Volumetric-based image guidance is superior to marker-based alignments for stereotactic body radiotherapy of prostate cancer.

PURPOSES: The aim of this study was to evaluate a dual marker-based and soft-tissue based image guidance for inter-fractional corrections in stereotactic body radiotherapy (SBRT) of prostate cancer. METHODS/MATERIALS: We reviewed 18 patients treated with SBRT for prostate cancer. An endorectal balloon was inserted at simulation and each treatment. Planning margins were 3 mm/0 mm posteriorly. Prior to each treatment, a dual image guidance protocol was applied to align three makers using stereoscopic x ray images and then to the soft tissue using kilo-voltage cone beam CT (kV-CBCT). After treatment, prostate (CTV), rectal wall, and bladder were delineated on each kV-CBCT, and delivered dose was recalculated. Dosimetric endpoints were analyzed, including V36.25 Gy for prostate, and D0.03 cc for bladder and rectal wall. RESULTS: Following initial marker alignment, additional translational shifts were applied to 22 of 84 fractions after kV-CBCT. Among the 22 fractions, ten fractions exceeded 3 mm shifts in any direction, including one in the left-right direction, four in the superior-inferior direction, and five in the anterior-posterior direction. With and without the additional kV-CBCT shifts, the average V36.25 Gy of the prostate for the 22 fractions was 97.6 ± 2.6% with the kV x ray image alone, and was 98.1 ± 2.4% after applying the additional kV-CBCT shifts. The improvement was borderline statistical significance using Wilcoxon signed-rank test (P = 0.007). D0.03 cc was 45.8 ± 6.3 Gy vs. 45.1 ± 4.9 Gy for the rectal wall; and 49.5 ± 8.6 Gy vs. 49.3 ± 7.9 Gy for the bladder before and after applying kV-CBCT shifts. CONCLUSIONS: Marker-based alignment alone is not sufficient. Additional adjustments are needed for some patients based kV-CBCT.

Evolving Paradigm of Radiotherapy for High-Risk Prostate Cancer: Current Consensus and Continuing Controversies.

High-risk prostate cancer is an aggressive form of the disease with an increased risk of distant metastasis and subsequent mortality. Multiple randomized trials have established that the combination of radiation therapy and long-term androgen deprivation therapy improves overall survival compared to either treatment alone. Standard of care for men with high-risk prostate cancer in the modern setting is dose-escalated radiotherapy along with 2-3 years of androgen deprivation therapy (ADT). There are research efforts directed towards assessing the efficacy of shorter ADT duration. Current research has been focused on assessing hypofractionated and stereotactic body radiation therapy (SBRT) techniques. Ongoing randomized trials will help assess the utility of pelvic lymph node irradiation. Research is also focused on multimodality therapy with addition of a brachytherapy boost to external beam radiation to help improve outcomes in men with high-risk prostate cancer.

Dose-Escalated Stereotactic Body Radiation Therapy for Patients With Intermediate- and High-Risk Prostate Cancer: Initial Dosimetry Analysis and Patient Outcomes.

