Multi-institutional Development and Validation of Contouring Guidelines for Para-aortic Elective Nodal Irradiation in Prostate Cancer Based on Patterns of Involvement on Targeted Molecular Imaging Positron Emission Tomography/Computed Tomography.

PURPOSE: Molecular imaging better identifies anatomic regions of metastatic spread of prostate cancer compared with conventional imaging, resulting in para-aortic (PA) nodal metastases being increasingly identified. Consequently, some radiation oncologists electively treat the PA lymph node region in patients with gross or high risk of PA nodal involvement. The anatomic locations of at-risk PA lymph nodes for prostate cancer are unknown. Our objective was to use molecular imaging to develop guidelines for the optimal delineation of the PA clinical target volume (CTV) in patients with prostate cancer. METHODS AND MATERIALS: We conducted a multi-institutional retrospective cohort study of patients with prostate cancer undergoing 18F-fluciclovine or 18F-DCFPyL prostate-specific membrane antigen positron emission tomography (PET)/computed tomography (CT). Images of patients with PET-positive PA nodes were imported into the treatment planning system, avid nodes were contoured, and measurements were taken in relation to anatomic landmarks. A contouring guideline that encompassed the location of ≥95% of PET-positive PA nodes was created using descriptive statistics and then validated in an independent data set. RESULTS: Five hundred fifty-nine patients had molecular PET/CT imaging in the development data set (78% 18F-fluciclovine, 22% prostate-specific membrane antigen). Seventy-six patients (14%) had evidence of PA nodal metastasis. We determined that expanding the CTV to 1.8 cm left of the aorta, 1.4 cm right of the inferior vena cava (IVC), 7 mm posterior to the aorta/IVC or to the vertebral body, and superiorly to the T11/T12 vertebral interface, with the anterior border 4 mm anterior to the aorta/IVC and inferior border at the bifurcation of the aorta/IVC, resulted in coverage of ≥95% of PET-positive PA nodes. When the guideline was used in the independent validation data set (246 patients with molecular PET/CT imaging, of whom 31 had PA nodal metastasis), 97% of nodes were encompassed, thereby validating our guideline. CONCLUSIONS: We used molecular PET/CT imaging to determine the anatomic locations of PA metastases to develop contouring guidelines for creating a prostate cancer PA CTV. Although the optimal patient selection and clinical benefits of PA radiation therapy remain uncertain, our results will aid in delineating the optimal target when PA radiation therapy is pursued.

Low-kilovoltage, single-dose intraoperative radiation therapy for breast cancer: results and impact on a multidisciplinary breast cancer program.

BACKGROUND: The Intrabeam (Carl Zeiss) brachytherapy device (IB) is an electronic brachytherapy device that can be used to deliver low energy x-rays (50 kV) to a lumpectomy cavity at the time of lumpectomy for breast cancer. Reported experience with IB for breast cancer in the United States has been extremely limited. Here we describe our experience and analyze the impact of IB on our multidisciplinary breast cancer program. STUDY DESIGN: This is a retrospective review of a prospectively collected breast cancer database. Patient characteristics, treatment characteristics, recurrence, and cosmesis were analyzed. Cost data were also analyzed to determine the impact of IB on the breast cancer program. RESULTS: Seventy-eight patients underwent 80 IB treatments in this series between November 2010 and October 2012. Most patients had invasive ductal carcinoma. Mean total operative time for patients receiving lumpectomy, sentinel node biopsy, and IB was 132 minutes (range 79 to 243 minutes). Intrabeam brachytherapy was the only adjuvant radiation required in 81% of patients, and only 15% of patients required additional operation after the index lumpectomy procedure. At 12 months of follow-up, cosmesis was good to excellent in 92% of patients. There have been no local recurrences in patients treated in this series. Intrabeam brachytherapy is associated with considerably lower costs ($1,857) than conventional whole breast radiation therapy ($9,653). CONCLUSIONS: Implementation of IB impacts treatment planning and operating room use in a multidisciplinary breast cancer program. The safety profile, ease of administration, and reduced costs of IB favor its more widespread use in selected patients with early-stage breast cancer.

Severe dry eye syndrome after radiotherapy for head-and-neck tumors.

