Systemic and tumor-directed therapy for oligometastatic prostate cancer: study protocol for a phase II trial for veterans with de novo oligometastatic disease.

BACKGROUND: The treatment paradigm for metastatic hormone-sensitive prostate cancer (mHSPC) patients is evolving. PET/CT now offers improved sensitivity and accuracy in staging. Recent randomized trial data supports escalated hormone therapy, local primary tumor therapy, and metastasis-directed therapy. The impact of combining such therapies into a multimodal approach is unknown. This Phase II single-arm clinical trial sponsored and funded by Veterans Affairs combines local, metastasis-directed, and systemic therapies to durably render patients free of detectable disease off active therapy. METHODS: Patients with newly-diagnosed M1a/b prostate cancer (PSMA PET/CT staging is permitted) and 1-5 radiographically visible metastases (excluding pelvic lymph nodes) are undergoing local treatment with radical prostatectomy, limited duration systemic therapy for a total of six months (leuprolide, abiraterone acetate with prednisone, and apalutamide), metastasis-directed stereotactic body radiotherapy (SBRT), and post-operative fractionated radiotherapy if pT ≥ 3a, N1, or positive margins are present. The primary endpoint is the percent of patients achieving a serum PSA of < 0.05 ng/mL six months after recovery of serum testosterone ≥150 ng/dL. Secondary endpoints include time to biochemical progression, time to radiographic progression, time to initiation of alternative antineoplastic therapy, prostate cancer specific survival, health related quality-of-life, safety and tolerability. DISCUSSION: To our knowledge, this is the first trial that tests a comprehensive systemic and tumor directed therapeutic strategy for patients with newly diagnosed oligometastatic prostate cancer. This trial, and others like it, represent the critical first step towards curative intent therapy for a patient population where palliation has been the norm. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03298087 (registration date: September 29, 2017).

Dosimetric and radiobiological comparison of Cyberknife and Tomotherapy in stereotactic body radiotherapy for localized prostate cancer.

BACKGROUND AND PURPOSE: As recent studies have suggested relatively low α/ß for prostate cancer, the interest in hypofractionated stereotactic body radiotherapy (SBRT) for prostate cancer is rising. The aim of this study is to compare dosimetric results of Cyberknife (CK) with Tomotherapy (HT) in SBRT for localized prostate cancer. Furthermore, the radiobiologic consequences of heterogeneous dose distribution are also analyzed. MATERIAL AND METHOD: A total of 12 cases of localized prostate cancer previously treated with SBRT were collected. Treatments had been planned and delivered using CK. Then HT plans were generated for comparison afterwards. The prescribed dose was 37.5Gy in 5 fractions. Dosimetric indices for target volumes and organs at risk (OAR) were compared. For radiobiological evaluation, generalized equivalent uniform dose (gEUD) and normal tissue complication probability (NTCP) were calculated and compared. RESULT: Both CK and HT achieved target coverage while meeting OAR constraints adequately. HT plans resulted in better dose homogeneity (Homogeneity index: 1.04±0.01 vs. 1.21±0.01; p = 0.0022), target coverage (97.74±0.86% vs. 96.56±1.17%; p = 0.0076) and conformity (new vonformity index: 1.16±0.05 vs. 1.21±0.04; p = 0.0096). HT was shown to predict lower late rectal toxicity as compared to CK. Integral dose to body was also significantly lower in HT plans (46.59±6.44 Gy'L vs 57.05±11.68 Gy'L; p = 0.0029). CONCLUSION: Based on physical dosimetry and radiobiologic considerations, HT may have advantages over CK, specifically in rectal sparing which could translate into clinical benefit of decreased late toxicities.

Stereotactic radiation therapy for progressive residual pilocytic astrocytomas.

