Clinical outcomes of conventional HDR intracavitary brachytherapy combined with complementary applicator-guided intensity modulated radiotherapy boost in patients with bulky cervical tumour.

OBJECTIVE: To investigate the clinical outcomes and toxicity in patients with locally advanced cervical cancer treated with supplementary applicator guided-intensity modulated radiation therapy (IMRT) based on conventional intracavitary brachytherapy (IC/IMRT). DESIGN: A retrospective cohort study. SETTING: Sichuan Cancer Hospital & Institute, Sichuan Cancer Centre, China. POPULATION: Large high-risk clinical target volume (HR-CTV) volume (>40 ml) at the time of brachytherapy cervical cancer patients were recruited. METHODS: This study is a retrospective analysis of 76 patients with locally advanced cervical cancer (FIGO IIB-IVA) treated with concurrent chemoradiotherapy followed by IC/IMRT between June 2010 and October 2016. External radiotherapy (45 Gy in 25 fractions) was adminstered with cisplatin chemotherapy treatment before IC/IMRT. The IMRT plan was optimised using the ICBT plan base dose plan by an inverse dose optimisation tool which allows the use of DVH constraints on the total dose of ICBT. A seven-field gantry angle IMRT plan was devised to avoid hotspots when optimising the boost plan. The prescription dose for HR-CTV and IR-CTV were 6 and 5 Gy per fraction for five fractions, respectively. RESULTS: Mean HR-CTV was 65.8 ± 23.6 ml at the time of brachytherapy. D90 for HR-CTV and IR-CTV were 88.7 ± 3.6 Gy and 78.1 ± 2.5 Gy. D2cc for bladder, rectum, sigmoid and small intestine were 71.8 ± 3.8, 64.6 ± 4.9, 63.9 ± 5.3 and 56.7 ± 8.7 Gy, respectively. Median follow-up was 85 months (47.9-124.2 months). Five-year local recurrence-free survival rate, metastasis recurrence-free survival rate, disease-free survival rate and cancer-special survival rate were 87.6, 82.4, 70.9 and 76.3%, respectively. The grade 1 + 2 gastrointestinal and urinary late toxicities were 15.8 and 21.1%, and grade 3 late toxicities were 3.9 and 5.2%, respectively. Neither acute nor late grade 4 gastrointestinal or urinary toxicities were seen. CONCLUSIONS: The combination of ICBT with an applicator-guided supplementary IMRT boost achieved excellent local control and overall survival with low toxicity for bulky residual cervical tumour.

Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial.

PURPOSE: Geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), is a major cause of blindness. Even while central visual acuity remains relatively well preserved, GA often causes considerable compromise of visual function and quality of life. No treatment currently exists. We evaluated the safety and efficacy of pegcetacoplan, a complement C3 inhibitor, for treatment of GA. DESIGN: Prospective, multicenter, randomized, sham-controlled phase 2 study. PARTICIPANTS: Two hundred forty-six patients with GA. METHODS: Patients with GA were assigned randomly in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg pegcetacoplan monthly or every other month (EOM) or sham intravitreal injections monthly or EOM for 12 months with follow-up at months 15 and 18. Area and growth of GA were measured using fundus autofluorescence imaging. MAIN OUTCOME MEASURES: The primary efficacy end point was mean change in square root GA lesion area from baseline to month 12. Secondary outcome measures included mean change from baseline in GA lesion area without the square root transformation, distance of GA lesion from the fovea, best-corrected visual acuity (BCVA), low-luminance BCVA, and low-luminance visual acuity deficit. The primary safety end point was the number and severity of treatment-emergent adverse events. RESULTS: In patients receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% confidence interval [CI], 9-49; P = 0.008) and 20% (95% CI, 0-40; P = 0.067) compared with the sham treatment group. Post hoc analysis showed that the effect was greater in the second 6 months of treatment, with observed reductions of 45% (P = 0.0004) and 33% (P = 0.009) for pegcetacoplan monthly and EOM, respectively. Two cases of culture-positive endophthalmitis and 1 case of culture-negative endophthalmitis occurred in the pegcetacoplan monthly group. New-onset investigator-determined exudative AMD was reported more frequently in pegcetacoplan-treated eyes (18/86 eyes [20.9%] and 7/79 eyes [8.9%] in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes [1.2%]). CONCLUSIONS: Local C3 inhibition with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham treatment. Phase 3 studies will define the efficacy and safety profile further.

Incidence of mesorectal node metastasis in locally advanced cervical cancer: its therapeutic implications.