PURPOSE: To investigate the incidence of severe dry eye syndrome (DES) after external beam radiotherapy for head-and-neck cancer and its dependence on the parameters relevant to external beam radiotherapy. METHODS AND MATERIALS: The present retrospective study included 78 patients treated for primary extracranial head-and-neck tumors between 1965 and 2000, whose lacrimal apparatus/entire globe was exposed to fractionated external beam radiotherapy. The dose received by the major lacrimal gland was used for analysis. The end point of the present study was the ophthalmologic diagnosis of severe DES leading to vision compromise. RESULTS: Of the 78 patients, 40 developed severe DES leading to visual compromise. The incidence of DES increased steadily from 6% at 35-39.99 Gy to 50% at 45-49.99 Gy and 90% at 60-64.99 Gy. With a mean of 0.9 years (range, 1 month to 3 years), the latency of DES was observed to be a function of the total dose and the dose per fraction. On univariate and multivariate analysis, the total dose (p < .0001 and p < .0001, respectively) and dose per fraction (p ≤ .0001 and p = .0044, respectively) were significant. However, age, gender, and the use of chemoradiotherapy were not. The actuarial analysis indicated a 5-year probability of freedom from DES of 93% for doses <45 Gy, 29% for 45-59.9 Gy, and 3% doses ≥60 Gy. A logistic normal tissue complication probability model fit to our data obtained a dose of 34 and 38 Gy corresponding to a 5% and 10% incidence of DES. CONCLUSION: With a dose of 34 Gy corresponding to a 5% incidence of DES, the risk of severe DES increased, and the latency decreased with an increase in the total dose and dose per fraction to the lacrimal gland. The effect of chemoradiotherapy and hyperfractionation on the risk of DES needs additional investigation.

A comparison of dose-response characteristics of four NTCP models using outcomes of radiation-induced optic neuropathy and retinopathy.

BACKGROUND: Biological models are used to relate the outcome of radiation therapy to dose distribution. As use of biological models in treatment planning expands, uncertainties associated with the use of specific models for predicting outcomes should be understood and quantified. In particular, the question to what extent model predictions are data-driven or dependent on the choice of the model has to be explored. METHODS: Four dose-response models--logistic, log-logistic, Poisson-based and probit--were tested for their ability and consistency in describing dose-response data for radiation-induced optic neuropathy (RION) and retinopathy (RIRP). Dose to the optic nerves was specified as the minimum dose, Dmin, received by any segment of the organ to which the damage was diagnosed by ophthalmologic evaluation. For retinopathy, the dose to the retina was specified as the highest isodose covering at least 1/3 of the retinal surface (D33%) that geometrically covered the observed retinal damage. Data on both complications were modeled separately for patients treated once daily and twice daily. Model parameters D50 and γ and corresponding confidence intervals were obtained using maximum-likelihood method. RESULTS: Model parameters were reasonably consistent for RION data for patients treated once daily, D50 ranging from 94.2 to 104.7 Gy and γ from 0.88 to 1.41. Similar consistency was seen for RIRP data which span a broad range of complication incidence, with D50 from 72.2 to 75.0 Gy and γ from 1.51 to 2.16 for patients treated twice daily; 72.2-74.0 Gy and 0.84-1.20 for patients treated once daily. However, large variations were observed for RION in patients treated twice daily, D50 from 96.3 to 125.2 Gy and γ from 0.80 to 1.56. Complication incidence in this dataset in any dose group did not exceed 20%. CONCLUSIONS: For the considered data sets, the log-logistic model tends to lead to larger D50 and lower γ compared to other models for all datasets. Statements regarding normal tissue radiosensitivity and steepness of dose-response, based on model parameters, should be made with caution as the latter are not only model-dependent but also sensitive to the range of complication incidence exhibited by clinical data.

Estimating normal tissue toxicity in radiosurgery of the CNS: application and limitations of QUANTEC.

Minimizing radiation-induced normal tissue damage in the central nervous system (CNS) is a key objective and primary impetus for stereotactic radiosurgery and radiotherapy. The recently published Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) study provides updated dose/volume/ outcome data on normal tissue tolerance for sixteen anatomic sites, including the CNS. Most of the data used to develop the relationship between dose, volume and normal tissue toxicity derived from large field, conventionally fractionated regimens, and quantitative dose/volume/outcome data at high doses per fraction to limited volumes is much sparser. Nonetheless, QUANTEC provides some limited recommendations for dose constraints in stereotactic radiosurgery/ radiotherapy of the CNS. This paper critically reviews the findings, recommendations and limitations of QUANTEC as they apply to radiosurgery of the CNS, as well as presenting suggestions to establish and validate clinically meaningful dose/volume/toxicity relationships in this setting.

Radiation therapy and hearing loss.

