 2 h, with the first 2 plans achieving the lowest V5 (36%) and V20 (30%) values together with the smallest hot spots. Both the 3-dimensional conformal and full IMRT plans occasionally led to unacceptable hot spots outside the PTV. Full RapidArc plans were fast and achieved comparable V20 values but led to slightly higher V5 values.Conclusions: Both h-IMRT and h-RapidArc permitted delivery of 66 Gy to large stage III lung tumors, and both were superior to either full IMRT or RapidArc plans for reducing lung doses. The clinical significance of small increases in V5 during chemo-radiation therapy delivery are unknown, but the present study suggests that h-IMRT and h-RapidArc are preferable for treatment of large tumors.

Meetings

2012-06-01

June 10-14, 2012 AAMD 37th Annual Meeting