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1.  Helical intensity-modulated Radiotherapy of the Pelvic Lymph Nodes with Integrated Boost to the Prostate Bed - Initial Results of the PLATIN 3 Trial 
BMC Cancer  2014;14:20.
Adjuvant and salvage radiotherapy of the prostate bed are established treatment options for prostate cancer. While the benefit of an additional radiotherapy of the pelvic lymph nodes is still under debate, the PLATIN 3 prospective phase II clinical trial was initiated to substantiate toxicity data on postoperative IMRT of the pelvic lymph nodes and the prostate bed.
From 2009 to 2011, 40 patients with high-risk prostate cancer after prostatectomy with pT3 R0/1 M0 or pT2 R1 M0 or a PSA recurrence and either > 20% risk of lymph node involvement and inadequate lymphadenectomy or pN + were enrolled. Patients received two months of antihormonal treatment (AT) before radiotherapy. AT continuation was mandatory during radiotherapy and was recommended for another two years. IMRT of the pelvic lymph nodes (51.0 Gy) with a simultaneous integrated boost to the prostate bed (68.0 Gy) was performed in 34 fractions. PSA level, prostate-related symptoms and quality of life were assessed at regular intervals for 24 months.
Of the 40 patients enrolled, 39 finished treatment as planned. Overall acute toxicity rates were low and no acute grade 3/4 toxicity occurred. Only 22.5% of patients experienced acute grade 2 gastrointestinal (GI) and genitourinary (GU) toxicity. During follow-up, 10.0% late grade 2 GI and 5.0% late grade 2 GU toxicity occurred, and one patient developed late grade 3 proctitis and enteritis. After a median observation time of 24 months the PLATIN 3 trial has shown in 97.5% of all patients sufficient safety and thus met its prospectively defined aims. After a median of 24 months, 34/38 patients were free of a PSA recurrence.
Postoperative whole-pelvis IMRT with an integrated boost to the prostate bed can be performed safely and without excessive toxicity.
Trial registration
Trial Numbers: ARO 2009–05, NCT01903408.
PMCID: PMC3893457  PMID: 24422782
Prostate; Postoperative Radiotherapy; Antihormonal treatment; Pelvic lymph nodes; IMRT; Tomotherapy
2.  A randomized hypofractionation dose escalation trial for high risk prostate cancer patients: interim analysis of acute toxicity and quality of life in 124 patients 
The α/β ratio for prostate cancer is postulated being in the range of 0.8 to 2.2 Gy, giving rise to the hypothesis that there may be a therapeutic advantage to hypofractionation. To do so, we carried out a randomized trial comparing hypofractionated and conventionally fractionated image-guided intensity modulated radiotherapy (IG-IMRT) in high-risk prostate cancer. Here, we report on acute toxicity and quality of life (QOL) for the first 124 randomized patients.
The trial compares 76 Gy in 38 fractions (5 fractions/week) (Arm 1) to 63 Gy in 20 fractions (4 fractions/week) (Arm 2) (IG-IMRT). Prophylactic pelvic lymph node irradiation with 46 Gy in 23 fractions sequentially (Arm 1) and 44 Gy in 20 fractions simultaneously (Arm 2) was applied. All patients had long term androgen deprivation therapy (ADT) started before RT. Both physician-rated acute toxicity and patient-reported QOL using EPIC questionnaire are described.
There were no differences in overall maximum acute gastrointestinal (GI) or genitourinary (GU) toxicity. Compared to conventional fractionation (Arm 1), GI and GU toxicity both developed significantly earlier but also disappeared earlier in the Arm 2, reaching significant differences from Arm 1 at week 8 and 9. In multivariate analyses, only parameter shown to be related to increased acute Grade ≥1 GU toxicity was the study Arm 2 (p = 0.049). There were no statistically significant differences of mean EPIC scores in any domain and sub-scales. The clinically relevant decrease (CRD) in EPIC urinary domain was significantly higher in Arm 2 at month 1 with a faster recovery at month 3 as compared to Arm 1.
Hypofractionation at 3.15 Gy per fraction to 63 Gy within 5 weeks was well tolerated. The GI and GU physician-rated acute toxicity both developed earlier but recovered faster using hypofractionation. There was a correlation between acute toxicity and bowel and urinary QOL outcomes. Longer follow-up is needed to determine the significance of these associations with late toxicity.
PMCID: PMC3846611  PMID: 24007322
3.  Hypofractionated helical tomotherapy (75 Gy at 2.5 Gy per fraction) for localized prostate cancer: long-term analysis of gastrointestinal and genitourinary toxicity 
OncoTargets and therapy  2014;7:553-566.
This study is a report on the long-term analysis of acute and late toxicities for patients with localized prostate cancer treated with hypofractionated helical tomotherapy.
From January 2008 through August 2013, 70 patients with localized prostate cancer were treated definitively with hypofractionated helical tomotherapy. The helical tomotherapy was designed to deliver 75 Gy in 2.5 Gy per fraction to the prostate gland, 63 Gy in 2.1 Gy per fraction to the seminal vesicles, and 54 Gy in 1.8 Gy per fraction to the pelvic lymph nodes. Incidence rates and predictive factors for radiation toxicities were analyzed retrospectively.
