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1.  Brachytherapy for cervix cancer: low-dose rate or high-dose rate brachytherapy – a meta-analysis of clinical trials 
Background
The literature supporting high-dose rate brachytherapy (HDR) in the treatment of cervical carcinoma derives primarily from retrospective series. However, controversy still persists regarding the efficacy and safety of HDR brachytherapy compared to low-dose rate (LDR) brachytherapy, in particular, due to inadequate tumor coverage for stage III patients. Whether LDR or HDR brachytherapy produces better results for these patients in terms of survival rate, local control rate and the treatment complications remain controversial.
Methods
A meta-analysis of RCT was performed comparing LDR to HDR brachytherapy for cervix cancer treated for radiotherapy alone. The MEDLINE, EMBASE, CANCERLIT and Cochrane Library databases, as well as abstracts published in the annual proceedings were systematically searched. We assessed methodological quality for each outcome by grading the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. We used "recommend" for strong recommendations, and "suggest" for weak recommendations.
Results
Pooled results from five randomized trials (2,065 patients) of HDR brachytherapy in cervix cancer showed no significant increase of mortality (p = 0.52), local recurrence (p = 0.68), or late complications (rectal; p = 0.7, bladder; p = 0.95 or small intestine; p = 0.06) rates as compared to LDR brachytherapy. In the subgroup analysis no difference was observed for overall mortality and local recurrence in patients with clinical stages I, II and III. The quality of evidence was low for mortality and local recurrence in patients with clinical stage I, and moderate for other clinical stages.
Conclusion
Our meta-analysis shows that there are no differences between HDR and LDR for overall survival, local recurrence and late complications for clinical stages I, II and III. By means of the GRADE system, we recommend the use of HDR for all clinical stages of cervix cancer.
doi:10.1186/1756-9966-28-47
PMCID: PMC2673206  PMID: 19344527
2.  Impact of point A asymmetry on local control and survival for low dose-rate (LDR) brachytherapy in cervical cancer 
Purpose
To evaluate whether Point A asymmetry in low dose-rate (LDR) brachytherapy is associated with local control (LC), disease-free survival (DFS) and/or overall survival (OS).
Material and methods
A retrospective analysis of disease control and survival outcomes was conducted for patients who underwent LDR brachytherapy for advanced cervical cancer. Institutional protocol entailed concurrent chemotherapy and whole pelvis radiotherapy (WPRT) over 5 weeks, followed by placement of Fletcher-Suit tandem and colpostat applicators at weeks 6 and 8. Objective Point A doses, 80-85 Gy, were accomplished by placement of Cesium-137 (Cs-137) sources. Cox proportional hazards regression models were used to assess associations between disease control and survival endpoints with variables of interest.
Results
The records of 50 patients with FIGO stage IB1-IVA cervical cancer undergoing LDR brachytherapy at our institution were identified. Thirty of these patients had asymmetry > 2.5%, and 11 patients had asymmetry > 5%. At a median survivor follow-up of 20.25 months, 15 patients had experienced disease failure (including 5 cervical/vaginal apex only failures and 2 failures encompassing the local site). Right/left dose asymmetry at Point A was associated with statistically significantly inferior LC (p = 0.035) and inferior DFS (p = 0.011) for patients with mean Point A dose of > 80 Gy. Insufficient evidence existed to conclude an association with OS.
Conclusions
LDR brachytherapy may be associated with clinically significant dose asymmetry. The present study demonstrates that patients with Point A asymmetry have a higher risk of failure for DFS and LC.
doi:10.5114/jcb.2012.27945
PMCID: PMC3551371  PMID: 23346133
brachytherapy; cervical; point A; Fletcher-Suit system
3.  High Dose Rate versus Low Dose Rate Brachytherapy for Oral Cancer – A Meta-Analysis of Clinical Trials 
PLoS ONE  2013;8(6):e65423.
Objective
To compare the efficacy and safety of high dose rate (HDR) and low dose rate (LDR) brachytherapy in treating early-stage oral cancer.
Data Sources
A systematic search of MEDLINE, EMBASE and Cochrane Library databases, restricted to English language up to June 1, 2012, was performed to identify potentially relevant studies.
Study Selection
Only randomized controlled trials (RCT) and controlled trials that compared HDR to LDR brachytherapy in treatment of early-stage oral cancer (stages I, II and III) were of interest.
Data Extraction and Synthesis
Two investigators independently extracted data from retrieved studies and controversies were solved by discussion. Meta-analysis was performed using RevMan 5.1. One RCT and five controlled trials (607 patients: 447 for LDR and 160 for HDR) met the inclusion criteria. The odds ratio showed no statistically significant difference between LDR group and HDR group in terms of local recurrence (OR = 1.12, CI 95% 0.62–2.01), overall mortality (OR = 1.01, CI 95% 0.61–1.66) and Grade 3/4 complications (OR = 0.86, CI 95% 0.52–1.42).
Conclusions
This meta-analysis indicated that HDR brachytherapy was a comparable alternative to LDR brachytherapy in treatment of oral cancer. HDR brachytherapy might become a routine choice for early-stage oral cancer in the future.
doi:10.1371/journal.pone.0065423
PMCID: PMC3677879  PMID: 23762369
4.  The impact of comorbidity and stage on ovarian cancer mortality: A nationwide Danish cohort study 
BMC Cancer  2008;8:31.
Background
The incidence of ovarian cancer increases sharply with age, and many elderly patients have coexisting diseases. If patients with comorbidities are diagnosed with advanced stages, this would explain the poor survival observed among ovarian cancer patients with severe comorbidity. Our aims were to examine the prevalence of comorbidity according to stage of cancer at diagnosis, to estimate the impact of comorbidity on survival, and to examine whether the impact of comorbidity on survival varies by stage.