PURPOSE: To report the short-term clinical outcomes and acute and late treatment-related genitourinary (GU) and gastrointestinal (GI) toxicities in patients with intermediate- and high-risk prostate cancer treated with dose-escalated stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Between 2011 and 2014, 24 patients with prostate cancer were treated with SBRT to the prostate gland and proximal seminal vesicles. A high-dose avoidance zone (HDAZ) was created by a 3-mm expansion around the rectum, urethra, and bladder. Patients were treated to a minimum dose of 36.25 Gy in 5 fractions, with a simultaneous dose escalation to a dose of 50 Gy to the target volume away from the HDAZ. Acute and late GU and GI toxicity outcomes were measured according to the National Cancer Institute Common Terminology Criteria for Adverse Events toxicity scale, version 4. RESULTS: The median follow-up was 25 months (range, 18-45 months). Nine patients (38%) experienced an acute grade 2 GU toxicity, which was medically managed, and no patients experienced an acute grade 2 GI toxicity. Two patients (8%) experienced late grade 2 GU toxicity, and 2 patients (8%) experienced late grade 2 GI toxicity. No acute or late grade ≥3 GU or GI toxicities were observed. The 24-month prostate-specific antigen relapse-free survival outcome for all patients was 95.8% (95% confidence interval 75.6%-99.4%), and both biochemical failures occurred in patients with high-risk disease. All patients are currently alive at the time of this analysis and continue to be followed. CONCLUSIONS: A heterogeneous prostate SBRT planning technique with differential treatment volumes (low dose: 36.25 Gy; and high dose: 50 Gy) with an HDAZ provides a safe method of dose escalation. Favorable rates of biochemical control and acceptably low rates of acute and long-term GU and GI toxicity can be achieved in patients with intermediate- and high-risk prostate cancer treated with SBRT.

Using daily diagnostic quality images to validate planning margins for prostate interfractional variations

The purpose of this study is to use the same diagnostic-quality verification and planning CTs to validate planning margin account for residual interfractional variations with image-guided soft tissue alignment of the prostate. For nine pros-tate cancer patients treated with IMRT to 78 Gy in 39 fractions, daily verification CT-on-rails images of the first seven and last seven fractions (n = 126) were retrospectively selected for this study. On these images, prostate, bladder, and rectum were delineated by the same attending physician. Clinical plans were cre-ated with a margin of 8 mm except for 5 mm posteriorly, referred to as 8/5mm. Three additional plans were created for each patient with the margins of 6/4 mm, 4/2mm, and 2 mm uniform. These plans were subsequently applied to daily images and radiation doses were recalculated. The isocenters of these plans were placed according to clinical online shifts, which were based on soft tissue alignment to the prostate. Retrospective offline shifts by aligning prostate contours were com-pared to online shifts. The resultant daily target dose was analyzed using D99, the percentage of the prescription dose received by 99% of CTV. The percent of blad-der volume receiving 65 Gy (V65Gy) and rectum V70Gy were also analyzed. After interfractional correction, using CTV D99 > 97% criteria, 8/5 mm, 6/4 mm, 4/2 mm, and 2 mm planning margins met the CTV dose coverage in 95%, 91%, 65%, and 53% of the 126 fractions with online shifts, and 99%, 98%, 85%, and 68% with offline shifts. The rectum V70Gy and bladder V65Gy were significantly decreased at each level of margin reduction (p < 0.05). With daily diagnostic quality imaging-guidance, the interfractional planning margin may be reduced from 8/5mm to 6/4 mm. The residual interfractional uncertainties most likely stem from prostate rotation anddeformation.

ACR Appropriateness Criteria® Metastatic Epidural Spinal Cord Compression and Recurrent Spinal Metastasis.

Metastatic epidural spinal cord compression (MESCC) is an oncologic emergency and if left untreated, permanent paralysis will ensue. The treatment of MESCC is governed by disease, patient, and treatment factors. Patient's preferences and goals of care are to be weighed into the treatment plan. Ideally, a patient with MESCC is evaluated by an interdisciplinary team promptly to determine the urgency of the clinical scenario. Treatment recommendations must take into consideration the risk-benefit profiles of surgical intervention and radiotherapy for the particular individual's circumstance, including neurologic status, performance status, extent of epidural disease, stability of the spine, extra-spinal disease status, and life expectancy. In patients with high spinal instability neoplastic score (SINS) or retropulsion of bone fragments in the spinal canal, surgical intervention should be strongly considered. The rate of development of motor deficits from spinal cord compression may be a prognostic factor for ultimate functional outcome, and should be taken into account when a treatment recommendation is made. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR Appropriateness Criteria(®) non-spine bone metastases.