OBJECTIVE: To evaluate the incidence and risk factors for mesorectal node metastasis (MRNM) in locally advanced cervical cancer. METHODS/MATERIALS: We performed an observational retrospective cohort study of 122 patients with cervical cancer who received definitive chemo-radiation treatment between December 2013 and June 2017 to evaluate the incidence of MRNM. Three diagnostic radiologists assessed all available pre-treatment images. In this study, the pelvic node metastasis was defined as ≥ 1.0 cm and MRNM as ≥ 0.5 cm for CT and MRI scans and as a maximum standardized uptake value of > 2.5 for PET/CT. The relationship of MRNM with FIGO stage, pelvic node metastasis, and mesorectal fascia involvement was evaluated. RESULTS: The incidence of MRNM in all 122 patients was 8 (6.6%). However, in advanced stage (III- IV) patients, MRNM occurred in 4 of 39 (10.3%) compared with 4 of 83 (4.8%) in early stage (IB1-IIB) patients (p = 0.27). In patients with a positive pelvic node, MRNM occurred in 7 of 55 (12.7%) and 1 of 67 (1.5%) in those with negative pelvic node (p = 0.02). In addition, the incidence of MRNM was 3 of 9 (33.3%) in the presence of mesorectal fascia involvement and 5 of 113 (4.4%) among those without mesorectal fascia involvement (p = 0.013). CONCLUSION: This study indicates that pelvic node metastasis and mesorectal fascia involvement are high-risk factors for MRNM. Therefore, vigilance of reviewing images in the mesorectum for MRNM is necessary for high-risk patients.

Efficacy and toxicity of conventionally fractionated pelvic radiation with a hypofractionated simultaneous versus conventionally fractionated sequential boost for patients with high-risk prostate cancer.

PURPOSE: To determine if high-risk prostate cancer responds differently to hypofractionation. MATERIAL AND METHODS: One hundred and fifty-seven men with NCCN high-risk (T3, PSA > 20, or Gleason ≥ 8) clinically localized prostate cancer treated between 1998 and 2010 met the inclusion criteria for the analysis. Eighty-two were treated with conventional WPRT with a conventionally fractionated sequential boost to the prostate (cRT), with the prostate receiving 75-77 Gy in 1.8-2.0 Gy fractions. Seventy-five were treated with pelvic IMRT with a hypofractionated simultaneous boost to the prostate (hRT), with the prostate receiving 70 Gy in 2.5 Gy fractions. The dose to the pelvic lymph nodes was 45 Gy in the cRT group and 50.4 Gy in the hRT group, both at 1.8 Gy per fraction. Ninety-two percent received neoadjuvant hormonal ablation therapy, typically beginning two months prior to the start of RT. RESULTS: Median follow-up was 6.5 years for men receiving cRT and 3.7 years for those receiving hRT. The actuarial rate of biochemical control at four years was 88% for cRT and 94% for hRT (p = 0.82). The rates of early rectal and urinary grade ≥ 2 toxicities were 35% (29 of 82) and 49% (40 of 82) for the cRT group and 36% (27 of 75) and 44% (33 of 75) for the hRT group. The actuarial rate of late grade ≥ 2 rectal toxicity at four years was 25% for the cRT group and 13% for the hRT group (p = 0.037). The rate of late grade 3 rectal complications was 4% (3 of 82) for patients receiving cRT and 1% (1 of 75) for patients receiving hRT. CONCLUSION: Initial follow-up indicates equivalent biochemical control between regimens. Patients receiving hRT experienced fewer late rectal complications.

Intraoperative ultrasound guidance during intracavitary brachytherapy applicator placement in cervical cancer: the University of Alabama at Birmingham experience.

OBJECTIVE: The objective of this study was to evaluate the University of Alabama at Birmingham experience with routine intraoperative ultrasound (IUS)-guided tandem placement for cervical cancer. METHODS: Between 1999 and 2008, 243 cervical cancer patients underwent IUS-guided tandem placement. One hundred thirty-nine patients received low-dose-rate brachytherapy, and 104 received high-dose-rate brachytherapy. Three hundred fifty-six IUS-guided procedures were performed. Clinical and imaging data were retrospectively analyzed to evaluate complications requiring reinsertion of tandem placement in the context of IUS. RESULTS: All 243 cervical cancer patients completed intracavitary brachytherapy. Five (1.4%) of 356 IUS-guided applicator placements resulted in uterine perforation. All of these patients underwent successful tandem insertion on the second attempt, and no significant clinical sequelae occurred. Intraoperative ultrasound enabled direct uterine visualization and facilitated real-time feedback for selection of a suitable tandem length and curvature; no suboptimal placements requiring return to the operating room occurred (excluding perforation). CONCLUSIONS: In this large series, IUS guidance substantially increased the rate of successful applicator placement and diminished the rate of uterine perforation relative to historical controls. We strongly recommend the use of IUS guidance during operative intrauterine tandem placement for cervical cancer.

Prostate Stereotactic Body Radiation Therapy With a Focal Simultaneous Integrated Boost: 5-Year Toxicity and Biochemical Recurrence Results From a Prospective Trial.