This report shows the results of stereotactic radiation therapy for progressive residual pilocytic astrocytomas. Medical records of patients who had undergone stereotactic radiation therapy for a progressive residual pilocytic astrocytoma were reviewed. Between 1995 and 2010, 12 patients with progression of a residual pilocytic astrocytoma underwent stereotactic radiation therapy at UCLA. Presentation was headache (4), visual defects (3), hormonal disturbances (2), gelastic seizures (2) and ataxia (1). MRI showed a cystic (9), mixed solid/cystic (2) or solid tumor (1); located in the hypothalamus (5), midbrain (3), thalamus (2), optic chiasm (1) or deep cerebellum (1). Median age was 21 years (range 5-41). Nine tumors received stereotactic radiotherapy (SRT). Three tumors received stereotactic radiosurgery (SRS), two of them to their choline positive regions. SRT median total dose was 50.4 Gy (40-50.4 Gy) in a median of 28 fractions (20-28), using a median fraction dose of 1.8 Gy (1.8-2 Gy) to a median target volume of 6.5 cm(3). (2.4-33.57 cm(3)) SRS median dose was 18.75 Gy (16.66-20 Gy) to a median target volume of 1.69 cm(3) (0.74-2.22 cm(3)). Median follow-up time was 37.5 months. Actuarial long-term progression-free and disease-specific survival probabilities were 73.3 and 91.7 %, respectively. No radiation-induced complications were observed. Stereotactic radiation therapy is a safe and effective modality to control progressive residual pilocytic astrocytomas. Better outcomes are obtained with SRT to entire tumor volumes than with SRS targeting choline positive tumor regions.

Comparison of treatment results between surgery alone, preoperative short-course radiotherapy, or long-course concurrent chemoradiotherapy in locally advanced rectal cancer.

BACKGROUND: The aim of this study is to compare the results between surgery alone, preoperative radiotherapy (RT), or preoperative concurrent chemoradiotherapy (CCRT) followed by surgery in the treatment of locally advanced rectal cancer in Asian patients. METHODS: This study included 151 consecutive patients with clinical T3, T4 or node-positive rectal cancer from Jan. 2005 to Dec. 2007. Eighty-six patients underwent total mesorectal excision (TME) alone, 28 patients received preoperative RT (25 Gy in 5 fractions) followed by TME in 1 week, and 37 patients received preoperative CCRT (50.4 Gy in 28 fractions) followed by TME in 4-6 weeks. RESULTS: The 3-year loco-regional recurrence (LRR), distant metastasis, overall and disease-free survival rates are comparable among Surgery, RT and CCRT groups. By multivariate analysis, pT4, distal margin <2 cm, the ratio of positive lymph nodes to totally dissected lymph nodes ≥ 0.2, and non-R0 resection were significant factors for LRR. In subgroup analysis, TME alone produced comparable LRR to RT or CCRT (3.3 vs.. 4.8%) for favorable patients (0-1 risk factors). For unfavorable patients (2 or more risk factors), the LRR rose to 37% in patients receiving surgery alone as compared with 15% in the RT or CCRT patients. CONCLUSIONS: Preoperative RT or CCRT followed by TME produced good local control in favorable and unfavorable patients with locally advanced rectal cancer. If preoperative RT or CCRT is not given, TME alone has a high incidence of local recurrence in unfavorable patients with 2 or more risk factors.

Consensus Statement Supporting the Presence of Onsite Radiation Oncology Departments at VHA Medical Centers.

Background: Although multiple studies demonstrate that radiotherapy is underused worldwide, the impact that onsite radiation oncology at medical centers has on the use of radiotherapy is poorly studied. The Veterans Health Administration (VHA) Palliative Radiotherapy Taskforce has evaluated the impact of onsite radiation therapy on the use of palliative radiation and has made recommendations based on these findings. Observations: Radiation consults and treatment occur in a more timely manner at VHA centers with onsite radiation therapy compared with VHA centers without onsite radiation oncology. Referring practitioners with onsite radiation oncology less frequently report difficulty contacting a radiation oncologist (0% vs 20%, respectively; P = .006) and patient travel (28% vs 71%, respectively; P < .001) as barriers to referral for palliative radiotherapy. Facilities with onsite radiation oncology are more likely to have multidisciplinary tumor boards (31% vs 3%, respectively; P = .11) and are more likely to be influenced by radiation oncology recommendations at tumor boards (69% vs 44%, respectively; P = .02). Conclusions: The VHA Palliative Radiotherapy Taskforce recommends the optimization of the use of radiotherapy within the VHA. Radiation oncology services should be maintained where present in the VHA, with consideration for expansion of services to additional facilities. Telehealth should be used to expedite consults and treatment. Hypofractionation should be used, when appropriate, to ease travel burden. Options for transportation services and onsite housing or hospitalization should be understood by treating physicians and offered to patients to mitigate barriers related to travel.