Bone metastases are a common clinical problem, affecting many types of cancer patients. The presence of tumor in bone can cause significant morbidity including pain, neurological dysfunction, hypercalcemia, and pathological fracture leading to functional loss. The optimal treatment of a patient with bone metastases depends on many factors, including evaluation of the patient's goals of care, performance status, mechanical stability of the affected bone, life expectancy, and overall extent of disease. Treatment options may include radiotherapy, systemic therapies, surgical stabilization, medical pain management, and radiopharmaceuticals. Ideal management of bone metastases requires a coordinated multidisciplinary approach among diagnostic radiologists, radiation oncologists, medical oncologists, orthopedic surgeons, pain specialists, physiatrists, and palliative care specialists. The American College of Radiology Appropriateness Criteria(®) are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guidelines development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR Appropriateness Criteria® pre-irradiation evaluation and management of brain metastases.

Pretreatment evaluation is performed to determine the number, location, and size of the brain metastases and magnetic resonance imaging (MRI) is the recommended imaging technique, particularly in patients being considered for surgery or stereotactic radiosurgery. A contiguous thin-cut volumetric MRI with gadolinium with newer gadolinium-based agents can improve detection of small brain metastases. A systemic workup and medical evaluation are important, given that subsequent treatment for the brain metastases will also depend on the extent of the extracranial disease and on the age and performance status of the patient. Patients with hydrocephalus or impending brain herniation should be started on high doses of corticosteroids and evaluated for possible neurosurgical intervention. Patients with moderate symptoms should receive approximately 4-8 mg/d of dexamethasone in divided doses. The routine use of corticosteroids in patients without neurologic symptoms is not necessary. There is no proven benefit of anticonvulsants in patient without seizures. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Feasibility of using nonflat photon beams for whole-breast irradiation with breath hold.

Removing a flattening filter or replacing it with a thinner filter alters the characteristics of a photon beam, creating a forward peaked intensity profile to make the photon beam nonflat. This study is to investigate the feasibility of applying nonflat photon beams to the whole-breast irradiation with breath holds for a potential of delivery time reduction during the gated treatment. Photon beams of 6 MV with flat and nonflat intensity profiles were commissioned. Fifteen patients with early-stage breast cancer, who received whole-breast radiation without breathing control, were retrospectively selected for this study. For each patient, three plans were created using a commercial treatment planning system: (a) the clinically approved plan using forward planning method (FP); (b) a hybrid intensity-modulated radiation therapy (IMRT) plan where the flat beam open fields were combined with the nonflat beam IMRT fields using direct aperture optimization method (mixed DAO); (c) a hybrid IMRT plan where both open and IMRT fields were from nonflat beams using direct aperture optimization (nonflat DAO). All plans were prescribed for ≥ 95% of the breast volume receiving the prescription dose of 50 Gy (2.0 Gy per fraction). In comparison, all plans achieved a similar dosimetric coverage to the targeted volume. The average homogeneity index of the FP, mixed DAO, and nonflat DAO plans were 0.882 ± 0.024, 0.879 ± 0.023, and 0.867 ± 0.027, respectively. The average percentage volume of V105 was 57.66% ± 5.21%, 34.67% ± 4.91%, 41.64% ± 5.32% for the FP, mixed, and nonflat DAO plans, respectively. There was no significant difference (p > 0.05) observed for the defined endpoint doses in organs at risk (OARs). In conclusion, both mixed DAO and nonflat DAO plans can achieve similar plan quality as the clinically approved FP plan, measured by plan homogeneity and endpoint doses to the ORAs. Nonflat beam plans may reduce treatment time in breath-hold treatment, especially for hypofractionated treatment.

Daily dose monitoring with atlas-based auto-segmentation on diagnostic quality CT for prostate cancer.