Methods
From the Danish Cancer Registry we identified 5,213 patients (> 15 years old) with ovarian cancer diagnosed from 1995 to 2003. We obtained information on comorbidities from the Danish National Hospital Discharge Registry. Vital status was determined through linkage to the Civil Registration System. We estimated the prevalence of comorbidity by stage and computed absolute survival and relative mortality rate ratios (MRRs) by comorbidity level (Charlson Index score 0, 1–2, 3+), using patients with Charlson Index score 0 as the reference group. We then stratified by stage and computed the absolute survival and MRRs according to comorbidity level, using patients with Charlson score 0 and localized tumour/FIGO I as the reference group. We adjusted for age and calendar time.
Results
Comorbidity was more common among patients with an advanced stage of cancer. One- and five-year survival was higher in patients without comorbidity than in patients with registered comorbidity. After adjustment for age and calendar time, one-year MRRs declined from 1.8 to 1.4 and from 2.7 to 2.0, for patients with Charlson scores 1–2 and 3+, respectively. After adjustment for stage, the MRRs further declined to 1.3 and 1.8, respectively. Five-year MRRs declined similarly after adjustment for age, calendar time, and stage. The impact of severe comorbidity on mortality varied by stage, particularly among patients with tumours with regional spread/FIGO-stages II and III.
Conclusion
The presence of severe comorbidity was associated with an advanced stage of ovarian cancer. Mortality was higher among patients with comorbidities and the impact of comorbidity varied by stage.
doi:10.1186/1471-2407-8-31
PMCID: PMC2266760  PMID: 18230177
5.  Minimal percentage of dose received by 90% of the urethra (%UD90) is the most significant predictor of PSA bounce in patients who underwent low-dose-rate brachytherapy (LDR-brachytherapy) for prostate cancer 
BMC Urology  2012;12:28.
Background
To clarify the significant clinicopathological and postdosimetric parameters to predict PSA bounce in patients who underwent low-dose-rate brachytherapy (LDR-brachytherapy) for prostate cancer.
Methods
We studied 200 consecutive patients who received LDR-brachytherapy between July 2004 and November 2008. Of them, 137 patients did not receive neoadjuvant or adjuvant androgen deprivation therapy. One hundred and forty-two patients were treated with LDR-brachytherapy alone, and 58 were treated with LDR-brachytherapy in combination with external beam radiation therapy. The cut-off value of PSA bounce was 0.1 ng/mL. The incidence, time, height, and duration of PSA bounce were investigated. Clinicopathological and postdosimetric parameters were evaluated to elucidate independent factors to predict PSA bounce in hormone-naïve patients who underwent LDR-brachytherapy alone.
Results
Fifty patients (25%) showed PSA bounce and 10 patients (5%) showed PSA failure. The median time, height, and duration of PSA bounce were 17 months, 0.29 ng/mL, and 7.0 months, respectively. In 103 hormone-naïve patients treated with LDR-brachytherapy alone, and univariate Cox proportional regression hazard model indicated that age and minimal percentage of the dose received by 30% and 90% of the urethra were independent predictors of PSA bounce. With a multivariate Cox proportional regression hazard model, minimal percentage of the dose received by 90% of the urethra was the most significant parameter of PSA bounce.
Conclusions
Minimal percentage of the dose received by 90% of the urethra was the most significant predictor of PSA bounce in hormone-naïve patients treated with LDR-brachytherapy alone.
doi:10.1186/1471-2490-12-28
PMCID: PMC3487947  PMID: 22974428
Prostate cancer; Brachytherapy; PSA bounce; Post-dosimetry; UD90 (%)
6.  Biological equivalence between LDR and PDR in cervical cancer: multifactor analysis using the linear-quadratic model 
Purpose
The purpose of this work was the biological comparison between Low Dose Rate (LDR) and Pulsed Dose Rate (PDR) in cervical cancer regarding the discontinuation of the afterloading system used for the LDR treatments at our Institution since December 2009.
Material and methods
In the first phase we studied the influence of the pulse dose and the pulse time in the biological equivalence between LDR and PDR treatments using the Linear Quadratic Model (LQM). In the second phase, the equivalent dose in 2 Gy/fraction (EQD2) for the tumor, rectum and bladder in treatments performed with both techniques was evaluated and statistically compared. All evaluated patients had stage IIB cervical cancer and were treated with External Beam Radiotherapy (EBRT) plus two Brachytherapy (BT) applications. Data were collected from 48 patients (26 patients treated with LDR and 22 patients with PDR).
Results
In the analyses of the influence of PDR parameters in the biological equivalence between LDR and PDR treatments (Phase 1), it was calculated that if the pulse dose in PDR was kept equal to the LDR dose rate, a small the-rapeutic loss was expected. If the pulse dose was decreased, the therapeutic window became larger, but a correction in the prescribed dose was necessary. In PDR schemes with 1 hour interval between pulses, the pulse time did not influence significantly the equivalent dose. In the comparison between the groups treated with LDR and PDR (Phase 2) we concluded that they were not equivalent, because in the PDR group the total EQD2 for the tumor, rectum and bladder was smaller than in the LDR group; the LQM estimated that a correction in the prescribed dose of 6% to 10% was ne-cessary to avoid therapeutic loss.