The incidences of grades 0, 1, and 2 acute gastrointestinal (GI) toxicity were 51.4%, 42.9%, and 5.7%, and those of acute genitourinary (GU) toxicity were 7.1%, 64.3%, and 28.6%, respectively. The maximum dose of rectum and bladder V40 and V50 were significant predictive factors for acute GI and GU toxicity. The cutoff value of rectum maximum dose and bladder V40 and V50 by receiver-operating characteristic curves analysis were 76.5 Gy, 17.3%, and 10.2%, respectively. The incidences of grades 0, 1, and 2 late GI toxicity were 82.0%, 14.0%, and 4.0%, and those of late GU toxicity were 18.0%, 56.0%, and 26.0%, respectively. Rectum V70 and bladder V70 and V75 were significant predictive factors for late GI and GU toxicity. The cutoff value of rectum V70 and bladder V70 and V75 by receiver-operating characteristic curves analysis was 2.8%, 2.8%, and 1.0%, respectively.
Hypofractionated helical tomotherapy using a schedule of 75 Gy at 2.5 Gy per fraction had favorable acute and late toxicity rates and no serious complication, such as grade 3 or worse toxicity. To minimize radiation toxicities, constraining the rectum maximum dose to less than 76.5 Gy, rectum V70 to less than 2.8%, bladder V40 to less than 17.3%, bladder V50 to less than 10.2%, bladder V70 to less than 2.8%, and bladder V75 to less than 1.0% would be necessary.
PMCID: PMC3986286  PMID: 24748805
prostate cancer; helical tomotherapy; hypofractionated radiotherapy; radiation toxicity; predictive factor
4.  Comparing two strategies of dynamic intensity modulated radiation therapy (dIMRT) with 3-dimensional conformal radiation therapy (3DCRT) in the hypofractionated treatment of high-risk prostate cancer 
To compare two strategies of dynamic intensity modulated radiation therapy (dIMRT) with 3-dimensional conformal radiation therapy (3DCRT) in the setting of hypofractionated high-risk prostate cancer treatment.
3DCRT and dIMRT/Helical Tomotherapy(HT) planning with 10 CT datasets was undertaken to deliver 68 Gy in 25 fractions (prostate) and simultaneously delivering 45 Gy in 25 fractions (pelvic lymph node targets) in a single phase. The paradigms of pelvic vessel targeting (iliac vessels with margin are used to target pelvic nodes) and conformal normal tissue avoidance (treated soft tissues of the pelvis while limiting dose to identified pelvic critical structures) were assessed compared to 3DCRT controls. Both dIMRT/HT and 3DCRT solutions were compared to each other using repeated measures ANOVA and post-hoc paired t-tests.
When compared to conformal pelvic vessel targeting, conformal normal tissue avoidance delivered more homogenous PTV delivery (2/2 t-test comparisons; p < 0.001), similar nodal coverage (8/8 t-test comparisons; p = ns), higher and more homogenous pelvic tissue dose (6/6 t-test comparisons; p < 0.03), at the cost of slightly higher critical structure dose (Ddose, 1–3 Gy over 5/10 dose points; p < 0.03). The dIMRT/HT approaches were superior to 3DCRT in sparing organs at risk (22/24 t-test comparisons; p < 0.05).
dIMRT/HT nodal and pelvic targeting is superior to 3DCRT in dose delivery and critical structure sparing in the setting of hypofractionation for high-risk prostate cancer. The pelvic targeting paradigm is a potential solution to deliver highly conformal pelvic radiation treatment in the setting of nodal location uncertainty in prostate cancer and other pelvic malignancies.
PMCID: PMC2249591  PMID: 18179695
5.  RTOG GU Radiation Oncology Specialists Reach Consensus on Pelvic Lymph Node Volumes for High-Risk Prostate Cancer 
Radiation therapy to the pelvic lymph nodes in high risk prostate cancer is required on several RTOG clinical trials. Based on a prior lymph node contouring project we have shown significant disagreement in the definition of pelvic lymph node volumes amongst GU radiation oncology specialists involved in developing and executing current RTOG trials.
A consensus meeting was held on October 3, 2007, to reach agreement on pelvic lymph node volumes. Data was presented to address the lymph node drainage of the prostate. Extensive discussion ensued to develop CTV pelvic lymph node consensus.
Consensus was obtained resulting in CT image-based pelvic lymph node CTVs. Based on this consensus the pelvic lymph node volumes to be irradiated include: distal common iliacpresacral lymph nodes (S1–S3)external iliac lymph nodesinternal iliac lymph nodesobturator lymph nodes Lymph node CTVs include the vessels (artery and vein) and a 7mm radial margin being careful to “carve out” bowel, bladder, bone, and muscle. Volumes begin at the L5/S1 interspace and end at the superior aspect of the pubic bone. Consensus on DVH constraints for OARs were also attained.
Consensus on pelvic lymph node CTVs for radiation therapy to address high-risk prostate cancer was attained and is available as web-based CT images as well as a descriptive format through the RTOG. This will allow for uniformity in evaluating the benefit and risk of such treatment.
PMCID: PMC2905150  PMID: 18947938
prostate cancer; pelvic lymph nodes; target volume; IMRT; Radiation OncologyGuidelines
6.  Quality-of-life outcomes in high-risk prostate cancer patients treated with helical tomotherapy in a hypofractionated radiation schedule with long-term androgen suppression 
Current Oncology  2012;19(3):e201-e210.