The Clinical Cell-Cycle Risk (CCR) Score Is Associated With Metastasis After Radiation Therapy and Provides Guidance on When to Forgo Combined Androgen Deprivation Therapy With Dose-Escalated Radiation.

PURPOSE: The clinical cell-cycle risk (CCR) score, which combines the University of California, San Francisco's Cancer of the Prostate Risk Assessment (CAPRA) and the cell cycle progression (CCP) molecular score, has been validated to be prognostic of disease progression for men with prostate cancer. This study evaluated the ability of the CCR score to prognosticate the risk of metastasis in men receiving dose-escalated radiation therapy (RT) with or without androgen deprivation therapy (ADT). METHODS AND MATERIALS: This retrospective, multi-institutional cohort study included men with localized National Comprehensive Cancer Network (NCCN) intermediate-, high-, and very high-risk prostate cancer (N = 741). Patients were treated with dose-escalated RT with or without ADT. The primary outcome was time to metastasis. RESULTS: The CCR score prognosticated metastasis with a hazard ratio (HR) per unit score of 2.22 (95% confidence interval [CI], 1.71-2.89; P < .001). The CCR score better prognosticated metastasis than NCCN risk group (CCR, P < .001; NCCN, P = .46), CAPRA score (CCR, P = .002; CAPRA, P = .59), or CCP score (CCR, P < .001; CCP, P = .59) alone. In bivariable analyses, CCR score remained highly prognostic when accounting for ADT versus no ADT (HR, 2.18; 95% CI, 1.61-2.96; P < .001), ADT duration as a continuous variable (HR, 2.11; 95% CI, 1.59-2.79; P < .001), or ADT given at or below the recommended duration for each NCCN risk group (HR, 2.19; 95% CI, 1.69-2.86; P < .001). Men with CCR scores below or above the multimodality threshold (CCR score, 2.112) had a 10-year risk of metastasis of 3.7% and 21.24%, respectively. Men with below-threshold scores receiving RT alone had a 10-year risk of metastasis of 3.7%, and for men receiving RT plus ADT, the 10-year risk of metastasis was also 3.7%. CONCLUSIONS: The CCR score accurately and precisely prognosticates metastasis and adds clinically actionable information relative to guideline-recommended therapies based on NCCN risk in men undergoing dose-escalated RT with or without ADT. For men with scores below the multimodality threshold, adding ADT may not significantly reduce their 10-year risk of metastasis.

Does hormone therapy exacerbate the adverse effects of radiotherapy in men with prostate cancer? A quality of life study.

PURPOSE: We examined whether short course androgen deprivation therapy as an adjunct to radiotherapy would impact health related quality of life outcomes in patients with localized prostate cancer treated definitively with external beam radiation therapy or permanent brachytherapy. MATERIALS AND METHODS: From 1999 to 2003 patients were enrolled in a prospective study at our institution and completed validated health related quality of life surveys at defined pretreatment and posttreatment intervals. A total of 81 men received radiotherapy alone and 67 received radiotherapy plus androgen deprivation therapy. Median androgen deprivation therapy duration was 4 months. Univariate and multivariate analysis was done to compare time to return to baseline in 6 distinct health related quality of life domains. RESULTS: On univariate analysis the radiotherapy plus androgen deprivation therapy group achieved baseline urinary symptoms more rapidly than the radiotherapy group (5 months, p = 0.002). On multivariate analysis time to return to baseline in any of the 6 health related quality of life domains was not significantly affected by adding androgen deprivation therapy. Factors associated with longer time to return to baseline mental composite scores on multivariate analysis included nonwhite ethnicity, cerebrovascular disease history and alcohol abuse history. Men treated with permanent brachytherapy monotherapy experienced longer time to return to baseline for urinary function and symptoms. Baseline sexual function and lack of a partner were associated with longer time to sexual recovery. CONCLUSIONS: Adding androgen deprivation therapy to definitive radiotherapy does not significantly impact the time to return to baseline health related quality of life. These data may be valuable for patients and physicians when weighing the toxicity and benefits of androgen deprivation therapy when added to definitive radiotherapy.