PURPOSE: To evaluate the feasibility of daily dose monitoring using a patient specific atlas-based autosegmentation method on diagnostic quality verification images. METHODS: Seven patients, who were treated for prostate cancer with intensity modulated radiotherapy under daily imaging guidance of a CT-on-rails system, were selected for this study. The prostate, rectum, and bladder were manually contoured on the first six and last seven sets of daily verification images. For each patient, three patient specific atlases were constructed using manual contours from planning CT alone (1-image atlas), planning CT plus first three verification CTs (4-image atlas), and planning CT plus first six verification CTs (7-image atlas). These atlases were subsequently applied to the last seven verification image sets of the same patient to generate the auto-contours. Daily dose was calculated by applying the original treatment plans to the daily beam isocenters. The autocontours and manual contours were compared geometrically using the dice similarity coefficient (DSC), and dosimetrically using the dose to 99% of the prostate CTV (D99) and the D5 of rectum and bladder. RESULTS: The DSC of the autocontours obtained with the 4-image atlases were 87.0% ± 3.3%, 84.7% ± 8.6%, and 93.6% ± 4.3% for the prostate, rectum, and bladder, respectively. These indices were higher than those from the 1-image atlases (p < 0.01) and comparable to those from the 7-image atlases (p > 0.05). Daily prostate D99 of the autocontours was comparable to those of the manual contours (p = 0.55). For the bladder and rectum, the daily D5 were 95.5% ± 5.9% and 99.1% ± 2.6% of the planned D5 for the autocontours compared to 95.3% ± 6.7% (p = 0.58) and 99.8% ± 2.3% (p < 0.01) for the manual contours. CONCLUSIONS: With patient specific 4-image atlases, atlas-based autosegmentation can adequately facilitate daily dose monitoring for prostate cancer.

ACR Appropriateness Criteria® follow-up and retreatment of brain metastases.

Multiple options for retreatment are available, which include whole-brain radiation therapy, stereotactic radiosurgery, surgery, chemotherapy, and supportive care. Size, number, timing, location, histology, performance status, and extracranial disease status all need to be carefully considered when choosing a treatment modality. There are no randomized trials examining the retreatment of brain metastases. Repeat whole-brain radiation has been examined in a single-institution experience, showing the potential for clinical responses in selected patients. Local control rates as high as 91% using stereotactic radiosurgery for relapses after whole-brain radiation are reported. Surgery can be indicated in progressive and/or hemorrhagic lesions causing mass effect. The role of chemotherapy in the recurrent setting is limited but some agents may have activity on the basis of experiences on a smaller scale. Supportive care continues to be an important option, especially in those with a poor prognosis. Follow-up for brain metastases patients is discussed, examining the modality, frequency of imaging, and imaging options in differentiating treatment effect from recurrence. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of the current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline.

PURPOSE: To present guidance for patients and physicians regarding the use of radiotherapy in the treatment of bone metastases according to current published evidence and complemented by expert opinion. METHODS AND MATERIALS: A systematic search of the National Library of Medicine's PubMed database between 1998 and 2009 yielded 4,287 candidate original research articles potentially applicable to radiotherapy for bone metastases. A Task Force composed of all authors synthesized the published evidence and reached a consensus regarding the recommendations contained herein. RESULTS: The Task Force concluded that external beam radiotherapy continues to be the mainstay for the treatment of pain and/or prevention of the morbidity caused by bone metastases. Various fractionation schedules can provide significant palliation of symptoms and/or prevent the morbidity of bone metastases. The evidence for the safety and efficacy of repeat treatment to previously irradiated areas of peripheral bone metastases for pain was derived from both prospective studies and retrospective data, and it can be safe and effective. The use of stereotactic body radiotherapy holds theoretical promise in the treatment of new or recurrent spine lesions, although the Task Force recommended that its use be limited to highly selected patients and preferably within a prospective trial. Surgical decompression and postoperative radiotherapy is recommended for spinal cord compression or spinal instability in highly selected patients with sufficient performance status and life expectancy. The use of bisphosphonates, radionuclides, vertebroplasty, and kyphoplasty for the treatment or prevention of cancer-related symptoms does not obviate the need for external beam radiotherapy in appropriate patients. CONCLUSIONS: Radiotherapy is a successful and time efficient method by which to palliate pain and/or prevent the morbidity of bone metastases. This Guideline reviews the available data to define its proper use and provide consensus views concerning contemporary controversies or unanswered questions that warrant prospective trial evaluation.