PURPOSE: Stereotactic body radiation therapy (SBRT) is increasingly used as a definitive treatment option for patients with prostate adenocarcinoma. The aim of this study was to assess the late toxicity, patient-reported quality of life outcomes, and biochemical recurrence rates after prostate SBRT with simultaneous integrated boost (SIB) targeting lesions defined by magnetic resonance imaging (MRI). METHODS AND MATERIALS: Patients were eligible if they had biopsy-proven low- or intermediate-risk prostate adenocarcinoma, one or more focal lesions on MRI, and an MRI-defined total prostate volume of <120 mL. All patients received SBRT delivered to the entire prostate to a dose of 36.25 Gy in 5 fractions with an SIB to the lesions seen on MRI to 40 Gy in 5 fractions. Late toxicity was defined as any possible treatment-related adverse event occurring after 3 months from the completion of SBRT. Patient-reported quality of life was ascertained using standardized patient surveys. RESULTS: A total of 26 patients were enrolled. Six patients (23.1%) had low-risk disease and 20 patients had intermediate-risk disease (76.9%). Seven patients (26.9%) received androgen deprivation therapy. Median follow-up was 59.5 months. No biochemical failures were observed. Three patients (11.5%) experienced late grade 2 genitourinary (GU) toxicity requiring cystoscopy, and 7 patients (26.9%) had late grade 2 GU toxicity requiring oral medications. Three patients (11.5%) had late grade 2 gastrointestinal toxicity characterized by hematochezia requiring colonoscopy and steroids per rectum. There were no grade 3 or higher toxicity events observed. The patient-reported quality-of-life metrics at the time of last follow-up were not significantly different than the pre-treatment baseline. CONCLUSIONS: The results of this study support that SBRT to the entire prostate to a dose of 36.25 Gy in 5 fractions with focal SIB to 40 Gy in 5 fractions has excellent biochemical control and is not associated with undue late gastrointestinal or GU toxicity or long-term quality of life decrement. Focal dose escalation with an SIB planning approach may be an opportunity to improve biochemical control while limiting dose to nearby organs at risk.

Hypofractionated radiation leads to more rapid bleeding cessation in women with vaginal bleeding secondary to gynecologic malignancy.

BACKGROUND: Vaginal bleeding (VB) is common in women with gynecologic (GYN) malignancies. Radiation therapy (RT) is used for the definitive treatment of GYN cancers and palliation of bleeding. The historical dogma is that high dose-per-fraction radiation leads to more rapid bleeding cessation, yet there is scant data supporting this claim. We sought to examine the effect of RT fraction size on VB via retrospective analysis of patients receiving hypofractionated radiation (HFRT) compared to conventionally fractionated radiation (CFRT) for control of bleeding secondary to GYN malignancies. METHODS: We identified patients receiving external beam RT for continuous VB from GYN malignancy treated in our department from 2012 to 2020. RT was classified as HFRT (> 2.0 Gy/fx) or CFRT (1.8-2.0 Gy/fx). Demographic information, disease characteristics, and treatment details were collected. The primary endpoint was days from RT initiation until bleeding resolution. Characteristics between groups were compared via Fisher's exact test. Time to bleeding cessation was assessed via Kaplan-Meier and log-rank test. Univariable and multivariable Cox-proportional hazards were used to identify factors associated with bleeding cessation. RESULTS: We identified 43 patients meeting inclusion criteria with 26 and 17 patients receiving CFRT and HFRT, respectively. Comparison of baseline characteristics revealed patients receiving HFRT were older (p = 0.001), more likely to be post-menopausal (p = 0.002), and less likely to receive concurrent chemotherapy (p = 0.004). Time to bleeding cessation was significantly shorter for patients receiving HFRT (log-rank p < 0.001) with median time to bleeding cessation of 5 days (HFRT) versus 16 days (CFRT). Stratification by dose-per-fraction revealed a dose-response effect with more rapid bleeding cessation with increased dose-per-fraction. While HFRT, age, recurrent disease, prior pelvic RT, and prior systemic therapy were associated with time to bleeding cessation on univariable analysis, HFRT was the only factor significantly associated with time to bleeding cessation in the final multivariable model (HR 3.26, p = 0.008). CONCLUSIONS: Patients with continuous VB from GYN tumors receiving HFRT experienced more rapid bleeding cessation than those receiving CFRT. For patients with severe VB, initiation of HFRT to control malignancy related bleeding quickly may be warranted.

Selection of brachytherapy applicators based on tumor size and shape for cervical cancer: simulation analysis of pear-shaped isodose dimensions.