Roles and types of radiation in breast cancer treatment: early breast cancer, locoregionally advanced, and metastatic disease.

PURPOSE OF REVIEW: To describe the current role of radiation therapy and specific types of radiation therapy used in the management of early stage, locoregionally advanced, and metastatic breast cancer. RECENT FINDINGS: The role of radiation therapy in the management of breast cancer has not changed in recent decades, however methods of treatment delivery have advanced considerably. Hypofractionation and accelerated partial breast irradiation, which substantially reduce radiation treatment duration, have emerged as appropriate alternatives to conventional whole breast radiation in select patient subsets, and intensity modulated radiation therapy, breathing-adapted radiation therapy, and prone-positioning technique address challenging anatomic issues and reduce treatment-associated toxicity. Stereotactic radiosurgery and stereotactic body radiation therapy continue to advance the management of distant metastatic disease. SUMMARY: Radiation therapy plays a significant role in the management of early stage, locoregionally advanced, and metastatic breast cancer. Technological advances are allowing for greater patient convenience and comfort in locoregional radiation therapy delivery and for expanded radiation therapy indications in the setting of metastatic disease.

Palliative Radiotherapy Within the Veterans Health Administration: Barriers to Referral and Timeliness of Treatment.

PURPOSE: Most Veterans Health Administration hospitals do not have radiation oncology (RO) departments on-site. The purpose of this study is to determine the impact of on-site RO on referral patterns and timeliness of palliative radiation therapy (PRT). MATERIALS AND METHODS: A survey was sent to medical directors at 149 Veterans Health Administration centers. Questions evaluated frequency of referral for PRT, timeliness of RO consults and treatment, and barriers to referral for PRT. Chi-square analysis was used to evaluate differences between centers that have on-site RO and centers that refer to outside facilities. RESULTS: Of 108 respondents, 33 (31%) have on-site RO. Chi-square analysis revealed that RO consult within 1 week is more likely at centers with on-site RO (68% v 31%; P = .01). Centers with on-site RO more frequently deliver PRT for spinal cord compression within 24 hours (94% v 70%; P = .01). Those without on-site RO were more likely to want increased radiation oncologist involvement (64% v 26%; P < .001). Barriers to referral for PRT included patient ability to travel (81%), patient noncompliance (31%), delays in consult and/or treatment (31%), difficulty contacting a radiation oncologist (14%), and concern regarding excessive number of treatments (13%). Respondents with on-site RO less frequently reported delays in consult and/or treatment (6% v 41%; P < .0001) and difficulty contacting a radiation oncologist (0% v 20%; P = .0056) as barriers. CONCLUSION: Respondents with on-site RO reported improved communication with radiation oncologists and more timely consultation and treatment initiation. Methods to improve timeliness of PRT for veterans at centers without on-site RO should be considered.

Medical Mask Wearing During Treatment for Patients Undergoing Radiotherapy in COVID-19 Pandemic - An Experience of Protocol Setup and Dosimetric Evaluation for Particle/Proton Beam Therapy.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has caused extreme challenges for the healthcare system. Medical masks have been proven to effectively block disease transmission. Radiotherapeutic departments are at unique risk for disease exposure with the repeated daily treatment schedule. A protocol of mask wearing during daily treatment was established, and the effect of wearing medical masks on dosimetry during proton beam therapy (PBT) was validated. METHODS: A department protocol of medical mask wearing was initiated after the COVID-19 pandemic. Medical masks that were made under standardized specification and regulation were obtained for analyses. The physical and dosimetric characteristics of these medical masks were measured by different proton energies using commercialized measurement tools. RESULTS: Patients and staff were able to adopt the protocol on a weekly basis, and no adverse events were reported. The average physical thickness of a single piece of medical mask was 0.5 mm with a water equivalent thickness (WET) of 0.1 mm. CONCLUSION: Our study revealed that mask wearing for patients undergoing daily radiotherapy is feasible and can provide basic protection for patients and staff. The impact of mask wearing on dosimetry was only 0.1 mm in WET, which has no impact on clinical PBT treatment. A medical mask-wearing policy can be applied safely without dosimetric concerns and should be considered as a standard practice for PBT centers during the COVID-19 pandemic.