A review of literature on the development of sensorineural hearing loss after high-dose radiation therapy for head-and-neck tumors and stereotactic radiosurgery or fractionated stereotactic radiotherapy for the treatment of vestibular schwannoma is presented. Because of the small volume of the cochlea a dose-volume analysis is not feasible. Instead, the current literature on the effect of the mean dose received by the cochlea and other treatment- and patient-related factors on outcome are evaluated. Based on the data, a specific threshold dose to cochlea for sensorineural hearing loss cannot be determined; therefore, dose-prescription limits are suggested. A standard for evaluating radiation therapy-associated ototoxicity as well as a detailed approach for scoring toxicity is presented.

Radiation effects on the auditory and vestibular systems.

Definitive or postoperative radiation therapy (RT) is commonly used for the management of intracranial and extracranial head and neck tumors. Because of the variability of tumor location and dimensions, sparing of nontarget normal tissue and organs may not be possible. Treatment modalities that deliver the highest doses of radiation to the auditory system include stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) for the treatment of vestibular schwannomas (VS), and fractionated radiotherapy (FRT) or intensity-modulated radiation therapy (IMRT) for the treatment of head and neck malignancies. Radiation therapy for VS is unique because of its involvement of the inner ear and preexisting auditory and vestibular dysfunction. Auditory and vestibular dysfunction following RT for VS may be limited by limiting the total dose of cranial nerve VIII irradiation and by fractionation.

Hypopituitarism after radiotherapy for extracranial head and neck cancers in pediatric patients.

OBJECTIVES: To investigate the incidence of postradiation therapy (postRT) hypopituitarism (hp-pit) in pediatric patients treated for extracranial head and neck tumors. METHODS: We retrospectively reviewed 30 pediatric patients treated with RT for extracranial head and neck tumors between 1970 and 2000. RT doses to the hypothalamic-pituitary axis were estimated by re-evaluating the treatment plans. RESULTS: Clinical hp-pit was observed in 16 (53.3%) patients; the median detection latency was 3.3 years and the median dose to the pituitary was 40.7 Gy. Univariate analysis of clinical hp-pit revealed that the total dose to the pituitary was significant (P = 0.034) as was the patient's age at the time of RT (P = 0.018) showing higher susceptibility and more damage in younger patients. Though fractionation (P = 0.018) and adjuvant chemotherapy (P = 0.016) were significant in univariate analysis, the total dose received by patients in these 2 groups was higher than the median dose for all patients. A limited multivariate analysis with 3 variables indicated that the total dose to the pituitary was significant, but chemoradiation and fractionation were not. The 5- and 10-year rates of freedom from clinical hp-pit were 42% and 37%, respectively. CONCLUSIONS: Clinical manifestations of late radiation toxicity to the hypothalamic-pituitary axis were observed among the pediatric patients with hormone deficiencies. The development of hp-pit depends on the total dose received by the hypothalamic-pituitary axis and the age of the patient. Dependence on chemoradiation and fractionation were inconclusive. Relatively long latency before clinical manifestations indicates that periodic testing after RT in pediatric patients is necessary for early detection and management of hormonal deficiencies.

Hypopituitarism after radiotherapy for extracranial head and neck cancers.

BACKGROUND: The purpose of this study was to investigate the incidence of radiotherapy-induced primary and secondary hypopituitarism. METHODS: Three hundred twelve patients treated with radiotherapy for extracranial head and neck tumors between 1964 and 2000 were evaluated. Radiotherapy doses to the hypothalamus and pituitary were estimated by reconstructing treatment plans. RESULTS: Clinical hypopituitarism was observed in 44 (14.1%) patients after a median interval of 5.6 years. Hypothalamic dysfunction was reported in 14 patients after a median interval of 4.4 years. Neither fractionation nor adjuvant chemotherapy significantly impacted clinical hypopituitarism on multivariate analysis, but total dose to the pituitary was significant (p = .0228). Twenty-three of 68 (33.8%) patients tested for hypopituitarism demonstrated subclinical hypopituitarism. The 5- and 10-year rates of freedom from clinical hypopituitarism were 93% and 72%. The 5- and 10-year rates of freedom from subclinical hypopituitarism were 85% and 65%. CONCLUSION: Clinical and subclinical manifestations of late radiation toxicity were observed in the hypothalamic-pituitary axis.

A dose comparison study between XVI and OBI CBCT systems.