Conclusions
A correction in the prescribed dose was necessary; this correction should be achieved by calculating the PDR dose equivalent to the desired LDR total dose.
doi:10.5114/jcb.2011.24820
PMCID: PMC3551353  PMID: 23346123
brachytherapy; cervical cancer; LDR; PDR; EQD2; LQM
7.  Evidence-based guideline recommendations on low-dose rate brachytherapy in patients with low- or intermediate-risk prostate cancer 
Objective:
The Genitourinary Cancer Disease Site Group (GU DSG) and Cancer Care Ontario’s Program in Evidence-Based Care (PEBC) in Ontario, Canada developed a guideline on low-dose rate brachytherapy (LDR-BT) in patients with early-stage low-grade prostate cancer in 2001. The current updated guideline focuses on the research questions regarding the effect of LDR-BT alone, the effect of LDR-BT with external beam radiation therapy (EBRT) and the selection of an isotope.
Methods:
This guideline was developed by using the methods of the Practice Guidelines Development Cycle and the core methodology was a systematic review. MEDLINE and EMBASE (from January 1996 to October 2011), the Cochrane Library, main guideline websites, and main annual meeting abstract websites specific for genitourinary diseases were searched. Internal and external reviews of the draft guideline were conducted.
Results:
The draft guideline was developed according to a total of 10 systematic reviews and 55 full text articles that met the pre-planned study selection criteria. The quality of evidence was low to moderate. The final report reflects integration of the feedback obtained through the internal review (two oncologists and a methodologist) and external review (five target reviewers and 48 professional consultation reviewers) process, with final approval given by the GU DSG and the PEBC.
Conclusion:
The main recommendations are: (1) For patients with newly diagnosed low-risk or intermediate-risk prostate cancer who require or choose active treatment, LDR-BT alone is a treatment option as an alternative to EBRT alone or RP alone; and (2) I-125 and Pd-103 are each reasonable isotope options.
doi:10.5489/cuaj.478
PMCID: PMC3699088  PMID: 23826053
8.  Canadian prostate brachytherapy in 2012 
Prostate brachytherapy can be used as a monotherapy for low- and intermediate-risk patients or in combination with external beam radiation therapy (EBRT) as a form of dose escalation for selected intermediate- and high-risk patients. Prostate brachytherapy with either permanent implants (low dose rate [LDR]) or temporary implants (high dose rate [HDR]) is emerging as the most effective radiation treatment for prostate cancer. Several large Canadian brachytherapy programs were established in the mid- to late-1990s. Prostate brachytherapy is offered in British Columbia, Alberta, Manitoba, Ontario, Quebec and New Brunswick. We anticipate the need for brachytherapy services in Canada will significantly increase in the near future. In this review, we summarize brachytherapy programs across Canada, contemporary eligibility criteria for the procedure, toxicity and prostate-specific antigen recurrence free survival (PRFS), as published from Canadian institutions for both LDR and HDR brachytherapy.
doi:10.5489/cuaj.218
PMCID: PMC3650818  PMID: 23671495
9.  The Onset Time of Tumor Repopulation for Cervical Cancer – First Evidence from Clinical Data 
Purpose
Accelerated tumor repopulation has significant implications in low-dose-rate (LDR) brachytherapy. Repopulation onset time remains undetermined for cervical cancer. The purpose of this study was to determine the onset time of accelerated repopulation in cervical cancer using clinical data.
Methods and Materials
The linear-quadratic (LQ) model extended for tumor repopulation was used to analyze the clinical data and MRI-based 3D tumor volumetric regression data of 80 cervical cancer patients who received external beam radiotherapy (EBRT) and low dose rate (LDR) brachytherapy. The LDR dose was converted to EBRT dose in 1.8 Gy fractions using the LQ formula, and the total dose ranged from 61.4 to 99.7 Gy. The patients were divided into 11 groups according to total dose and treatment time. The tumor control probability (TCP) was calculated for each group. The least χ2 method was used to fit the TCP data with two free parameters: onset time (Tk) of accelerated repopulation and the number of clonogens (K) while other LQ model parameters were adopted from the literature, due to the limited patient data.
Results
Among the 11 patient groups, TCP varied from 33% to 100% as a function of radiation dose and overall treatment time. Higher dose and shorter treatment duration were associated higher TCP. Using the LQ model, the best fit was achieved with the onset time Tk=19 days, K=139, with uncertainty ranges of (11, 22) days for Tk, and (48, 1822) for K, respectively.
Conclusion
This is the first report of accelerated repopulation onset time in cervical cancer, derived directly from the clinical data using the LQ model. Our study verifies that accelerated repopulation does exist in cervical cancer and has a relatively short onset time. Dose escalation may be required to compensate for the effects of tumor repopulation if the radiation therapy course is protracted.
doi:10.1016/j.ijrobp.2011.12.037
PMCID: PMC3369115  PMID: 22386374
Cervical cancer; Radiation therapy; Tumor control probability; Tumor repopulation onset time; Linear-quadratic model
10.  Sigmoid Dose Using 3D Imaging in Cervical-Cancer Brachytherapy 
Background and Purpose
To evaluate the proximity, variance, predictors of dose, and complications to the sigmoid in cervical-cancer brachytherapy using 3D planning.
Materials and Methods
Over 36 months, 50 patients were treated for cervical cancer with either low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy. The distance from the central tandem to the sigmoid, the D0.1cc and the D2cc to the sigmoid, rectum and bladder doses, and toxicity were analyzed.
Results
The median sigmoid EQD2 D0.1cc and D2cc were 84 Gy and 68.3 Gy for HDR versus 71.1 Gy and 65.9 Gy for LDR (p=0.02 and 0.98, respectively). Twenty percent of the HDR fractions required manipulation of the superior dwell positions to decrease the sigmoid dose. The median distance from the sigmoid to the tandem was 1.7 cm (range [rg], 0.1 – 6.16 cm) for HDR and 2.7 cm (rg, 1.17 – 4.52 cm) for LDR; from the sigmoid to the 100% isodose region the median distances were – 0.1 cm (rg, -1.4 – 2.5 cm) and 0.44 cm (rg. -0.73 – 5.2 cm), respectively. The proximity of the sigmoid to the tandem is significantly related to sigmoid dose (p<0.0001). Within-patient (among-fraction) variation in sigmoid-to-tandem distance during HDR was substantial (coefficient of variation = 40%). No grade 3-4 sigmoid toxicity was seen after a median 31-month follow-up period.