The purpose of study is to measure Point A pear-shaped isodose dimensions of the conventional intracavitary brachytherapy with various sizes of colpostats and analyze which size of tumor is the optimal for 3-D interstitial brachytherapy. CT simulation was performed with Fletcher type applicator using various sizes of colpostats (2.0, 2.5, and 3.0 cm diameter). The Manchester standard loading (dwell time) system was used to generate pear-shaped isodose envelopes with high-dose rate iridium-192 according to the colpostat sizes. The size of the pear-shaped envelope was measured at 5 different levels: A-level (center of the colpostats), B-level (top of the colpostats), C-level (between B and D), D-level (Point A), and E-level (1.0 cm above Point A). In this study, it was assumed that uterine tandem was located at the center of tumor. For width of pear-shape: At the A-level, 6.4, 7.3, and 8.0 cm for 2.0, 2.5, and 3.0 cm colpostats, respectively. At the B-level, 5.8, 6.4, and 6.8 cm for 2, 2.5, and 3.0 cm colpostats, respectively. At the C-level, 4.6, 4.8, and 4.8 for 2.0, 2.5, and 3.0 cm colpostats, respectively. At the D-level, 4.0 cm for all different size. At the E-level, 3.8 cm for all 3 different size colpostats. A-level was the largest dimension of pear-shape. However, it was located in the upper vagina below the main cervical mass. The center of the effective pear-shape size for tumor was between the C and D levels. For thickness, all 5 different levels were ranging 3.7 to 4.0 cm. For height, the length of height was dependent on the tandem length. Therefore, the pear-shape envelope was able to accommodate up to 4.0 cm diameter volume. According to our analysis of conventional pear-shape dimension, 3-D interstitial brachytherapy should be considered for tumors larger than 4.0 cm for symmetrical tumor.

Ranibizumab for neovascular age-related macular degeneration.

BACKGROUND: Ranibizumab--a recombinant, humanized, monoclonal antibody Fab that neutralizes all active forms of vascular endothelial growth factor A--has been evaluated for the treatment of neovascular age-related macular degeneration. METHODS: In this multicenter, 2-year, double-blind, sham-controlled study, we randomly assigned patients with age-related macular degeneration with either minimally classic or occult (with no classic lesions) choroidal neovascularization to receive 24 monthly intravitreal injections of ranibizumab (either 0.3 mg or 0.5 mg) or sham injections. The primary end point was the proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months. RESULTS: We enrolled 716 patients in the study. At 12 months, 94.5% of the group given 0.3 mg of ranibizumab and 94.6% of those given 0.5 mg lost fewer than 15 letters, as compared with 62.2% of patients receiving sham injections (P<0.001 for both comparisons). Visual acuity improved by 15 or more letters in 24.8% of the 0.3-mg group and 33.8% of the 0.5-mg group, as compared with 5.0% of the sham-injection group (P<0.001 for both doses). Mean increases in visual acuity were 6.5 letters in the 0.3-mg group and 7.2 letters in the 0.5-mg group, as compared with a decrease of 10.4 letters in the sham-injection group (P<0.001 for both comparisons). The benefit in visual acuity was maintained at 24 months. During 24 months, presumed endophthalmitis was identified in five patients (1.0%) and serious uveitis in six patients (1.3%) given ranibizumab. CONCLUSIONS: Intravitreal administration of ranibizumab for 2 years prevented vision loss and improved mean visual acuity, with low rates of serious adverse events, in patients with minimally classic or occult (with no classic lesions) choroidal neovascularization secondary to age-related macular degeneration. (ClinicalTrials.gov number, NCT00056836 [ClinicalTrials.gov].).

Ranibizumab versus verteporfin for neovascular age-related macular degeneration.

BACKGROUND: We compared ranibizumab--a recombinant, humanized, monoclonal antibody Fab that neutralizes all active forms of vascular endothelial growth factor A--with photodynamic therapy with verteporfin in the treatment of predominantly classic neovascular age-related macular degeneration. METHODS: During the first year of this 2-year, multicenter, double-blind study, we randomly assigned patients in a 1:1:1 ratio to receive monthly intravitreal injections of ranibizumab (0.3 mg or 0.5 mg) plus sham verteporfin therapy or monthly sham injections plus active verteporfin therapy. The primary end point was the proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months. RESULTS: Of the 423 patients enrolled, 94.3% of those given 0.3 mg of ranibizumab and 96.4% of those given 0.5 mg lost fewer than 15 letters, as compared with 64.3% of those in the verteporfin group (P<0.001 for each comparison). Visual acuity improved by 15 letters or more in 35.7% of the 0.3-mg group and 40.3% of the 0.5-mg group, as compared with 5.6% of the verteporfin group (P<0.001 for each comparison). Mean visual acuity increased by 8.5 letters in the 0.3-mg group and 11.3 letters in the 0.5-mg group, as compared with a decrease of 9.5 letters in the verteporfin group (P<0.001 for each comparison). Among 140 patients treated with 0.5 mg of ranibizumab, presumed endophthalmitis occurred in 2 patients (1.4%) and serious uveitis in 1 (0.7%). CONCLUSIONS: Ranibizumab was superior to verteporfin as intravitreal treatment of predominantly classic neovascular age-related macular degeneration, with low rates of serious ocular adverse events. Treatment improved visual acuity on average at 1 year. (ClinicalTrials.gov number, NCT00061594 [ClinicalTrials.gov].).