We examined the impact of hypofractionated radiation therapy and androgen suppression therapy (ast) on quality of life (qol) in high-risk prostate cancer patients.
Between March 2005 and March 2007, 60 patients with high-risk prostate cancer were enrolled in a prospective phase ii study. All patients received 68 Gy (2.72 Gy per fraction) to the prostate gland and 45 Gy (1.8 Gy per fraction) to the pelvic lymph nodes in 25 fractions over 5 weeks. Of the 60 patients, 58 received ast. The University of California–Los Angeles Prostate Cancer Index questionnaire was used to prospectively measure qol at baseline (month 0) and at 1, 6, 12, 18, 24, 30, and 36 months after radiation treatment. The generalized estimating equation approach was used to compare the qol scores at 1, 6, 12, 18, 24, 30, and 36 months with those at baseline.
We observed a significant decrease in qol items related to bowel and sexual function. Several qol items related to bowel function were significantly adversely affected at both 1 and 6 months, with improvement toward 6 months. Although decreased qol scores persisted beyond the 6-month mark, they began to re-approach baseline at the 18- to 24-month mark. Most sexual function items were significantly adversely affected at both 1 and 6 months, but the effects were not considered to be a problem by most patients. A complete return to baseline was not observed for either bowel or sexual function. Urinary function items remained largely unaffected, with overall urinary function being the only item adversely affected at 6 months, but not at 1 month. Urinary function returned to baseline and remained unimpaired from 18 months onwards.
In our study population, who received hypofractionated radiation delivered using dynamic intensity-modulated radiotherapy with inclusion of the pelvic lymph nodes, and 2–3 years of ast prescription, qol with respect to bowel and sexual function was significantly affected; qol with respect to urinary function was largely unaffected. Our results are comparable to those in other published studies.
PMCID: PMC3364781  PMID: 22670110
Prostate cancer; quality of life; hypofractionation; imrt; toxicity; ast
7.  The technical feasibility of an image-guided intensity-modulated radiotherapy (IG-IMRT) to perform a hypofractionated schedule in terms of toxicity and local control for patients with locally advanced or recurrent pancreatic cancer 
The purpose of this study was to evaluate the technical feasibility of an image-guided intensity modulated radiotherapy (IG-IMRT) using involved-field technique to perform a hypofractionated schedule for patients with locally advanced or recurrent pancreatic cancer.
From May 2009 to November 2011, 12 patients with locally advanced or locally recurrent pancreatic cancer received hypofractionated CCRT using TomoTherapy Hi-Art with concurrent and sequential chemotherapy at Seoul St. Mary’s Hospital, the Catholic University of Korea. The total dose delivered was 45 Gy in 15 fractions or 50 Gy in 20 fractions. The target volume did not include the uninvolved regional lymph nodes. Treatment planning and delivery were performed using the IG-IMRT technique. The follow-up duration was a median of 31.1 months (range: 5.7-36.3 months).
Grade 2 or worse acute toxicities developed in 7 patients (58%). Grade 3 or worse gastrointestinal and hematologic toxicity occurred in 0% and 17% of patients, respectively. In the response evaluation, the rates of partial response and stable disease were 58% and 42%, respectively. The rate of local failure was 8% and no regional failure was observed. Distant failure was the main cause of treatment failure. The progression-free survival and overall survival durations were 7.6 and 12.1 months, respectively.
The involved-field technique and IG-IMRT delivered via a hypofractionated schedule are feasible for patients with locally advanced or recurrent pancreatic cancer.
PMCID: PMC3551741  PMID: 23216796
Unresectable pancreatic cancer; Hypofractionated radiotherapy; Image-guided; Intensity-modulated radiotherapy
8.  Target volume definition in high-risk prostate cancer patients using sentinel node SPECT/CT and 18 F-choline PET/CT 
To assess the influence of sentinel lymph nodes (SNs) SPECT/CT and 18 F-choline (18 F-FCH) PET/CT in radiotherapy (RT) treatment planning for prostate cancer patients with a high-risk for lymph node (LN) involvement.
Twenty high-risk prostate cancer patients underwent a pelvic SPECT acquisition following a transrectal ultrasound guided injection of 99mTc-Nanocoll into the prostate. In all patients but one an 18 F-FCH PET/CT for RT treatment planning was performed. SPECT studies were coregistered with the respective abdominal CTs. Pelvic SNs localized on SPECT/CT and LN metastases detected by 18 F-FCH PET/CT were compared to standard pelvic clinical target volumes (CTV).
A total of 104 pelvic SNs were identified on SPECT/CT (mean 5.2 SNs/patient; range 1–10). Twenty-seven SNs were located outside the standard pelvic CTV, 17 in the proximal common iliac and retroperitoneal regions above S1, 9 in the pararectal fat and 1 in the inguinal region. SPECT/CT succeeded to optimize the definition of the CTV and treatment plans in 6/20 patients due to the presence of pararectal SNs located outside the standard treatment volume. 18 F-FCH PET/CT identified abnormal tracer uptake in the iliac LN region in 2/19 patients. These abnormal LNs were negative on SPECT/CT suggesting a potential blockade of lymphatic drainage by metastatic LNs with a high tumour burden.