The purpose of this study is to establish a comprehensive set of dose measurements data obtained from the X-ray Volumetric Imager (XVI, Elekta Oncology Systems) and the On-Board Imager (OBI, Varian Medical Systems) cone-beam CT (CBCT) systems. To this end, two uniform-density cylindrical acrylic phantoms with diameters of 18 cm (head phantom) and 30 cm (body phantom) were used for all measurements. Both phantoms included ion chamber placement holes in the center and at periphery (2 cm below surface). For the XVI unit, the four standard manufacturer-supplied protocols were measured. For the OBI unit, the full bow tie and half bow tie (and no bow tie) filters were used in combination with the two scanning modes; namely, full-fan and half-fan. The total milliampere x seconds (mA s) setting was also varied for each protocol to establish the linear relationship between the dose deposited and the mA s used (with all other factors being held constant). Half-value layers in aluminum (Al) were also measured for beam characteristic determination. For the XVI unit, the average dose ranged from 0.1 to 3.5 cGy with the highest dose measured using the "prostate" protocol with the body phantom. For the OBI unit, the average dose ranged from 1.1 to 8.3 cGy with the highest dose measured using the full-fan protocol with the head phantom. The measured doses were highly linear as a function of mA s, for both units, where the measurement points followed a linear relationship very closely with R2 > 0.99 for all cases. Half-value layers were between 4.6- and 7.0-mm-Al for the two CBCT units where XVI generally had more penetrating beams at the similar kVp settings. In conclusion, a comprehensive series of dose measurements were performed on the XVI and the OBI CBCT units. In the process, many of the important similarities and differences between the two systems were observed and summarized in this work.

Primary and central hypothyroidism after radiotherapy for head-and-neck tumors.

PURPOSE: To investigate the incidence of radiotherapy (RT)-induced central and primary hypothyroidism regarding total dose, fractionation, and adjuvant chemotherapy. METHODS AND MATERIALS: We retrospectively reviewed the data from 312 patients treated with RT for extracranial head-and-neck tumors between 1964 and 2000. The cervical lymph nodes were irradiated in 197 patients. The radiation doses to the thyroid gland and hypothalamic-pituitary axis were estimated by reconstructing the treatment plans. RESULTS: Clinical central hypothyroidism (CH) was observed in 17 patients (5.4%); the median clinical latency was 4.8 years. Clinical primary hypothyroidism (PH) was observed in 40 patients (20.3%); the median clinical latency was 3.1 years. Multivariate analysis of clinical CH revealed that fractionation, adjuvant chemotherapy, and total dose to the pituitary were not significant. Multivariate analysis of clinical PH revealed that the total dose to the thyroid (p = 0.043) was significant, but adjuvant chemotherapy, age, and gender were not. Of the patients tested for hypopituitarism, 14 (20.3%) of 69 demonstrated subclinical CH and 17 (27.4%) of 62 demonstrated subclinical PH. The 5-year and 10-year rates of freedom from clinical CH and PH were 97% and 87% and 68% and 67%, respectively. Of the patients tested, the 5-year and 10-year rates of freedom from subclinical CH and PH were 91% and 78% and 71% and 71%, respectively. CONCLUSION: Clinical and subclinical manifestations of late radiation toxicity were observed in the thyroid and hypothalamic-pituitary axis. Although CH did not indicate a dependence on fractionation, adjuvant chemotherapy, or total dose to the pituitary, PH showed a dependence on the total dose to the thyroid gland.

Ototoxicity after radiotherapy for head and neck tumors.

PURPOSE: To investigate the incidence of radiation-induced ototoxicity according to the total dose delivered to specific parts of the auditory system, fractionation, and chemotherapy. METHODS AND MATERIALS: Records of 325 patients treated for primary extracranial head and neck tumors with curative intent who received radiotherapy between 1964 and 2000 (median follow-up, 5.4 years) were retrospectively reviewed. Reconstructions of the treatment plans were generated to estimate the doses received by components of the auditory system. RESULTS: Radiotherapy-induced morbidity developed in 41.8% of patients (external ear, 33.2%; middle ear, 28.6%; and inner ear, 26.8%). Univariate/multivariate analyses indicate that total dose received by parts of the auditory system seem to be significant, though fractionation and chemoradiation may contribute to the incidence of ototoxicities. Sensorineural hearing loss (SNHL) was observed in 49 patients (15.1%). Univariate and multivariate analyses indicated that age (p = 0.0177 and p = 0.005) and dose to cochlea (p < 0.0001 and p < 0.0001) were significant, and chemoradiation (p = 0.0281 and p = 0.006) may increase the incidence of SNHL. Five-year and 10-year actuarial risk of clinically overt SNHL increased to 37% (p > 0.0001) above doses of 60.5 Gy compared to 3% at doses below 60.5 Gy. For patients treated with adjuvant chemotherapy, clinically overt SNHL increased to 30% compared to 18% in the no-chemotherapy group at 10 years (p = 0.0281). CONCLUSION: Radiotherapy toxicity was observed in all parts of the auditory system with median doses for incidence varying between 60 Gy to 66 Gy. Total dose to organ seems to be a significant factor though fractionation and chemo-radiation may contribute to ototoxicities.