Dosimetric comparison between RapidArc and HyperArc techniques in salvage stereotactic body radiation therapy for recurrent nasopharyngeal carcinoma.

BACKGROUND: To evaluate dosimetric differences of salvage irradiations using two commercially available volumetric modulated arc therapy (VMAT) stereotactic body radiation therapy (SBRT) techniques: RapidArc (RA) and HyperArc (HA), for recurrent nasopharyngeal carcinoma (NPC) after initial radiation therapy. METHODS: Ten patients with recurrent NPC status previously treated with radiation therapy were considered suitable candidates for salvage SBRT using VMAT approach. Two separate treatment plans were created with HA and RA techniques for each case, with dosimetric outcomes compared with respect to tumor target coverage and organs-at-risk (OARs) sparing. Furthermore, the cumulative radiobiological effects to the relevant OARs from the original radiotherapy to the respective salvage SBRT plans were analyzed in terms of biologically effective dose (BED). RESULTS: Treatment with HA exhibited similar target dose coverage as with RA, while delivering a higher mean dose to the targets. Using RA technique, the mean maximal doses to optic apparatus and the mean brain dose were reduced by 1 to 1.5 Gy, comparing to HA technique. The conformity index, gradient radius, and intermediate dose spillage in HA plans were significantly better than those in RA. With HA technique, the volume of brain receiving 12 Gy or more was reduced by 44%, comparing to RA technique. The cumulative BEDs to spinal cord and optic apparatus with RA technique were 1 to 2 Gy3 less than those with HA. HA technique significantly reduced the volume within body that received more than 100 Gy. CONCLUSIONS: With better dose distribution than RA while maintaining sufficient target dose coverage, HA represents an attractive salvage SBRT technique for recurrent NPC.

Postradiation hypothyroidism in head and neck cancers: A Department of Veterans Affairs single-institution case-control dosimetry study.

We performed a case-control study to characterize the dose-volume relationship and other variables leading to hypothyroidism after head and neck (H&N) cancer radiation therapy (RT) in a homogenous Veterans Affairs (VA) population. All records of patients receiving RT for various H&N cancers at a single VA medical center between 2007 and 2013 (n = 143) were screened for post-RT thyroid stimulating hormone (TSH) levels (n = 77). The thyroid gland was contoured on each slice of the planning computed tomography scan when available (hypothyroid: n = 18; euthyroid > 2 years: n = 16), and dose-volume histograms based on physical dose and biologically equivalent dose (BED) were compared systematically to find the significant dose-volume thresholds that distinguish the patients who developed clinical hypothyroidism. Dosimetric and clinical variables were considered in univariate and multivariate analysis. Preirradiation prevalence of hypothyroidism was 8 of 143 (5.6%). After RT, 36 of 77 (47%) screened patients had abnormally high TSH, of which 22 of 36 (61%) had clinical hypothyroidism after 1.29 ± 0.99 years. The median follow-up durations were 3.3 years and 4.7 years for euthyroid and hypothyroid patients, respectively. Compared with the euthyroid cohort (n = 41), these hypothyroid patients displayed no significant difference in age, gender, primary tumor site, thyroid volume, hypertension, diabetes, or use of chemotherapy, surgery, or intensity-modulated radiation therapy (IMRT). They were more likely to have had stage 3 or 4 cancer than euthyroid patients (86.5% vs 73.2%, p = 0.01). The odds ratios of hypothyroidism for stage 3 + 4 cancers and V50Gy < 75% were 5.0 and 0.2, respectively (p < 0.05). Equivalent BED threshold of V75Gy3 < 75% gave an odds ratio of 0.156 for developing hypothyroidism (p = 0.02). The prevalence of post-RT clinical hypothyroidism was relatively high for patients with H&N cancers and warrants routine surveillance, especially in those with higher stage malignancy. V50Gy < 75% may be a useful guideline to avoid hypothyroidism. We also show BED data which could be used for unconventionally fractionated schemes, and V75Gy3 < 75% may be a useful guideline.