Prostate Stereotactic Body Radiation Therapy With a Focal Simultaneous Integrated Boost: Acute Toxicity and Dosimetry Results From a Prospective Trial.

PURPOSE: This study aimed to report the early toxicity results of a prospective clinical trial of prostate stereotactic body radiation therapy (SBRT) to the entire prostate with a simultaneous integrated boost (SIB) to magnetic resonance imaging (MRI)-defined focal lesions. METHODS AND MATERIALS: Eligible patients included men with biopsy-proven prostate stage T1c to T2c adenocarcinoma, a Gleason score ≤7, and prostate-specific antigen values of ≤20 ng/mL, who had at least 1 focal lesion visible on MRI and a total prostate volume no greater than 120 cm3. SBRT consisted of a dose of 36.25 Gy to the entire prostate with an SIB of 40 Gy to the MRI-defined lesions, delivered in 5 fractions. The primary purpose of the study was to confirm the feasibility of treatment planning/delivery and to estimate the rate of urinary retention requiring placement of a Foley catheter within 90 days of treatment. This study was to be considered successful if urinary retention occurred in no more than 15% of cases, with a planned enrollment of at least 25 patients. RESULTS: A total of 26 men were enrolled, and all underwent SBRT as planned. Twenty patients (77%) had intermediate-risk features, and the remainder were low risk. A treatment plan that met the protocol-defined goals for all cases was developed. Two patients (7.7%) developed acute urinary symptoms that required the temporary placement of a Foley catheter. No grade 3+ toxicity events were observed. CONCLUSIONS: Planning and delivery of prostate SBRT with a whole prostate dose of 36.25 Gy and a focal 40 Gy SIB is feasible. Early follow-up suggests that this treatment is not associated with undue morbidity.

Conventional high-dose-rate brachytherapy with concomitant complementary IMRT boost: a novel approach for improving cervical tumor dose coverage.

PURPOSE: To investigate the feasibility of combining conventional high-dose-rate (HDR) brachytherapy with a concomitant complementary intensity-modulated radiotherapy (IMRT) boost for improved target coverage in cervical cancers. METHODS AND MATERIALS: Six patients with cervical cancer underwent conventional HDR (C-HDR) treatment. Computed tomography (CT) and magnetic resonance imaging (MRI) scans were acquired with a CT/MRI-compatible applicator in place. The clinical target volumes (CTVs), defined as the gross target volume with a 3-mm margin and the uterus, were delineated on the CT scans, along with the organs at risk (OARs). The IMRT plans were optimized to generate dose distributions complementing those of C-HDR to cover the CTV while maintaining low doses to the OARs (IMRT-HDR). For comparison, dwell-weight optimized HDR (O-HDR) plans were also generated to cover the CTV and spare the OARs. The three treatment techniques (C-HDR, O-HDR, and IMRT-HDR) were compared. The percentage of volume receiving 95% of the prescription dose (V(95)) was used to evaluate dose coverage to the CTV, and the minimal doses in the 2.0-cm(3) volume receiving the greatest dose were calculated to compare the doses to the OARs. RESULTS: The C-HDR technique provided very poor CTV coverage in 5 cases (V(95) <62%). Although O-HDR provided excellent gross tumor volume coverage (V(95) > or =96.9%), it resulted in unacceptably high doses to the OARs in all 6 cases and unsatisfactory coverage to the whole CTV in 3 cases. IMRT-HDR not only yielded substantially improved CTV coverage (average V(95) = 95.3%), but also kept the doses to the bladder and rectum reasonably low. CONCLUSION: Compared with C-HDR and O-HDR, concomitant IMRT boost complementary to C-HDR not only provided excellent CTV coverage, but also maintained reasonably low doses to the OARs.

Dynamics of the vaginal wall dose in HDR interstitial brachytherapy for gynecological cancer: Systematic analysis of phantom vs patient case.

This study aimed to investigate the dynamics of the vaginal wall dose for interstitial brachytherapy (ISBT). A patient undergoing ISBT was selected as the patient case. The phantom case was generated to simulate the patient case in all regards with the exception of parallel needle positions. The vaginal wall was contoured as a 0.5-cm expansion around the vaginal surface of the obturator. The prescribed ISBT dose was 20 Gy in 4 fractions. Six treatment plans were generated by modifying relative dwell times and needle positions (DTNP). The volume of the vaginal wall receiving > 150% of prescription dose (V> 150%) and D2cc of the vaginal wall were compared among plans. The V> 150% was much larger in the patient case (49.3%) due to unparallel needles compared with the phantom case (14.3%) without modification (plan 1). Among the 6 plans, reduced dwell time (plan 3) and no dwell time (plans 5 and 6) on the vaginal surface needles had the lowest vaginal wall doses with the use of a central obturator needle in both cases. In comparison of patient case plans 1, 3, 5, and 6, V150% was 49.2%, 19.0%, 21.3%, and 28.7%, respectively, and D2cc was 41.15 Gy, 33.10 Gy, 36.51 Gy, and 34.37 Gy, respectively, which was limited around each loaded needle. Modification of DTNP is able to reduce the vaginal wall volume exceeding 150% of the prescription dose in the patient case. Understanding these dynamics of the vaginal wall dose will improve dose optimization of ISBT and may reduce vaginal morbidities.