Conclusions
3D imaging in cervical cancer brachytherapy shows the sigmoid in close proximity to the tandem. The sigmoid to tandem distance varies substantially between fractions, indicating the importance of sigmoid dose-volume evaluation with each fraction.
doi:10.1016/j.radonc.2009.06.032
PMCID: PMC2867463  PMID: 19665244
cervical cancer; brachytherapy; normal tissue dose
11.  Prognostic Impact of Comorbidity in Patients with Bladder Cancer 
European urology  2007;53(3):581-589.
Objective
To determine the impact of comorbidity on survival of bladder cancer patients.
Methods
The population included 675 patients with newly diagnosed bladder cancer whose medical information was abstracted from a hospital cancer registry. Adult Comorbidity Evaluation-27, a validated instrument, was used to prospectively categorize comorbidity. Independent variables assessed include comorbidity, American Joint Committee on Cancer (AJCC) stage, grade, age, gender, and race. Outcome measure was overall survival. We analyzed the entire cohort, patients with noninvasive disease, and patients requiring cystectomy. Cox proportional hazards analysis was used to assess impact of independent variables on survival.
Results
Median age at diagnosis for the entire cohort was 71 yr and median follow-up was 45 mo. Of 675 patients, 446 had at least one comorbid condition and 301 died during follow-up. On multivariable analysis for the entire cohort, comorbidity (p = 0.0001), AJCC stage (p = 0.0001), age (p = 0.0001), and race (p = 0.0045) significantly predicted overall survival. On subset analysis of noninvasive bladder cancer patients, comorbidity (p = 0.0001) and age (p = 0.0001) independently predicted overall survival, whereas stage, grade, race, and gender did not. On subset analysis of cystectomy patients, comorbidity (p = 0.0053), stage (p = 0.0001), and race (p = 0.0449) significantly predicted overall survival.
Conclusions
Comorbidity is an independent predictor of overall survival in the entire cohort of bladder cancer patients, the subset with noninvasive disease, and the subset treated with cystectomy.
doi:10.1016/j.eururo.2007.10.069
PMCID: PMC2262100  PMID: 17997024
Bladder cancer; Comorbidity; Cystectomy; Epidemiology; Prognosis
12.  Brachytherapy in the therapy of prostate cancer – an interesting choice 
Contemporary Oncology  2013;17(5):407-412.
Brachytherapy is a curative alternative to radical prostatectomy or external beam radiation [i.e. 3D conformal external beam radiation therapy (CRT), intensity-modulated radiation therapy (IMRT)] with comparable long-term survival and biochemical control and the most favorable toxicity. HDR brachytherapy (HDR-BT) in treatment of prostate cancer is most frequently used together with external beam radiation therapy (EBRT) as a boost (increasing the treatment dose precisely to the tumor). In the early stages of the disease (low, sometimes intermediate risk group), HDR-BT is more often used as monotherapy. There are no significant differences in treatment results (overall survival rate – OS, local recurrence rate – LC) between radical prostatectomy, EBRT and HDR-BT. Low-dose-rate brachytherapy (LDR-BT) is a radiation method that has been known for several years in treatment of localized prostate cancer. The LDR-BT is applied as a monotherapy and also used along with EBRT as a boost. It is used as a sole radical treatment modality, but not as a palliative treatment. The use of brachytherapy as monotherapy in treatment of prostate cancer enables many patients to keep their sexual functions in order and causes a lower rate of urinary incontinence. Due to progress in medical and technical knowledge in brachytherapy (“real-time” computer planning systems, new radioisotopes and remote afterloading systems), it has been possible to make treatment time significantly shorter in comparison with other methods. This also enables better protection of healthy organs in the pelvis. The aim of this publication is to describe both brachytherapy methods.
doi:10.5114/wo.2013.38557
PMCID: PMC3934024  PMID: 24596528
HDR brachytherapy; LDR brachytherapy; prostate cancer; seeds
13.  Comorbidity in Adult Bone Sarcoma Patients: A Population-Based Cohort Study 
Sarcoma  2014;2014:690316.
Background. Comorbidity is an important prognostic factor for survival in different cancers; however, neither the prevalence nor the impact of comorbidity has been investigated in bone sarcoma. Methods. All adult bone sarcoma patients from western Denmark treated at the Aarhus Sarcoma Centre in the period from 1979 to 2008 were identified through a validated population-based database. Charlson Comorbidity Index scores were computed, using discharge diagnoses from the Danish National Patient Registry. Survival was assessed as overall and disease-specific mortality. The impact of comorbidity was examined as rates according to the level of comorbidity as well as uni- and multivariately using proportional hazard models. Results. A total of 453 patients were identified. The overall prevalence of comorbidity was 19%. The prevalence increased with age and over the study period. In patients with Ewing/osteosarcoma, comorbidity was not associated with an increased overall or disease-specific mortality. However, patients with bone sarcomas other than Ewing/osteosarcoma had increased overall mortality. Independent prognostic factors for disease-specific survival were age, tumor size, stage at diagnosis, soft tissue involvement, grade, and surgery. Conclusion. The prevalence of comorbidity in bone sarcoma patients is low. Comorbidity impaired survival in patients with non-Ewing/nonosteosarcoma, histology. This emphasizes the importance of not only treating the sarcoma but also comorbidity.
doi:10.1155/2014/690316
PMCID: PMC3958755  PMID: 24723789
14.  Somatic comorbidity in anorexia nervosa: First results of a 21-year follow-up study on female inpatients 
Background
Anorexia nervosa is a severe psychosomatic disease with somatic complications in the long-term course and a high mortality rate. Somatic comorbidities independent of anorexia nervosa have rarely been studied, but pose a challenge to clinical practitioners. We investigated somatic comorbidities in an inpatient cohort and compared somatically ill anorexic patients and patients without a somatic comorbidity. In order to evaluate the impact of somatic comorbidity for the long-term course of anorexia nervosa, we monitored survival in a long-term follow-up.