Treatment outcomes with whole-field versus split-field intensity-modulated radiotherapy for patients with nasopharyngeal carcinoma.

BACKGROUND: The purpose of this study was to present our comparison of the clinical outcome of patients with nasopharyngeal carcinoma (NPC) treated with whole-field intensity-modulated radiotherapy (whole-field-IMRT) or split-field-IMRT. METHODS: We retrospectively studied 388 patients with M0 NPC. The median lower neck doses were 50 Gy in 1.35 Gy/fractions for the 240 whole-field-IMRT patients, and 50.4 Gy in 1.8 to 2.0 Gy/fractions for the 148 split-field-IMRT patients. RESULTS: The IMRT technique did not affect the overall survival (OS; P = .077) and locoregional control (P = .231) rates. However, the split-field-IMRT group had more locoregional recurrences at the whole neck (P = .005) but not at the nasopharynx (P = .968) or the lower neck (P = .485). The patients treated with split-field-IMRT (43.2%) had more grade III neck fibrosis than the patients who received whole-field-IMRT (18.3%; P < .001). Only 1 patient had temporal lobe necrosis in our study. CONCLUSION: Our study shows that whole-field-IMRT using a lower dose/fraction for the lower neck results in at least comparable locoregional control and less fibrosis compared to conventional fraction with split-field-IMRT.

The influence of cardiovascular disease on health related quality of life in men with prostate cancer: a 4-year followup study.

PURPOSE: Presence of comorbid conditions has consistently been associated with less aggressive treatment and worse overall survival in men with prostate cancer. However, little is known about the impact of comorbidity on health related quality of life outcomes, which may help men and their physicians facing decisions on primary treatment. MATERIALS AND METHODS: We evaluated patterns of health related quality of life in men with both prostate cancer and cardiovascular disease during 4 years of followup in a cohort of 475 prostate cancer survivors. We measured generic and disease specific health related quality of life at diagnosis and 11 times afterward. Repeated measures analyses with mixed modeling were used to examine changes in health related quality of life in subjects with cardiovascular disease and compare outcomes with those of an age, stage and treatment matched sample without cardiovascular disease. RESULTS: Men with cardiovascular disease had worse baseline physical health related quality of life (p = 0.003) and showed worse scores over time in this domain than did matched controls (p = 0.003). We found no significant interaction between treatment and cardiovascular disease on physical health related quality of life outcomes, suggesting that cardiovascular disease had the same detrimental effect on health related quality of life in this specific domain for radical prostatectomy, brachytherapy or external beam radiotherapy. The negative effect of cardiovascular disease on physical health related quality of life over time appeared to be stronger for those with worse baseline scores. The presence of cardiovascular disease was also associated with worse baseline sexual function (p = 0.004) and a trend toward worse scores over time (p = 0.07). CONCLUSIONS: Our observations suggest that patients with prostate cancer with cardiovascular disease have worse physical and sexual health related quality of life before and following treatment.

Patterns of failure after postoperative intensity-modulated radiotherapy for locally advanced buccal cancer: Initial masticator space involvement is the key factor of recurrence.

BACKGROUND: The purpose of this study was to determine failure patterns and clinicopathologic prognostic factors in patients with locally advanced buccal cancer after postoperative intensity-modulated radiotherapy (IMRT). METHODS: Eighty-two patients with locally advanced (American Joint Committee on Cancer [AJCC] stage III/IV) buccal cancer who underwent surgery followed by postoperative IMRT between January 2007 and October 2012 were retrospectively analyzed. RESULTS: Eighteen patients had local recurrences as the first recurrent site and 11 had supramandibular notch recurrences; the majority of recurrences were classified as marginal failures. The median time from the first local or regional recurrence to death was 5.9 months. In multivariate analyses of survivals, the initial masticator space involvement was the most important prognostic factor. Masticator space involvement, N classification, and maxillectomy were the significant prognostic predictors for supramandibular notch recurrences. CONCLUSION: Postoperative IMRT for buccal cancer should not include the surgical beds alone, rather, it should be based on the potential patterns of spread.

Improvements in prostate brachytherapy dosimetry due to seed stranding.