Dosimetric evaluation between megavoltage cone-beam computed tomography and body mass index for intracranial, thoracic, and pelvic localization.

The aim of this study was to evaluate radiation dose for organs at risk (OAR) within the cranium, thorax, and pelvis from megavoltage cone-beam computed tomography (MV-CBCT). Using a clinical treatment planning system, CBCT doses were calculated from 60 patient datasets using 27.4 × 27.4 cm(2) field size and 200° arc length. The body mass indices (BMIs) for these patients range from 17.2-48.4 kg/m(2). A total of 60 CBCT plans were created and calculated with heterogeneity corrections, with monitor units (MU) that varied from 8, 4, and 2 MU per plan. The isocenters of these plans were placed at defined anatomical structures. The maximum dose, dose to the isocenter, and mean dose to the selected critical organs were analyzed. The study found that maximum and isocenter doses were weakly associated with BMI, but linearly associated with the total MU. Average maximum/isocenter doses in the cranium were 10.0 (± 0.18)/7.0 (± 0.08) cGy, 5.0 (± 0.09)/3.5 (± 0.05) cGy, and 2.5 (± .04)/1.8 (± 0.05) cGy for 8, 4, and 2 MU, respectively. Similar trends but slightly larger maximum/isocenter doses were found in the thoracic and pelvic regions. For the cranial region, the average mean doses with a total of 8 MU to the eye, lens, and brain were 9.7 (± 0.12) cGy, 9.1 (± 0.16) cGy, and 7.2 (± 0.10) cGy, respectively. For the thoracic region, the average mean doses to the lung, heart, and spinal cord were 6.6 (± 0.05) cGy, 6.9 (± 1.2) cGy, and 4.7 (± 0.8) cGy, respectively. For the pelvic region, the average mean dose to the femoral heads was 6.4 (± 1.1) cGy. The MV-CBCT doses were linearly associated with the total MU but weakly dependent on patients' BMIs. Daily MV-CBCT has a cumulative effect on the total body dose and critical organs, which should be carefully considered for clinical impacts.

Long-term outcomes of Gamma Knife radiosurgery in patients with vestibular schwannomas.

OBJECT: The authors sought to determine the long-term tumor control and side effects of Gamma Knife radiosurgery (GKRS) in patients with vestibular schwannomas (VS). METHODS: One hundred seventeen patients with VS underwent GKRS between January 1997 and February 2003. At the time of analysis, at least 5 years had passed since GKRS in all patients. The mean patient age was 60.9 years. The mean maximal tumor diameter was 1.77 ± 0.71 cm. The mean tumor volume was 1.95 ± 2.42 ml. Eighty-two percent of lesions received 1300 cGy and 14% received 1200 cGy. The median dose homogeneity ratio was 1.97 and the median dose conformality ratio was 1.78. Follow-up included MR imaging or CT scanning approximately every 6-12 months. Rates of progression to surgery were calculated using the Kaplan-Meier method. RESULTS: Of the 117 patients in whom data were analyzed, 103 had follow-up MR or CT images and 14 patients were lost to follow-up. Fifty-three percent of patients had stable tumors and 37.9% had a radiographically documented response. Imaging-documented tumor progression was present in 8 patients (7.8%), but in 3 of these the lesion eventually stabilized. Only 5 patients required a neurosurgical intervention. The estimated 1-, 3-, and 5-year rates of progression to surgery were 1, 4.6, and 8.9%, respectively. One patient (1%) developed trigeminal neuropathy, 4 patients (5%) developed permanent facial neuropathy, 3 patients (4%) reported vertigo, and 7 patients (18%) had new gait imbalance following GKRS. CONCLUSIONS: Gamma Knife radiosurgery results in excellent local control rates with minimal toxicity for patients with VS. The authors recommend standardized follow-up to gain a better understanding of the long-term effects of GKRS.