Method
One hundred and sixty-nine female inpatients with anorexia nervosa were treated at the Charité University Medical Centre, Campus Benjamin Franklin, Berlin, between 1979 and 2011. We conducted retrospective analyses using patient's medical and psychological records. Information on survival and mortality were required through the local registration office and was available for one hundred patients. The mean follow-up interval for this subgroup was m = 20.9 years (sd = 4.7, min = 13.3, max = 31.6, range = 18.3). We conducted survival analysis using cox regression and included somatic comorbidity in a multivariate model.
Results
N = 41 patients (24.3%) showed a somatic comorbidity, n = 13 patients (7.7%) showed somatic comorbidities related to anorexia nervosa and n = 26 patients (15.4%) showed somatic comorbidities independent of anorexia nervosa, n = 2 patients showed somatic complications related to other psychiatric disorders. Patients with a somatic comorbidity were significantly older (m = 29.5, sd = 10.3 vs m = 25.0, sd = 8.7; p = .006), showed a later anorexia nervosa onset (m = 24.8, sd = 9.9 vs. m = 18.6, sd = 5.1; p < .000) and a longer duration of treatment in our clinic (m = 66.6, sd = 50.3 vs. m = 50.0, sd = 47; p = .05) than inpatients without somatic comorbidity. Out of 100 patients, 9 patients (9%) had died, on average at age of m = 37 years (sd = 9.5). Mortality was more common among inpatients with somatic comorbidity (n = 6, 66.7%) than among inpatients without a somatic disease (n = 3, 33.3%; p = .03). Somatic comorbidity was a significant coefficient in a multivariate survival model (B = 2.32, p = .04).
Conclusion
Somatic comorbidity seems to be an important factor for anorexia nervosa outcome and should be included in multivariate analyses on the long-term course of anorexia nervosa as an independent variable. Further investigations are needed in order to understand in which way anorexia nervosa and a somatic disease can interact.
doi:10.1186/1751-0759-6-4
PMCID: PMC3299644  PMID: 22300749
anorexia nervosa; long-term course; somatic comorbidity; mortality
15.  A Phase II Trial of Brachytherapy Alone Following Lumpectomy for Select Breast Cancer: tumor control and survival outcomes of RTOG 95-17 
Purpose:
RTOG 95-17 is a prospective Phase II cooperative group trial of APBI alone using multicatheter brachytherapy following lumpectomy in select early stage breast cancers. Tumor control and survival outcomes are reported.
Materials and Methods:
Eligibility criteria included stage I/II breast carcinoma confirmed to be <3cm, unifocal, invasive non-lobular histology with 0-3 positive axillary nodes without extracapsular extension. APBI treatment was delivered with either Low Dose Rate (LDR) (45 Gy in 3.5-5 days) or High Dose Rate (HDR) (34 Gy in 10 BID fractions over 5 days). Endpoints evaluated included in-breast control, regional control, mastectomy-free rate, mastectomy-free survival, disease-free survival and overall survival. The study was designed to analyze the HDR and LDR groups separately and without comparison.
Results:
Between 1997 and 2000, 100 patients were accrued and 99 were eligible; 66 treated with HDR and 33 treated with LDR. Eighty seven patients had T1 lesions and 12 had T2 lesions. Seventy nine were pathologically N0 and 20 were N1. Median follow-up in the HDR group is 6.14 years with the 5-year estimates of in-breast, regional and contralateral failure rates of 3%, 5% and 2%, respectively. The LDR group experienced similar results with a median follow-up of 6.22 years. The 5-year estimates of in-breast, regional and contralateral failure rates of 6%, 0% and 6%, respectively.
Conclusion:
Patients treated with multicatheter partial breast brachytherapy on this trial experienced excellent in-breast control rates and overall outcome that compare to reports from APBI studies with similar extended follow-up.
doi:10.1016/j.ijrobp.2007.12.056
PMCID: PMC2604132  PMID: 18294778
Brachytherapy; breast cancer; breast cancer trials; radiation therapy for breast cancer; accelerated partial breast irradiation
16.  Comorbidity in elderly cancer patients in relation to overall and cancer-specific mortality 
British Journal of Cancer  2012;106(7):1353-1360.
Background:
Aims of this study were to describe the prevalence of comorbidity in newly diagnosed elderly cancer cases compared with the background population and to describe its influence on overall and cancer mortality.
Methods:
Population-based study of all 70+ year-olds in a Danish province diagnosed with breast, lung, colorectal, prostate, or ovarian cancer from 1 January 1996 to 31 December 2006. Comorbidity was measured according to Charlson's comorbidity index (CCI). Prevalence of comorbidity in newly diagnosed cancer patients was compared with a control group by conditional logistic regression, and influence of comorbidity on mortality was analysed by Cox proportional hazards method.
Results:
A total of 6325 incident cancer cases were identified. Elderly lung and colorectal cancer patients had significantly more comorbidity than the background population. Severe comorbidity was associated with higher overall mortality in the lung, colorectal, and prostate cancer patients, hazard ratios 1.51 (95% CI 1.24–1.83), 1.41 (95% CI 1.14–1.73), and 2.14 (95% CI 1.65–2.77), respectively. Comorbidity did not affect cancer-specific mortality in general.