PURPOSE: Prostate brachytherapy with suture embedded seeds has emerged as a popular technique to reduce seed migration and to improve dosimetry. Various trials have shown improved dosimetry with seed fixity, whereas others have shown no benefit and possible detriment to suture embedded seeds. In order to contribute to the understanding of whether seed stranding improves dosimetry, we present retrospective data from our institution. METHODS AND MATERIALS: We analyzed 80 patients treated between April 29, 2001 and June 19, 2006, receiving I-125 monotherapy for prostate cancer. Brachytherapy patients at the University of California, Los Angeles (UCLA) were initially treated using a transperineal approach with loose seeds. Subsequent to October 26, 2002, all patients were implanted using suture embedded seeds. Dosimetric quantifiers were calculated based on a CT obtained 1-month postimplantation. RESULTS: Dosimetry of patients treated with stranded seeds showed significant improvement. Specifically, the V100 (volume of the prostate receiving 100% of the prescribed dose) improved from 88% to 92% (p<0.05), and the D90 (maximum dose received by 90% of the prostate) improved from 143 to 155 Gy (p<0.05). CONCLUSIONS: At UCLA, the use of suture embedded seeds resulted in a significant improvement in our dosimetric quantifiers. Based upon other published studies, this improvement in dosimetry may translate into improved patient outcomes.

Dose escalation via brachytherapy boost for nasopharyngeal carcinoma in the era of intensity-modulated radiation therapy and combined chemotherapy.

To investigate if dose escalation using intracavitary brachytherapy (ICBT) improves local control for nasopharyngeal carcinoma (NPC) in the era of intensity-modulated radiation therapy (IMRT) and concurrent chemoradiation treatment (CCRT). We retrospectively analyzed 232 patients with Stage T1-3 N0-3 M0 NPC who underwent definitive IMRT with or without additional ICBT boost between 2002 and 2013. For most of the 124 patients who had ICBT boost, the additional brachytherapy was given as 6 Gy in 2 fractions completed within 1 week after IMRT of 70 Gy. CCRT with or without adjuvant chemotherapy was used for 176 patients, including 88 with and 88 without ICBT boost, respectively. The mean follow-up time was 63.1 months. The 5-year overall survival and local control rates were 81.5% and 91.5%, respectively. ICBT was not associated with local control prediction (P = 0.228). However, in a subgroup analysis, 75 T1 patients with ICBT boost had significantly better local control than the other 71 T1 patients without ICBT boost (98.1% vs 85.9%, P = 0.020), despite having fewer patients who had undergone chemotherapy (60.0% vs 76.1%, P = 0.038). Multivariate analysis showed that both ICBT (P = 0.029) and chemotherapy (P = 0.047) influenced local control for T1 patients. Our study demonstrated that dose escalation with ICBT can improve local control of the primary tumor for NPC patients with T1 disease treated with IMRT, even without chemotherapy.

Modeling growth kinetics and statistical distribution of oligometastases.