Image-based three-dimensional treatment planning of intracavitary brachytherapy for cancer of the cervix: dose-volume histograms of the bladder, rectum, sigmoid colon, and small bowel.

PURPOSE: The purpose of this study was to evaluate dose-volume histograms (DVHs) of bladder, rectum, sigmoid colon, and small bowel using image-based three-dimensional treatment planning for intracavitary brachytherapy. METHODS AND MATERIALS: Between 2001 and 2003, 22 patients with cancer of the cervix (1 IB1, 5 IB2, 11 IIB, 5 IIIB) were treated with computerized tomography (CT)-compatible high-dose-rate intracavitary applicators and underwent postimplant pelvic CT scans with the applicator in place. The volumes of organs at risk were digitized. For radiography-based planning, International Commission on Radiation Units and Measurements (ICRU) bladder and rectum point doses were calculated. For the CT-based planning, the DVHs were computed for the bladder, rectum, sigmoid colon, and small bowel. To compare doses to organs at risk, the minimum dose in 2.0cm(3) volume receiving the highest dose (D(2)) was determined from DVHs. These D(2) doses were compared with radiography-based ICRU point doses. RESULTS: The mean ICRU bladder point dose (401cGy) was markedly underestimated compared to the mean bladder D(2) dose (484cGy). However, the mean ICRU rectal point dose (412cGy) did not differ significantly from the mean rectal D(2) dose (373cGy). The most frequent organ receiving the highest D(2) dose was the sigmoid colon in 9 of 22 patients (41%) followed by the rectum in 7 of 22 patients (32%) and small bowel in 6 of 22 patients (27%). CONCLUSIONS: From CT-based three-dimensional (3-D) evaluation, the ICRU bladder point dose was substantially lower than bladder D(2) dose. Special attention should also be given to the areas of proximal rectum and sigmoid colon due to more frequent high D(2) dose in these areas.

Subcutaneous adipose tissue characteristics and the risk of biochemical recurrence in men with high-risk prostate cancer.

PURPOSE/OBJECTIVE(S): To assess subcutaneous adipose tissue characteristics by computed tomography (CT) as potential imaging biomarkers predictive of biochemical recurrence in men with high-risk prostate cancer receiving radiotherapy (RT). MATERIALS AND METHODS: This retrospective study included men with high-risk prostate cancer (PSA>20ng/ml, Gleason score ≥8, or clinical extraprostatic extension) treated between 2001 and 2012. All patients received definitive, dose-escalated external beam RT along with a course of neoadjuvant, concurrent, and adjuvant androgen deprivation therapy (ADT). Each patient also had a treatment planning CT that included the L4-L5 vertebral interface and prostate specific antigen (PSA) measurements for at least 2 years following RT. The subcutaneous adipose tissue was contoured on a single axial CT slice at the level of L4-L5. The average CT attenuation, in Hounsfield units (HU), of the structure was calculated and defined as SATHU. SATAREA was defined as the cross-sectional area of the structure (in cm2) that was then normalized by the square of patient height. Biochemical failure (BF) was defined as a PSA rise of 2ng/ml from the nadir. Freedom from BF (FFBF) was calculated from start time of ADT using the Kaplan-Meier method. Estimates of FFBF were stratified by SATHU and SATAREA quartiles. RESULTS: A total of 171 men met the inclusion criteria with a median follow-up of 5.6 years. The mean SATHU (±standard deviation) was -99.2HU (±6.1HU), and the mean SATAREA was 93.2cm2/m2 (±39.4cm2/m2). The 5- and 8-year rates of FFBF across all patients were 81.5% and 73.5%, respectively. Patients in the lowest quartile of SATHU experienced significantly higher FFBF compared to the other quartiles (Q4 vs. Q1, P = 0.017; Q4 vs. Q2, P = 0.045; Q4 vs. Q3, P = 0.044). No other differences in FFBF were observed between quartiles of SATAREA or other quartiles of SATHU. CONCLUSION: Lower subcutaneous adipose tissue density was associated with a lower rate of BF following RT with ADT for men with high-risk prostate cancer. Further research is needed to elucidate the biological underpinnings of this clinical finding and the role adipose tissue plays in modulating oncologic behavior and outcomes.

Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration: year 1 results of the FOCUS Study.