Conclusion:
Colorectal and lung cancer was associated with increased comorbidity burden in the elderly compared with the background population. Comorbidity was associated with increased overall mortality in elderly cancer patients but not consistently with cancer-specific mortality.
doi:10.1038/bjc.2012.46
PMCID: PMC3314782  PMID: 22353805
aged; elderly; comorbidity; survival
17.  The impact of cardiovascular comorbidities on the outcome of surgery for non-small-cell lung cancer 
OBJECTIVES
The presence of cardiovascular comorbidity in non-small-cell lung cancer (NSCLC) patients increases with age. Therefore, the influence of cardiovascular comorbidity in NSCLC patients on their short- or long-term prognosis remains controversial. This study evaluated the possible risk factors related to the short-term and long-term survivals in NSCLC patients with cardiovascular comorbidity.
METHODS
One thousand one hundred and sixty-two consecutive patients with NSCLC who had undergone a surgical resection between 1984 and 2010 were enrolled in this study. A total of 360 (31%) patients with cardiovascular comorbidities were analysed to identify the risk factors for postoperative complications and prognostic factors.
RESULTS
The patients with cardiovascular comorbidity included 301 with hypertension, 28 with coronary artery disease, 35 with peripheral vascular disease, 23 with arrhythmia and 11 with abdominal aortic aneurysm. Eighty-three patients exhibited more than one type of comorbidity. The postoperative cardiovascular morbidity rates were 3.6% in the cardiovascular comorbidity patients and 3.3% among patients without cardiovascular comorbidity (P = 0.73). No correlation was observed between preoperative cardiovascular comorbidity and postoperative pulmonary complications (P = 0.52). The operative mortality rates were 1.0% for the cardiovascular comorbidity patients and 0.8% for the other patients (P = 0.51). No difference in the postoperative outcomes was observed between the patients with and without cardiovascular comorbidity. The 5-year survival rates were 62.5% in comparison with 65.4% among patients without cardiovascular comorbidity (P = 0.48).
CONCLUSIONS
Patients with cardiovascular comorbidity were not found to be at increased risk of mortality and morbidity following surgery for NSCLC. In addition, cardiovascular comorbidity did not influence the long-term outcomes of patients after a pulmonary resection for NSCLC.
doi:10.1093/icvts/ivs489
PMCID: PMC3568808  PMID: 23223675
Non-small-cell lung cancer; Surgery; Cardiovascular comorbidity; Survival
18.  Long-Term Results of stereotactic Brachytherapy (Temporary 125Iodine Seeds) for the Treatment of Low-Grade Astrocytoma (Grade II) 
Background
Treatment of low-grade astrocytoma (WHO grade II) (LGA II) remains a challenge. There is limited information regarding the long-term effects of stereotactic brachytherapy (SBT) (temporary 125Iodine seeds) on patients with LGA II.
Objectives
The purpose of this study was to evaluate disease control and survival after stereotactic brachytherapy in patients with circumscribed and relatively small size tumors.
Materials and Methods
A retrospective review of 29 patients, treated between 1991 and 2011, was conducted to evaluate survival, complications, and local disease control after stereotactic brachytherapy. They belonged to a larger group of 48 cases with low-grade gliomas, treated with stereotactic brachytherapy. The demographic and clinical characteristics in patients including age, sex, and survival time were extracted from records.
Results
Thirteen patients were male and 16 were female, with the median age of 29 years (range, 2.5 – 64 years). The median follow-up was 95 (range, 6 – 240) months. Based on Pignatti classification, 10 patients were at low- and 19 patients at high-risk. The median overall as well as progression-free survivals for patients were 135 months (95% confidence interval: 76 – 194) and 96 months (95% confidence interval: 1 – 199), respectively. Five- and 10-year progression-free survivals were 41.4 % and 34.5 %, respectively, and the 5- and 10-year overall survivals were 65.5 % and 44.8%, respectively. Progression-free survival was not significantly higher in smaller size tumors (P = 0.224), nor for spherical versus non-spherical tumors (P = 0.307). There was no treatment-related morbidity after stereotactic brachytherapy, and no radiogenic complications occurred during the follow-up period. Mortality due to tumor progression occurred in 4 patients (14%), and 11 patients were alive at the last follow-up.
Conclusions
The stereotactic brachytherapy for patients with circumscribed and relatively small size tumors appears to be a safe, feasible, and minimally-invasive treatment.
doi:10.5812/ircmj.4322
PMCID: PMC3589779  PMID: 23487004
Survival; Long-Term; Astrocytoma; Brachytherapy
19.  Comorbidity as a prognostic variable in multiple myeloma: comparative evaluation of common comorbidity scores and use of a novel MM–comorbidity score 
Blood Cancer Journal  2011;1(9):e35-.
Comorbidities have been demonstrated to affect progression-free survival (PFS) and overall survival (OS), although their impact in multiple myeloma (MM) patients is as yet unsettled. We (1) assessed various comorbidities, (2) compared established comorbidity indices (CIs; Charlson comorbidity index (CCI), hematopoietic cell transplantation-specific comorbidity index (HCT-CI)), Kaplan Feinstein (KF) and Satariano index (SI) and (3) developed a MM-CI (Freiburger comorbidity index, FCI) in 127 MM patients. Univariate analysis determined moderate or severe pulmonary disease (hazard ratio (HR): 3.5, P<0.0001), renal impairment (via estimated glomerular filtration rate (eGFR); HR: 3.4, P=0.0018), decreased Karnofsky Performance Status (KPS, HR: 2.7, P=0.0004) and age (HR: 2, P=0.0114) as most important variables for diminished OS. Through multivariate analysis, the eGFR ⩽30 ml/min/1.73m2, impaired lung function and KPS ⩽70% were significant for decreased OS, with HRs of 2.9, 2.8 and 2.2, respectively. Combination of these risk factors within the FCI identified significantly different median OS rates of 118, 53 and 25 months with 0, 1 and 2 or 3 risk factors, respectively, (P<0.005). In light of our study, comorbidities are critical prognostic determinants for diminished PFS and OS. Moreover, comorbidity scores are important treatment decision tools and will be valuable to implement into future analyses and clinical trials in MM.