Multimodality imaging which combines SPECT/CT prostate lymphoscintigraphy and 18 F-FCH PET/CT identified SNs outside standard pelvic CTVs or highly suspicious pelvic LNs in 40% of high-risk prostate cancer patients, highlighting the potential impact of this approach in RT treatment planning.
PMCID: PMC3561224  PMID: 22873771
Prostate cancer; Radiotherapy; SPECT; Sentinel node; 18 F-choline PET/CT
9.  High-dose-rate brachytherapy and hypofractionated external beam radiotherapy combined with long-term hormonal therapy for high-risk and very high-risk prostate cancer: outcomes after 5-year follow-up 
Journal of Radiation Research  2013;55(3):509-517.
The purpose of this study was to report the outcomes of high-dose-rate (HDR) brachytherapy and hypofractionated external beam radiotherapy (EBRT) combined with long-term androgen deprivation therapy (ADT) for National Comprehensive Cancer Network (NCCN) criteria-defined high-risk (HR) and very high-risk (VHR) prostate cancer. Data from 178 HR (n = 96, 54%) and VHR (n = 82, 46%) prostate cancer patients who underwent 192Ir-HDR brachytherapy and hypofractionated EBRT with long-term ADT between 2003 and 2008 were retrospectively analyzed. The mean dose to 90% of the planning target volume was 6.3 Gy/fraction of HDR brachytherapy. After five fractions of HDR treatment, EBRT with 10 fractions of 3 Gy was administered. All patients initially underwent ≥6 months of neoadjuvant ADT, and adjuvant ADT was continued for 36 months after EBRT. The median follow-up was 61 months (range, 25–94 months) from the start of radiotherapy. The 5-year biochemical non-evidence of disease, freedom from clinical failure and overall survival rates were 90.6% (HR, 97.8%; VHR, 81.9%), 95.2% (HR, 97.7%; VHR, 92.1%), and 96.9% (HR, 100%; VHR, 93.3%), respectively. The highest Radiation Therapy Oncology Group-defined late genitourinary toxicities were Grade 2 in 7.3% of patients and Grade 3 in 9.6%. The highest late gastrointestinal toxicities were Grade 2 in 2.8% of patients and Grade 3 in 0%. Although the 5-year outcome of this tri-modality approach seems favorable, further follow-up is necessary to validate clinical and survival advantages of this intensive approach compared with the standard EBRT approach.
PMCID: PMC4014151  PMID: 24222312
high-dose-rate brachytherapy; prostate cancer; androgen deprivation therapy; high-risk; very high-risk
10.  Hypofractionated external-beam radiation therapy (HEBRT) versus conventional external-beam radiation (CEBRT) in patients with localized prostate cancer: a systematic review and meta-analysis 
Core Evidence  2013;8:1-13.
The purpose of this work was to conduct a systematic review and meta-analysis of all randomized controlled trials comparing the efficacy and side effect profile of hypofractionated versus conventional external-beam radiation therapy for prostate cancer.
Several databases were searched, including Medline, EmBase, LiLACS, and Central. The endpoints were freedom from biochemical failure and side effects. We performed a meta-analysis of the published data. The results are expressed as the hazard ratio (HR) or risk ratio (RR), with the corresponding 95% confidence interval (CI).
The final analysis included nine trials comprising 2702 patients. Freedom from biochemical failure was reported in only three studies and was similar in patients who received hypofractionated or conventional radiotherapy (fixed effect, HR 1.03, 95% CI 0.88–1.20; P = 0.75), with heterogeneity [χ2 = 15.32, df = 2 (P = 0.0005); I2 = 87%]. The incidence of acute adverse gastrointestinal events was higher in the hypofractionated group (fixed effect, RR 2.02, 95% CI 1.45–2.81; P < 0.0001). We also found moderate heterogeneity on this analysis [χ2 = 7.47, df = 5 (P = 0.19); I2 = 33%]. Acute genitourinary toxicity was similar among the groups (fixed effect, RR 1.19, 95% CI 0.95–1.49; P = 0.13), with moderate heterogeneity [χ2 = 5.83, df = 4 (P = 0.21); I2 = 31%]. The incidence of all late adverse events was the same in both groups (fixed effect, gastrointestinal toxicity, RR 1.17, 95% CI 0.79–1.72, P = 0.44; and acute genitourinary toxicity, RR 1.16, 95% CI 0.80–1.68, P = 0.44).
Hypofractionated radiotherapy in localized prostate cancer was not superior to conventional radiotherapy and showed higher acute gastrointestinal toxicity in this meta-analysis. Because the number of published studies is still small, future assessments should be conducted to clarify better the true role of hypofractionated radiotherapy in patients with prostate cancer.
PMCID: PMC3596128  PMID: 23526383
hypofractionated; radiotherapy; prostate cancer; systematic review; acute radiation effects
11.  Low rate of lymphedema after extended pelvic lymphadenectomy followed by pelvic irradiation of node-positive prostate cancer 
The aim of the present study was to evaluate the prevalence and severity of lower limb lymphedema after pelvic lymphadenectomy and radiotherapy to the pelvic lymph nodes in patients with prostate cancer.