OBJECTIVE: To investigate the safety and efficacy of intravitreal ranibizumab treatment combined with verteporfin photodynamic therapy (PDT) in patients with predominantly classic choroidal neovascularization secondary to age-related macular degeneration. METHODS: In this 2-year, phase I/II, multicenter, randomized, single-masked, controlled study, patients received monthly ranibizumab (0.5 mg) (n = 106) or sham (n = 56) injections. The PDT was performed 7 days before initial ranibizumab or sham treatment and then quarterly as needed. MAIN OUTCOMES MEASURES: Proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months (primary efficacy outcome) and the incidence and severity of adverse events. RESULTS: At 12 months, 90.5% of the ranibizumab-treated patients and 67.9% of the control patients had lost fewer than 15 letters (P<.001). The most frequent ranibizumab-associated serious ocular adverse events were intraocular inflammation (11.4%) and endophthalmitis (1.9%; 4.8% if including presumed cases). On average, patients with serious inflammation had better visual acuity outcomes at 12 months than did controls. Key serious nonocular adverse events included myocardial infarctions in the PDT-alone group (3.6%) and cerebrovascular accidents in the ranibizumab-treated group (3.8%). CONCLUSION/APPLICATION TO CLINICAL PRACTICE: Ranibizumab + PDT was more efficacious than PDT alone for treating neovascular age-related macular degeneration. Although ranibizumab treatment increased the risk of serious intraocular inflammation, affected patients, on average, still experienced visual acuity benefit.

Low-dose-rate vs. high-dose-rate intracavitary brachytherapy for carcinoma of the cervix: The University of Alabama at Birmingham (UAB) experience.

PURPOSE: To review the clinical outcome retrospectively of cervical cancer patients treated definitively with either high-dose-rate (HDR) or low-dose-rate (LDR) brachytherapy. METHODS AND MATERIALS: One hundred sixty patients (44 Stage I, 83 Stage II, and 33 Stage III) were treated from 1990 to 2000 with curative intent for carcinoma of the cervix. One hundred three LDR patients were compared to 57 HDR patients. Two groups were treated during the same period. An external beam dose of 45 Gy to the entire pelvis was delivered at 1.8 Gy per fraction to most patients before the first intracavitary insertion in both groups. Brachytherapy was delivered in one to two LDR implants or four to five HDR implants at 6 Gy per fraction. The prescribed dose to Point A for LDR was at least 80-85 Gy. Patient characteristics were similar for each cohort. Point A doses were similar for each stage. The primary endpoints assessed were survivals and failure sites. Endpoints were estimated using the Kaplan-Meier method and comparisons between treatment groups were performed using the log-rank test. RESULTS: The median followup was 48 months for the LDR group and 59 months for the HDR group. For all stages combined and stage for stage in both groups, there was no statistically significant difference in locoregional control, cause-specific survival, and overall survival for LDR compared with HDR. Locoregional control and overall survival were 78% and 60% for LDR compared to 76% and 55% for HDR at 3 years, respectively (p = 0.96 and p = 0.48). Median cause-specific survival values for LDR vs. HDR were 71 and 81 months, respectively (p = 0.62). The cause-specific survival for LDR patients was 62% compared with 59% for HDR patients at 3 years. For Stage IB2, II, and III LDR patients, cause-specific survival rates were 62%, 67%, and 45%, compared to 67%, 57%, and 33% for HDR at 3 years, respectively (p = 0.75, p = 0.95, and p = 0.48). For patients with a recorded site of first failure, the most common site was locoregional (56%) and then distant metastases (26%). Eight patients who were cancer free developed late complications requiring surgical intervention. Two patients were in the HDR group (3.5%) and 5 in the LDR group (4.8%). CONCLUSIONS: Similar outcome was observed for LDR compared with HDR intracavitary brachytherapy for the entire cohort. In this review, HDR group was not inferior to LDR group in advanced stages. This is likely because our patients were treated with brachytherapy after a high dose of external pelvic radiotherapy in both LDR and HDR patients.

Image-based intracavitary brachytherapy in the treatment of inoperable uterine cancer: individual dose specification at specific anatomical sites.

PURPOSE: With advances in imaging studies, dose specification for uterine cancer can be defined at specific anatomical sites such as the myometrium or the serosal surface rather than at arbitrary points or milligram-hours. This report presents our experience with image-based brachytherapy for inoperable uterine cancer. METHODS AND MATERIALS: Eight patients with organ-confined uterine cancer (2 Stage I GI, 3 Stage I G2, 3 Stage I G3) underwent definitive radiation therapy because of poor medical condition. All the patients underwent a CT or MRI scan of the pelvis before intracavitary application. Based on the size of the uterine cavity, a single-channel intrauterine applicator was selected for a small uterus, and a multiple-channel intrauterine applicator was used for a large uterus. A CT (n=5) or MRI (n=3) scan of the pelvis was performed with the applicator in place in addition to orthogonal pelvic films. Individualized dose specification was 75Gy to the midmyometrium and limited to 50Gy to the serosal surface of the uterus based on imaging information. RESULTS: Four patients with Stage I G1-2 disease had intracavitary brachytherapy alone. Four patients with Stage I G2-3 disease were treated with a combination of external pelvic radiation and intracavitary brachytherapy. Six patients had low-dose-rate brachytherapy, and 2 patients had high-dose-rate brachytherapy. Five patients had single-channel intrauterine brachytherapy, and 3 patients had multiple-channel brachytherapy. Based on the measurements of the uterine wall thickness by the imaging studies, the dose specification was prescribed to 1.5 cm lateral to the central axis of the uterus in 4 patients, 2.0 cm in 3 patients, and 2.5 cm in 1 patient. The medium followup time after radiation treatment was 38 months. Six patients are alive without evidence of disease, and 2 patients died of other causes. All patients had local control without major side effects. CONCLUSIONS: Image-based brachytherapy based on individualized dose specification at specific anatomical sites can be done easily and provides excellent local control for inoperable uterine cancer.