Five year biochemical recurrence free survival for intermediate risk prostate cancer after radical prostatectomy, external beam radiation therapy or permanent seed implantation.

OBJECTIVE: To compare biochemical recurrence-free survival (bRFS) for patients with intermediate-risk prostate cancer treated by retropubic radical prostatectomy (RRP), laparoscopic radical prostatectomy (LRP), external beam radiation therapy (RT), or permanent seed implantation (PI). METHODS: Patients treated for intermediate-risk prostate cancer per National Comprehensive Cancer Network guidelines from 1996 to 2005 were studied. Variables potentially affecting bRFS were examined using univariate and multivariate Cox regression analysis. Five-year bRFS rates were calculated by actuarial methods; bRFS was calculated using Kaplan-Meier analysis. Nadir +2 definition of biochemical failure was used for RT and PI patients; a PSA ≥ 0.4 ng/mL was used for radical prostatectomy (RP) patients. Time to initiation of salvage therapy was compared for each treatment group using the Kruskal-Wallis test. RESULTS: Nine-hundred seventy-nine patients were analyzed with a median follow-up of 65 months. Five years bRFS rate was 82.8% for all patients (89.5% PI, 85.7% RT, 79.9% RRP, and 60.2% LRP). Patients treated by LRP had significantly worse bRFS than RT (P < .0001), PI (P < .0001), or RRP patients (P = .0038). Treatment modality (P < .0001) and average number of PSA tests per year (P < .0001) were the only independent predictors of bRFS on multivariate analysis. Median time to initiation of salvage therapy from time of treatment was 28.6 months for all patients (26.1 RP, 21.0 LRP, 47.4 PI, 47.8 RT; P < .0001). CONCLUSIONS: Patients with intermediate-risk prostate cancer choosing PI, RT, or RRP appear to have improved 5-year bRFS and delayed salvage therapy compared with LRP.

Involvement of phosphatidylinositol-3-kinase in membrane ruffling induced by P-glycoprotein substrates in multidrug-resistant carcinoma cells.

P-glycoprotein (P-gp) is a transmembrane protein that transports a variety of structurally and functionally diverse drugs. We recently found that the interaction of drugs with P-gp promoted invasion and metastasis. In this study, we sought to determine the mechanism by which the interaction of P-gp with its substrates leads to the earliest membrane changes associated with cellular invasion, i.e., membrane ruffling. We focused on the activation of phosphatidylinositol-3-kinase (PI-3-kinase), a lipid kinase that regulates actin cytoskeletal organization and cell movement. Sensitive or multidrug-resistant (MDR) MCF-7 (human breast cancer) or KB (human oral carcinoma) cells were treated with drugs or vehicle, and then were stained with phalloidin-tetramethyl-rhodamine isothiocyanate. Membrane ruffles were visualized using a fluorescence microscope. PI-3-kinase activity was determined by an in vitro immune-complex kinase assay and thin-layer chromatography. Drugs transported by P-gp, vinblastine and trans-flupenthixol, increased membrane ruffling and PI-3-kinase activity in the MDR cell lines, MCF-7/AdrR and KBV-1, which overexpress P-gp. This effect was not seen with mechlorethamine, a drug that is not transported by P-gp, and was not detected in sensitive parental cell lines that do not express P-gp. A similar effect was also observed in the MDR1 transfectant, MCF-7/BC-19. Wortmannin, an inhibitor of PI-3-kinase, blocked the effect of VBL and tFPT on membrane ruffling and the activity of PI-3-kinase in MDR cells. These results indicate that drugs transported by P-gp induce membrane ruffling, an early indicator of cellular motility and metastatic potential, in cancer cells overexpressing P-gp and that this effect may be mediated through activation of PI-3-kinase.