Twenty-six patients underwent combined treatment for high-risk node-positive prostate cancer at Skåne University Hospital between April 2008 and March 2011. The treatment consisted of extended pelvic lymphadenectomy followed by androgen deprivation therapy and radiotherapy. The pelvic lymphnodes, prostate and seminal vesicles were treated with external beam radiotherapy (EBRT) to an absorbed dose of 50 Gy followed by a brachytherapy (BT) boost of 2x10 Gy to the prostate only. Twenty-two patients accepted an invitation to a clinical examination with focus on lower limb swelling. The median time between the end of radiotherapy and examination was 2.2 years (range 1.2–4.1).
Six patients (27%) experienced grade 1 lymphedema and two patients (9%) grade 2 while none had grade 3 or 4 according to the CTC Common Toxicity Criteria scale 4.0. Three patients required treatment with compression stockings.
Brachytherapy and pelvic EBRT have a low incidence of lymphedema (at median 2.2 y after treatment) in patients with high-risk node-positive prostate cancer that have undergone pelvic lymph node dissection.
PMCID: PMC3842657  PMID: 24252686
Prostate cancer; Lymphadenectomy; Pelvic irradiation; Node-positive; Lymphedema
12.  Rationale, conduct, and outcome using hypofractionated radiotherapy in prostate cancer 
Seminars in radiation oncology  2008;18(4):249-256.
Hypofractionated radiation therapy for prostate cancer has become of increasing interest with the recognition of a potential improvement in therapeutic ratio with treatments delivered in larger-sized fractions. In addition, the associated reduction in fraction number produces attractive cost and patient convenience advantages as well.
A still limited but growing number of hypofractionation trials have reported acceptable short-term levels of toxicity and biochemical control, but most have insufficient follow-up to assure the long-term safety and efficacy of this approach. This situation will improve as many currently active trials mature, particularly several high value randomized trials. In contrast, extreme hypofractionation, with schedules delivering only on the order of 5 fractions, is truly in its infancy for prostate cancer, with extremely limited tolerance and efficacy information currently available.
Several uncertainties in the radiobiology of hypofractionation mitigate for an organized, cautious investigational approach. The fractionation response (α/β ratio) of prostate cancers and, for that matter, late responding normal tissues, has yet to be rigorously defined. Additionally, the linear quadratic (LQ) model used in the design of hypofractionation schedules is subject to its own uncertainties, particularly with respect to the upper limit of fraction sizes for which it remains valid.
Contemporary dose escalated radiation therapy is already highly effective, making it imperative that ongoing and future studies of hypofractionation be carried out in carefully designed, randomized clinical trials. Clinical validation permitting, the adaptation of hypofractionation as a standard of care could profoundly influence future management of localized prostate cancer.
PMCID: PMC2674313  PMID: 18725112
13.  Image Guided Hypofractionated Radiotherapy by Helical Tomotherapy for Prostate Carcinoma: Toxicity and Impact on Nadir PSA 
BioMed Research International  2014;2014:541847.
Aim. To evaluate the toxicity of a hypofractionated schedule for primary radiotherapy (RT) of prostate cancer as well as the value of the nadir PSA (nPSA) and time to nadir PSA (tnPSA) as surrogate efficacy of treatment. Material and Methods. Eighty patients underwent hypofractionated schedule by Helical Tomotherapy (HT). A dose of 70.2 Gy was administered in 27 daily fractions of 2.6 Gy. Acute and late toxicities were graded on the RTOG/EORTC scales. The nPSA and the tnPSA for patients treated with exclusive RT were compared to an equal cohort of 20 patients treated with conventional fractionation and standard conformal radiotherapy. Results. Most of patients (83%) did not develop acute gastrointestinal (GI) toxicity and 50% did not present genitourinary (GU) toxicity. After a median follow-up of 36 months only grade 1 of GU and GI was reported in 6 and 3 patients as late toxicity. Average tnPSA was 30 months. The median value of nPSA after exclusive RT with HT was 0.28 ng/mL and was significantly lower than the median nPSA (0.67 ng/mL) of the conventionally treated cohort (P = 0.02). Conclusions. Hypofractionated RT schedule with HT for prostate cancer treatment reports very low toxicity and reaches a low level of nPSA that might correlate with good outcomes.
PMCID: PMC3976914  PMID: 24745018
14.  Intensity modulated radiotherapy for high risk prostate cancer based on sentinel node SPECT imaging for target volume definition 
BMC Cancer  2005;5:91.
The RTOG 94-13 trial has provided evidence that patients with high risk prostate cancer benefit from an additional radiotherapy to the pelvic nodes combined with concomitant hormonal ablation. Since lymphatic drainage of the prostate is highly variable, the optimal target volume definition for the pelvic lymph nodes is problematic. To overcome this limitation, we tested the feasibility of an intensity modulated radiation therapy (IMRT) protocol, taking under consideration the individual pelvic sentinel node drainage pattern by SPECT functional imaging.
Patients with high risk prostate cancer were included. Sentinel nodes (SN) were localised 1.5–3 hours after injection of 250 MBq 99mTc-Nanocoll using a double-headed gamma camera with an integrated X-Ray device. All sentinel node localisations were included into the pelvic clinical target volume (CTV). Dose prescriptions were 50.4 Gy (5 × 1.8 Gy / week) to the pelvis and 70.0 Gy (5 × 2.0 Gy / week) to the prostate including the base of seminal vesicles or whole seminal vesicles. Patients were treated with IMRT. Furthermore a theoretical comparison between IMRT and a three-dimensional conformal technique was performed.