doi:10.1038/bcj.2011.34
PMCID: PMC3255252  PMID: 22829196
multiple myeloma; comorbidities; comorbidity scores; prognosis
20.  Outcomes of Gleason Score ≤8 among High Risk Prostate Cancer Treated with 125I Low Dose Rate Brachytherapy Based Multimodal Therapy 
Yonsei Medical Journal  2013;54(5):1207-1213.
Purpose
To investigate the role of low dose rate (LDR) brachytherapy-based multimodal therapy in high-risk prostate cancer (PCa) and analyze its optimal indications.
Materials and Methods
We reviewed the records of 50 high-risk PCa patients [clinical stage ≥T2c, prostate-specific antigen (PSA) >20 ng/mL, or biopsy Gleason score ≥8] who had undergone 125I LDR brachytherapy since April 2007. We excluded those with a follow-up period <3 years. Biochemical recurrence (BCR) followed the Phoenix definition. BCR-free survival rates were compared between the patients with Gleason score ≥9 and Gleason score ≤8.
Results
The mean initial PSA was 22.1 ng/mL, and mean D90 was 244.3 Gy. During a median follow-up of 39.2 months, biochemical control was obtained in 72% (36/50) of the total patients; The estimated 3-year BCR-free survival was 92% for the patients with biopsy Gleason scores ≤8, and 40% for those with Gleason scores ≥9 (p<0.001). In Cox multivariate analysis, only Gleason score ≥9 was observed to be significantly associated with BCR (p=0.021). Acute and late grade ≥3 toxicities were observed in 20% (10/50) and 36% (18/50) patients, respectively.
Conclusion
Our results showed that 125I LDR brachytherapy-based multimodal therapy in high-risk PCa produced encouraging relatively long-term results among the Asian population, especially in patients with Gleason score ≤8. Despite small number of subjects, biopsy Gleason score ≥9 was a significant predictor of BCR among high risk PCa patients after brachytherapy.
doi:10.3349/ymj.2013.54.5.1207
PMCID: PMC3743192  PMID: 23918571
Prostate cancer; brachytherapy; high risk group; biochemical recurrence
21.  Impact of comorbidity in elderly prostate cancer patients treated with brachytherapy 
Objective
To analyze the correlations among comorbidity and overall survival (OS), biochemical progression-free survival (b-PFS) and toxicity in elderly patients with localized prostate cancer treated with 125I brachytherapy.
Methods
Elderly men, aged ≥65 years, with low-intermediate risk prostate cancer, were treated with permanent 125I brachytherapy as monotherapy. Comorbidity data were obtained from medical reports using age-adjusted Charlson comorbidity index (a-CCI). The patients were categorized into two age groups (<75 and ≥75 years old), and two comorbidity score groups (a-CCI ≤3 and >3). Toxicity was scored with Radiation Therapy Oncology Group (RTOG) scale.
Results
From June 2003 to October 2009, a total of 92 elderly patients underwent prostate brachytherapy, including 57 men (62%) with low-risk prostate cancer, and 35 men (38%) with intermediate-risk prostate cancer. The median age of patients was 75 years (range, 65-87 years). Forty-seven patients (51%) had a-CCI ≤3 and 45 patients (49%) a-CCI >3. With a median follow-up period of 56 months (range, 24-103 months), the 5-year actuarial OS and b-PFS were 91.3% and 92.4% respectively, without statistical significance between two Charlson score groups. Toxicity was mild. None of the patients experienced gastrointestinal (GI) toxicity, and only 4 patiens (4%) experienced late genitourinary (GU) grade-3 (G3) toxicity. No correlation between acute GU and GI toxicity and comorbidity was showed (P=0.50 and P=0.70, respectively).
Conclusions
Our data suggest that elderly men with low-intermediate risk prostate cancer and comorbidity can be considered for a radical treatment as 125I low-dose rate brachytherapy.
doi:10.3978/j.issn.1000-9604.2013.06.06
PMCID: PMC3696714  PMID: 23825903
Prostate cancer; brachytherapy; elderly; comorbidity; toxicity; overall survival; biochemical control
22.  High dose rate brachytherapy for oral cancer 
Journal of Radiation Research  2012;54(1):1-17.
Brachytherapy results in better dose distribution compared with other treatments because of steep dose reduction in the surrounding normal tissues. Excellent local control rates and acceptable side effects have been demonstrated with brachytherapy as a sole treatment modality, a postoperative method, and a method of reirradiation. Low-dose-rate (LDR) brachytherapy has been employed worldwide for its superior outcome. With the advent of technology, high-dose-rate (HDR) brachytherapy has enabled health care providers to avoid radiation exposure. This therapy has been used for treating many types of cancer such as gynecological cancer, breast cancer, and prostate cancer. However, LDR and pulsed-dose-rate interstitial brachytherapies have been mainstays for head and neck cancer. HDR brachytherapy has not become widely used in the radiotherapy community for treating head and neck cancer because of lack of experience and biological concerns. On the other hand, because HDR brachytherapy is less time-consuming, treatment can occasionally be administered on an outpatient basis. For the convenience and safety of patients and medical staff, HDR brachytherapy should be explored. To enhance the role of this therapy in treatment of head and neck lesions, we have reviewed its outcomes with oral cancer, including Phase I/II to Phase III studies, evaluating this technique in terms of safety and efficacy. In particular, our studies have shown that superficial tumors can be treated using a non-invasive mold technique on an outpatient basis without adverse reactions. The next generation of image-guided brachytherapy using HDR has been discussed. In conclusion, although concrete evidence is yet to be produced with a sophisticated study in a reproducible manner, HDR brachytherapy remains an important option for treatment of oral cancer.
doi:10.1093/jrr/rrs103
PMCID: PMC3534285  PMID: 23179377
brachytherapy; oral cancer; high dose rate
23.  Comparison of Scoring Methods for ACE-27: Simpler Is Better 
Journal of geriatric oncology  2012;3(3):238-245.