Does altered fractionation influence the risk of radiation-induced optic neuropathy?

PURPOSE: To analyze the parameters that influence the risk of radiation-induced optic neuropathy (RION) after radiotherapy for head-and-neck tumors. METHODS AND MATERIALS: Between 1964 and 2000, 273 patients with tumors of the nasopharynx, paranasal sinuses, nasal cavity, and hard palate adenoid cystic carcinomas were treated with curative intent and had radiation fields that included the optic nerves and/or chiasm. Patients were followed for at least 1 year after radiotherapy. RESULTS: Radiation-induced optic neuropathy developed in 32 eyes of 24 patients (9%). The 5-year rates of freedom from RION according to the total dose and once- vs. twice-daily fractionation were as follows: < or =63 Gy once daily, 95%; < or =63 Gy twice daily, 98%; >63 Gy once daily, 78%; and >63 Gy twice daily, 91%. Multivariate analysis revealed that the total dose affected the risk of RION (p = 0.0047), with patient age (p = 0.0909), once-daily vs. twice-daily fractionation (p = 0.0684), and overall treatment time (p = 0.0972) were marginally significant. The use of adjuvant chemotherapy did not significantly influence the likelihood of developing RION. CONCLUSION: The likelihood of developing RION is primarily influenced by the total dose. Hyperfractionation may reduce the risk of experiencing this complication.

Preventing radiation retinopathy with hyperfractionation.

PURPOSE: The purpose of this study was to determine factors associated with the development of radiation retinopathy in a large series of patients with head-and-neck cancer. In particular, we addressed whether the use of hyperfractionated radiation therapy was effective in reducing the risk of retinopathy. METHODS AND MATERIALS: One hundred eighty-six patients received a significant dose to the retina as part of curative radiotherapy. Primary sites included: nasopharynx, 46; paranasal sinus, 64; nasal cavity, 69; and palate, 7. Prescription doses varied depending on primary site and histology. Hyperfractionated (twice-daily) radiation was delivered to 42% of the patients in this study, typically at 1.10 to 1.20 Gy per fraction. The remainder were treated once-daily. Retinal doses were determined from computerized dosimetry plans when available. For all other patients, retinal doses were retrospectively calculated using reconstructed off-axis dosimetry taken from contours through the center of the globes. Retinal dose was defined as the minimum dose received by at least 25% of the globe. The median retinal dose was 56.85 Gy. Patients were followed for a median of 7.6 years. RESULTS: Thirty-one eyes in 30 patients developed radiation retinopathy, resulting in monocular blindness in 25, bilateral blindness in 1, and decreased visual acuity in 4. The median time to the diagnosis of retinopathy was 2.6 years (range, 11 months to 5.3 years). The actuarial incidence of developing radiation retinopathy was 20% at both 5 and 10 years. The incidence of developing ipsilateral blindness due to retinopathy was 16% at 5 years and 17% at 10 years. Site-specific incidences varied considerably, with ethmoid sinus (9 of 25, 36%), nasal cavity (13 of 69, 19%), and maxillary sinus (6 of 35, 17%) being the most common sites associated with radiation retinopathy. Three of 72 patients (4%) receiving retinal doses less than 50 Gy developed retinopathy. Higher retinal doses resulted in a steady increase in the incidence of retinopathy, with 25 of the 30 cases occurring after 60 Gy or more. Of the patients receiving more than 50 Gy to the retina, hyperfractionation was associated with a significantly lower incidence of radiation retinopathy (37% vs. 13%; p = 0.0037). On multivariate analysis, retinal dose (p < 0.0001), fractionation schedule (p = 0.0003), age (p = 0.0365), and prolonged overall treatment time (p = 0.0213) were significant predictors of radiation retinopathy. CONCLUSION: The incidence of ipsilateral radiation retinopathy after treatment of nasal cavity/paranasal tumors is 20% at 5 and 10 years. Retinal dose and fractionation schedule are the strongest predictors of retinopathy. Hyperfractionated radiotherapy is associated with a significant reduction in the incidence of radiation retinopathy, especially when the retina receives more than 50 Gy.