Bulb of penis as a marker for prostatic apex in external beam radiotherapy of prostate cancer.

PURPOSE: To investigate the relationship between the bulb of the penis and the peak of the urethrogram, and to compare this measurement with the ischial tuberosities (ITs) to peak distance. METHODS AND MATERIALS: Pelvic CT scans from 50 consecutive patients with localized prostate cancer were analyzed to identify the penile bulb. Each patient was required to undergo retrograde urethrography during CT-based treatment planning with 3-mm slices. The peak of the urethrogram was defined as the last CT slice in which the contrast dye in the urethra could be visualized. Measurements were taken from the slice containing the most superior aspect of the penile bulb to the last slice of the urethrogram peak. The superior aspect of the penile bulb was defined as the CT slice nearest the peak that contained a bulbous structure at the base of the penis. This distance was defined as the bulb-peak distance. Similarly, the IT-peak distance was recorded for comparison. RESULTS: The mean bulb-peak and IT-peak distances were calculated for 47 of 50 patients. The peak of the urethrogram was unable to be evaluated in 3 patients. The mean, median, and range bulb-peak distance was 2.4 mm (SD 1.8), 3 mm, and 0-6 mm, respectively. The mean, median, and range IT-peak distance was 20.1 mm (SD 6.6), 21 mm, and 6-33 mm, respectively. No patient had the bulb located above the apex of the urethrogram. CONCLUSION: The bulb of the penis is a relatively consistent soft-tissue landmark compared with the ITs and is located an average of 3 mm below the peak of the urethrogram. Therefore, the bulb of the penis is another landmark for the identification of the prostatic apex and is less invasive than retrograde urethrography.

IMRT dose escalation for positive para-aortic lymph nodes in patients with locally advanced cervical cancer while reducing dose to bone marrow and other organs at risk.

PURPOSE: To evaluate the feasibility of dose-escalated para-aortic lymph node (PALN) intensity modulated radiation therapy (IMRT) in reducing the dose to bone marrow, bowel, spinal cord, and kidneys, compared with conventional radiation techniques of PALNs in patients with locally advanced cervical cancer and PALN metastases. METHODS AND MATERIALS: Computed tomography scans and MRI studies of 5 cervical cancer patients with PALN involvement were transferred to an IMRT treatment planning workstation (Eclipse/Helios) for image fusion and definition of target volumes and critical structures. The positive PALNs identified on fused computed tomography-magnetic resonance images were defined as the gross target volume (GTV), and the PALN region was defined as the planning target volume. There were 2 distinct treatment regions: the PALN region superior to the isocenter and the whole-pelvis region inferior to the isocenter. Three treatment planning techniques were compared: AP/PA (both regions), 4-field box (both regions), and PALN-IMRT with 4-field box to the whole-pelvis field. With IMRT, the radiation dose to the GTV was escalated from the conventional 45 Gy to 60 Gy (2.4 Gy/fraction), whereas the planning target volume and whole-pelvis region received 45 Gy. The treatment planning isocenter was placed at the L4-L5 vertebral body interspace, and this allowed the two treatment regions to be abutted using independent jaws. RESULTS: This study has demonstrated the feasibility of escalating the dose delivered to grossly positive PALNs to 60 Gy (2.4 Gy/fraction) with a 95.6% median GTV coverage, concomitantly with conventional treatment of the whole-pelvis region. PALN-IMRT significantly reduced V(40) bone marrow compared to the AP/PA and 4-field box techniques with a median of 21.3%, 98%, and 49.7%, respectively. The PALN-IMRT and 4-field box techniques showed a reduction in V(45) bowel over the AP/PA technique, but a level of statistical significance was not reached. The spinal cord received a significantly higher maximum dose when PALNs were treated with AP/PA fields. Alternatively, the use of the 4-field box technique yielded a significant increase in V(22) kidney on both sides. The placement of the treatment planning isocenter at the L4-L5 interspace allowed the PALN-IMRT and whole-pelvis regions to be treated with a relatively uniform dose at the abutment region. CONCLUSION: In this dosimetric analysis, we demonstrated that dose-escalated PALN-IMRT with conventional whole-pelvis radiotherapy is feasible with significant sparing of critical normal structures compared to PALN conventional radiation techniques.