Objective
To examine the prognostic value of different comorbidity coding schemes for predicting survival of newly diagnosed elderly cancer patients.
Materials and Methods
We analyzed data from 8,867 patients aged 65 years of age or older, newly diagnosed with cancer. Comorbidities present at the time of diagnosis were collected using the Adult Comorbidity Evaluation-27 index (ACE-27). We examined multiple scoring schemes based on the individual comorbidity ailments, and their severity rating. Harrell’s c index and Akaike Information Criterion (AIC) were used to evaluate the performance of the different comorbidity models.
Results
Comorbidity led to an increase in c index from 0.771 for the base model to 0.782 for a model that included indicator variables for every ailment. The prognostic value was however much higher for prostate and breast cancer patients. A simple model which considered linear scores from 0 to 3 per ailment, controlling for cancer type, was optimal according to AIC.
Conclusion
The presence of comorbidity impacts on the survival of elderly cancer patients, especially for less lethal cancers, such as prostate and breast cancers. Different ailments have different impacts on survival, necessitating the use of different weights per ailment in a simple summary score of the ACE-27.
doi:10.1016/j.jgo.2012.01.006
PMCID: PMC3375822  PMID: 22712031
Comorbidity; comorbid ailment; elderly; cancer patients; prognostic; survival
24.  Comparative evaluation of ASA classification and ACE-27 index as morbidity scoring systems in oncosurgeries 
Indian Journal of Anaesthesia  2010;54(3):219-225.
The primary intention of the study was to find out whether Adult Comorbidity Evaluation Index (ACE-27) was better than the American Society of Anaesthesiologists’ (ASA) risk classification system in predicting postoperative morbidity in head and neck oncosurgery. Another goal was to identify other risk factors for complications which are not included in these indexes. Univariate and multivariate analyses were performed on 250 patients to determine the impact of seven variables on morbidity-ACE-27 grade, ASA class, age, sex, duration of anaesthesia, chemotherapy and radiotherapy. In univariate analysis ACE-27 index, ASA score, duration of anaesthesia, radiotherapy and chemotherapy were significant. As both comorbidity scales were significant in univariate analysis they were analyzed together and separately in multivariate analysis to illustrate their individual strength. In the first multivariate analysis (excluding ACE-27 grade) ASA class, duration of anaesthesia, radiotherapy and chemotherapy were significant. The positive predictive value (PPV) of this model to predict morbidity was 60.86% and negative predictive value (NPV) was 77.9%. The sensitivity was 75% and specificity 62.2%. In the second multivariate analysis (excluding ASA class) ACE-27 grade, duration of anaesthesia and radiotherapy were significant. The PPV of this model to predict morbidity was 62.1% and NPV was 76.5%. The sensitivity was 61.6% and specificity 70.9%. In the third multivariate analysis which included both ACE-27 grade and ASA class only ASA class, duration of anaesthesia, radiotherapy and chemotherapy remained significant. In conclusion, ACE-27 grade and ASA class were reliable predictors of major complications but ASA class had more impact on complications than ACE-27 grade.
doi:10.4103/0019-5049.65366
PMCID: PMC2933480  PMID: 20885868
Morbidity prediction; perioperative complications; surgery
25.  Three-dimensional dosimetric considerations from different point A definitions in cervical cancer low-dose-rate brachytherapy 
Purpose
To investigate the dosimetric difference due to the different point A definitions in cervical cancer low-dose-rate (LDR) intracavitary brachytherapy.
Material and methods
Twenty CT-based LDR brachytherapy plans of 11 cervical patients were retrospectively reviewed. Two plans with point As following the modified Manchester system which defines point A being 2 cm superior to the cervical os along the tandem and 2 cm lateral (Aos), and the American Brachytherapy Society (ABS) guideline definition in which the point A is 2 cm superior to the vaginal fornices instead of os (Aovoid) were generated. Using the same source strength, two plans prescribed the same dose to Aos and Aovoid. Dosimetric differences between plans including point A dose rate, treatment volume encompassed by the prescription isodose line (TV), and dose rate of 2 cc of the rectum and bladder to the prescription dose were measured.
Results
On average Aovoid was 8.9 mm superior to Aos along the tandem direction with a standard deviation of 5.4 mm. With the same source strength and arrangement, Aos dose rate was 19% higher than Aovoid dose rate. The average TV(Aovoid) was 118.0 cc, which was 30% more than the average TV(Aos) of 93.0 cc. D2cc/D(Aprescribe) increased from 51% to 60% for rectum, and increased from 89% and 106% for bladder, if the prescription point changed from Aos to Aovoid.
Conclusions
Different point A definitions lead to significant dose differences. Careful consideration should be given when changing practice from one point A definition to another, to ensure dosimetric and clinical equivalency from the previous clinical experiences.
doi:10.5114/jcb.2013.38836
PMCID: PMC3899635  PMID: 24474971
cervical cancer; LDR brachytherapy; point A

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