Since 08/2003 6 patients were treated with this protocol. All patients had detectable sentinel lymph nodes (total 29). 4 of 6 patients showed sentinel node localisations (total 10), that would not have been treated adequately with CT-based planning ('geographical miss') only. The most common localisation for a probable geographical miss was the perirectal area. The comparison between dose-volume-histograms of IMRT- and conventional CT-planning demonstrated clear superiority of IMRT when all sentinel lymph nodes were included. IMRT allowed a significantly better sparing of normal tissue and reduced volumes of small bowel, large bowel and rectum irradiated with critical doses. No gastrointestinal or genitourinary acute toxicity Grade 3 or 4 (RTOG) occurred.
IMRT based on sentinel lymph node identification is feasible and reduces the probability of a geographical miss. Furthermore, IMRT allows a pronounced sparing of normal tissue irradiation. Thus, the chosen approach will help to increase the curative potential of radiotherapy in high risk prostate cancer patients.
PMCID: PMC1190164  PMID: 16048656
15.  Modeling of α/β for late rectal toxicity from a randomized phase II study: conventional versus hypofractionated scheme for localized prostate cancer 
Recently, the use of hypo-fractionated treatment schemes for the prostate cancer has been encouraged due to the fact that α/β ratio for prostate cancer should be low. However a major concern on the use of hypofractionation is the late rectal toxicity, it is important to be able to predict the risk of toxicity for alternative treatment schemes, with the best accuracy. The main purpose of this study is to evaluate the response of rectum wall to changes in fractionation and to quantify the α/β ratio for late rectal toxicity
162 patients with localized prostate cancer, treated with conformal radiotherapy, were enrolled in a phase II randomized trial. The patients were randomly assigned to 80 Gy in 40 fractions over 8 weeks (arm A) or 62 Gy in 20 fractions over 5 weeks (arm B). The median follow-up was 30 months. The late rectal toxicity was evaluated using the Radiation Therapy Oncology Group (RTOG) scale. It was assumed ≥ Grade 2 (G2) toxicity incidence as primary end point. Fit of toxicity incidence by the Lyman-Burman-Kutcher (LKB) model was performed.
The crude incidence of late rectal toxicity ≥ G2 was 14% and 12% for the standard arm and the hypofractionated arm, respectively. The crude incidence of late rectal toxicity ≥ G2 was 14.0% and 12.3% for the arm A and B, respectively. For the arm A, volumes receiving ≥ 50 Gy (V50) and 70 Gy (V70) were 38.3 ± 7.5% and 23.4 ± 5.5%; for arm B, V38 and V54 were 40.9 ± 6.8% and 24.5 ± 4.4%. An α/β ratio for late rectal toxicity very close to 3 Gy was found.
The ≥ G2 late toxicities in both arms were comparable, indicating the feasibility of hypofractionated regimes in prostate cancer. An α/β ratio for late rectal toxicity very close to 3 Gy was found.
PMCID: PMC2733302  PMID: 19689825
16.  Phase I Trial of Pelvic Nodal Dose Escalation with Hypofractionated IMRT for High Risk Prostate Cancer 
Toxicity concerns have limited pelvic nodal prescriptions to doses that may be suboptimal for controlling microscopic disease. In a prospective trial, we tested whether image-guided IMRT can safely deliver escalated nodal doses while treating the prostate with hypofractionated radiotherapy in 5–1/2 weeks.
Methods and Materials
Pelvic nodal and prostatic image-guided IMRT was delivered to 53 NCCN high risk patients to a nodal dose of 56 Gy in 2 Gy fractions with concomitant treatment of the prostate to 70 Gy in 28 fractions of 2.5 Gy, and 50 of 53 patients received androgen deprivation for a median duration of 12 months.
The median follow-up was 25.4 months (range 4.2–57.2). No early grade 3 (Gr3) RTOG or CTCAE v.3.0 GU or GI toxicities were seen. The cumulative actuarial incidence of Gr2 early GU toxicity (primarily alpha blocker initiation) was 38%. The rate was 32% for Gr2 early GI toxicity. None of the dose-volume descriptors correlated with GU toxicity, and only the volume of bowel receiving ≥30 Gy correlated with early GI toxicity (p=0.029). Maximum late grades 1,2 and 3 GU toxicities were seen in in 30%, 25% and 2%, respectively. Maximum late grade 1 and 2 GI toxicities were seen in 30% and 8% (rectal bleeding requiring cautery), respectively. The estimated 3-year biochemical control (nadir + 2) was 81.2 ± 6.6%. No patient manifested pelvic nodal failure, while two experienced para-aortic nodal failure outside the field. The 6 other clinical failures were distant only.
Pelvic IMRT nodal dose escalation to 56 Gy was delivered concurrently with 70 Gy of hypofractionated prostate radiotherapy in a convenient, resource-efficient and well-tolerated 28 fraction schedule. Pelvic nodal dose escalation may be an option in any future exploration of potential benefits of pelvic radiation therapy in high-risk prostate cancer patients.
PMCID: PMC3347884  PMID: 21163590
Pelvic Lymph Node Dose Escalation; Bowel Displacement Board; Rectal Balloon; Hypofractionated Radiation Therapy; Image-Guided Prostate IMRT
17.  Hypofractionated radiotherapy and adjuvant chemotherapy do not increase radiation-induced dermatitis in breast cancer patients 
Current Oncology  2010;17(5):22-27.