The kinetics of development of micrometastases, and especially of small numbers of metastases (oligometastases), was explored by using simple assumptions to develop concepts that may be useful for framing future research. The conclusions depend on the assumptions and hence must be considered speculative. It is assumed that beyond a threshold size for initiation of metastatic spread, which varies widely from tumor to tumor, the rate at which a primary tumor sheds new metastases increases exponentially, in parallel with its exponential growth. This increasing rate of release of new metastatic clonogens from the primary tumor is accompanied by a similar exponential growth of each of the micrometastases newly established at a secondary site. This creates a log-log linear relationship between the volume distribution of metastases and number of metastases, there being one largest metastasis followed by an exponentially expanding number of logarithmically smaller micrometastases. For example, if the micrometastases and the primary tumor grew at the same rate for 6 doublings after initiation of the first metastasis, then the primary tumor would have increased its volume by a factor of 64 (2(6)) and would be shedding metastatic clonogens at 64 times the initial rate. The first metastasis would undergo 6 doublings and contain 64 cells; the succeeding 2 metastases, released as the primary doubled in volume, would undergo 5 doublings and each would contain 32 cells; and so forth down to the 64 most recently developed single-cell metastases. However, the growth rate of metastases is expected to be faster than that of the primary tumor so that the rate of increase in volume of the micrometastases would be faster than the rate of increase in their numbers (through release of new metastases from the primary). Thus, although the log-log linear relationship is maintained, the slope of the volume frequency curve is changed; if the micrometastases grew 5 times faster than the primary, the slope would change by a factor of 5. Removal of the primary tumor as a source of new metastases truncates the expansion in numbers of metastases without affecting the growth rate of existing micrometastases, with the result that the volume-frequency relationship is maintained but the whole curve is shifted to larger volumes as micrometastases grow toward clinical detectability. The development of an oligometastatic distribution requires that the exponential expansion in the number of new metastases be stopped by eliminating the primary tumor soon after the first metastasis is shed. A cell destined to become part of an oligometastatic distribution had just been newly deposited at its metastatic site at the time the primary tumor was removed and must undergo about 30 doublings to become clinically detectable as an overt metastasis (2(30) or 10(9) cells). Thus, the time interval between removal of the primary and subsequent appearance of oligometastases will be toward the upper end of a distribution of "metastasis-free" intervals for its particular class of tumor. The actual time to appearance of a solitary metastasis, or of oligometastases, in any particular patient will depend on the growth rate of the metastases in that individual but will always require about 30 volume doublings. An apparently solitary metastasis appearing synchronously with the primary tumor is unlikely to be solitary because, to do so, it would have to have undergone about 30 doublings without further release of metastatic clonogens from the primary that is, in our model, within 1 doubling in volume of the primary tumor. For the same reason, a synchronous or early appearing oligometastatic distribution is unlikely, but if it were to exist, there would be a steep gradient between the volumes of largest and smallest metastases because the growth rate of the micrometastases to produce synchronous metastases, without having further metastases shed from the primary, would have to be fast (up to 30x) relative to the growth rate of the primary. Conversely, a steep gradient in volumes of successive echelons of metastases reflects fast growth of metastases relative to the primary and favors the possibility of an oligometastatic distribution. This ratio of growth rates of metastases to primary is defined by the slope of the log-log curve for the volume-frequency distribution of metastases, which, in clinical practice, is difficult to determine over a wide range and is, by definition, essentially impossible for oligometastases. However, the volume-frequency relationship, measured over a wide range, is the same as the ratio of the volume of the largest to second-largest metastases in an oligometastatic situation. For example, if the metastasis doubled 5 times faster than the primary, the largest metastasis would be larger by 5 doublings than its closest follower(s), that is, by a factor of 2(5) or 32, equivalent to a 3.2-fold difference in diameter if the metastases were spherical. Alternatively, if an initially solitary and measurable metastasis is subsequently joined by measurable followers, the number of volume doublings separating successive echelons in the series can be determined directly, and the larger the difference (measured in doublings), the greater the probability that there will be a limited, oligometastatic condition (ie, in clinical terms, subsequent metastases will stop appearing after the large leader metastasis and a short succession of followers have been removed at 1 or more operations). In summary, the probability of there being an oligometastatic distribution is increased as the interval between removal of the primary tumor and appearance of metastases lengthens. It is also more likely the faster the metastases are growing relative to the growth rate of the primary tumor before its removal. Effective systemic cytotoxic treatment (eg, chemotherapy, hormonal manipulation, biological agents) given in the perioperative period, or concomitantly with radiation therapy for the primary tumor, would truncate the volume-frequency distribution toward an oligometastatic one by eliminating the smallest, most recently formed "tail-ender" metastases. That process, which only occurs at the threshold volume of the primary at which metastases are first initiated, would not be influenced by whether surgery or radiation therapy was chosen to treat the primary tumor, regardless of the overall duration of radiation therapy. Chemotherapy adjuvant to surgery is not usually indicated in the curative treatment of solitary or oligometastases because they represent a truncated distribution with few or no stragglers. If subclinical stragglers exist, they would usually be relatively large and, even though subclinical, too large to be cured by chemotherapy. Exceptions would be early rapidly growing oligometastases, especially from a slowly growing primary, or solitary metastases from an unknown primary where second echelon metastases, if they exist, may still be small. Otherwise chemotherapy could be postponed and used for palliative growth restraint of unusually large and/or numerous stragglers.