Radiation-induced dermatitis is a common side effect of breast irradiation, with hypofractionation being a well-known risk factor. In the context of the widespread adoption of hypofractionated breast radiotherapy, we evaluated the effect of hypofractionated radiotherapy on the incidence of skin toxicity in patients receiving adjuvant chemotherapy.
Patients and Methods
We retrospectively reviewed the records of patients with breast cancer treated from 2004 to 2006 at a single institution. Patients undergoing lumpectomy with or without adjuvant chemotherapy followed by hypofractionated radiotherapy consisting of 42.4 Gy in 16 fractions were included in the study. Using cosmetic and skin toxicity scales, all patients were evaluated weekly during treatment and at scheduled follow-up visits with the radiation oncologist.
During the study period, 162 patients underwent radiotherapy, and 30% of those (n = 48) received chemotherapy. Radiotherapy boost to the tumour bed was more common in the chemotherapy group [n = 20 (42%)] than in the radiotherapy-alone group [n = 30 (26%)]. We observed no statistically significant difference between the groups with regard to acute skin toxicity of grade 3 or higher (2.1% in the chemotherapy group vs. 4.4% in the radiation-alone group, p = 0.67) or of grades 1–2 toxicity (62.5% vs. 51.7% respectively, p = 0.23). There was also no significant difference in late grade 3 or higher skin toxicity between the groups (2.1% vs. 0% respectively, p = 0.30) or in grades 1–2 toxicity (20.8% vs. 25.5% respectively, p = 0.69). Similarly, excellent or good cosmetic result scores were similar in both groups (p = 0.80)
In our single-institution review, we observed no adverse effects of chemotherapy in combination with hypofractionated whole-breast irradiation. Further investigations are necessary to better elucidate the effects of chemotherapy on skin toxicity in the context of hypofractionated irradiation.
PMCID: PMC2949365  PMID: 20975875
Breast cancer; hypofractionated radiotherapy; chemotherapy; skin toxicity
18.  Dose to organs at risk in the upper abdomen in patients treated with extended fields by helical tomotherapy: a dosimetric and clinical preliminary study 
The aim of this work was to determine the technical feasibility and safety of extended-field radiotherapy (EF), performed by Helical TomoTherapy, in patients with positive pelvic and/or para-aortic nodes. Dosimetric data were collected and acute and sub-acute toxicities of the upper abdominal organs at risk (OAR) were evaluated.
Twenty-nine patients suitable for EF irradiation for local disease and/or nodal disease in the pelvic or para-aortic area were treated. The prescription dose was 50.4/54 Gy (1.7-1.8 Gy/fraction) for prophylactic lymph nodes (N-) and 60–70.5 Gy (2–2.35 Gy/fraction) for clinically evident gross disease (N+). Modulation factor (MF), pitch and field width (FW) were chosen to optimize dose distribution and treatment duration. Dose values of PTVs and OAR were analysed. The length of the treatment field, the N + and N- volumes, and treatment duration were reported. To evaluate the safety of treatment, haematological, hepatic, renal and pancreatic functions were assessed before, during and after treatment. The median follow-up time was 17.6 months (range: 6–22 months).
The treatment was well tolerated and all patients but one completed treatment without interruption. Four of the 29 patients experienced G3 haematological acute toxicity (13.8%), but no patient experienced sub-acute grade G3 toxicity. Ten patients experienced G1 and three G2 acute gastrointestinal toxicity (nausea). No sub-acute gastrointestinal or renal toxicity was observed. Only one (3.7%) patient had a persistent slight increase of pancreatic enzymes and two (7.4%) patients a slight increase of hepatic enzymes six months after radiotherapy (G1 toxicity).
With our treatment design and dose regimen, we found that EF treatment by TomoTherapy could be safely and effectively delivered with minimal acute and sub-acute toxicities in the upper abdomen area.
PMCID: PMC3816584  PMID: 24160769
Upper abdominal organ at risks; Helical TomoTherapy; Extended fields; Toxicity
19.  Short-course palliative radiotherapy for uterine cervical cancer 
Radiation Oncology Journal  2013;31(4):216-221.
The purpose of this retrospective study was to evaluate the efficacy and feasibility of short-course hypofractionated radiotherapy (RT) for the palliation of uterine cervical cancer.
Materials and Methods
Seventeen patients with cancer of the uterine cervix, who underwent palliative hypofractionated 3-dimensional conformal radiotherapy between January 2002 and June 2012, were retrospectively analyzed. RT was delivered to symptomatic lesions (both the primary mass and/or metastatic regional lymph nodes). The total dose was 20 to 25 Gy (median, 25 Gy) in 5 Gy daily fractions.
The median follow-up duration was 12.2 months (range, 4 to 24 months). The median survival time was 7.8 months (range, 4 to 24 months). Vaginal bleeding was the most common presenting symptom followed by pelvic pain (9 patients). The overall response rates were 93.8% and 66.7% for vaginal bleeding control and pelvic pain, respectively. Nine patients did not have any acute side effects and 7 patients showed minor gastrointestinal toxicity. Only 1 patient had grade 3 diarrhea 1 week after completion of treatment, which was successfully treated conservatively. Late complications occurred in 4 patients; however, none of these were of grade 3 or higher severity.
Short-course hypofractionated RT was effective and well tolerated as palliative treatment for uterine cervical cancer.
PMCID: PMC3912235  PMID: 24501709
Cervix uteri; Carcinoma; Palliation; Hypofractionation; Radiotherapy
20.  Sense and Nonsense of an Extended Pelvic Lymph Node Dissection in Prostate Cancer 
Advances in Urology  2011;2012:983058.
Lymph node metastases associated with prostate cancer (PCa) has been shown to be a poor prognostic factor. The role of pelvic lymph node dissection (PLND) itself in relation to survival remains unclear, however. A Medline search was conducted to address this issue. The following conclusions were drawn. Only recently, improved survival due to completion of radical prostatectomy (RP) (compared to abandoning RP) in known or presumed lymph-node-positive patients has been shown. Lymph node sampling can only be considered representative if an adequate number of nodes is removed. While several authors have suggested that a therapeutic benefit in patients undergoing RP is not provided by PLND, the reliability of these studies is uncertain. Contrary to this, several studies have indicated the possibility of long-term survival even in the presence of limited lymph node metastases. The role and timing of initiation of adjuvant androgen deprivation therapy (ADT) in patients who have node-positive disease after RP is controversial. Recent studies suggest that delaying ADT may not adversely impact survival.
PMCID: PMC3189454  PMID: 22007203
21.  Clinical value of extended pelvic lymph node dissection in patients subjected to radical prostatectomy 
Extended pelvic lymph node dissection (ePLND) is advised to complement radical prostatectomy (RP) in intermediate and high risk prostate cancer patients.
To assess the risk of nodal involvement in patients subjected to laparoscopic radical prostatectomy and to characterize the group of patients with lymph node (LN) metastases.
Material and methods
Data of patients subjected to laparoscopic radical prostatectomy with ePLND between February 2011 and June 2013 were analyzed. The LN that were removed included presacral nodes, common, external and internal iliac nodes and obturator ones.
Mean number of removed LNs was 19. Metastases within LN were found in 13 (16.6%) patients. In comparison to those without LN involvement, patients who were found to have LN metastases had a greater number of positive biopsy cores (3.7 vs. 5.3, p < 0.01), maximum percentage of cancer in biopsy core (47.0 vs. 67.6, p < 0.01), greater biopsy and specimen Gleason scores (7.0 vs. 7.7 and 7.0 vs. 7.8) and more frequently advanced clinical and pathological stage. The most frequent landing sites of prostate cancer were obturator and presacral nodes (100% and 38%). Eleven patients (85%) among those with positive LN had locally advanced disease.
The risk of LN metastases in intermediate and high risk prostate cancer patients is significant. Therefore, if radical prostatectomy is chosen, ePLND should be performed. The majority of patients with involvement of pelvic LN have locally advanced disease which would refer them to adjuvant radiation if managed without nodal dissection.
PMCID: PMC3983552  PMID: 24729812
extended pelvic lymph node dissection; laparoscopic radical prostatectomy; prostate cancer
22.  Review of Hypofractionated Radiotherapy for Prostate Cancer 
ISRN Oncology  2012;2012:410892.
Hypofractionated radiotherapy for prostate cancer has become of increasing interest with the recognition of a potential improvement in therapeutic outcome with treatments delivered in large-sized daily fractions. In addition, hypofractionation offers a reduction in fraction number and produces attractive cost and increased convenience for patients. There is convincing evidence, by several clinical trials, that biochemical control is significantly improved with higher administered radiation doses to the prostate gland. Furthermore, the improved radiation delivery techniques such as 3D conformal radiotherapy (3DCRT) or, better, intensity modulated radiation therapy (IMRT) allow high administered doses to the prostate while sparing the normal surrounding tissues. Several studies of the radiobiology of prostate cancer suggest that it may be more susceptible to large fraction sizes compared with conventional fractionation of external beam radiation.
PMCID: PMC3425812  PMID: 22934194
The α/β ratio for prostate cancer is postulated to be between 1 and 3, giving rise to the hypothesis that there may be a therapeutic advantage to hypofractionation. The dosimetry and acute toxicity are described in the first 100 men enrolled in a randomized trial.
Patients and Methods
The trial compares 76 Gy in 38 fractions (Arm I) to 70.2 Gy in 26 fractions (Arm II) using intensity modulated radiotherapy. The planning target volume (PTV) margins in Arms I and II were 5 mm and 3 mm posteriorly and 8 mm and 7 mm in all other dimensions. The PTV D95% was at least the prescription dose.
The mean PTV doses for Arms I and II were 81.1 and 73.8 Gy. There were no differences in overall maximum acute gastrointestinal (GI) or genitourinary (GU) toxicity acutely. However, there was a slight but significant increase in Arm II GI toxicity during Weeks 2, 3, and 4. In multivariate analyses, only the combined rectal DVH parameter of V65 Gy/V50 Gy was significant for GI toxicity and the bladder volume for GU toxicity.
Hypofractionation at 2.7 Gy per fraction to 70.2 Gy was well tolerated acutely using the planning conditions described.
PMCID: PMC1892754  PMID: 16242256
IMRT; Dosimetry; Hypofractionation; Toxicity
24.  Hypofractionation in Prostate Cancer: Radiobiological Basis and Clinical Appliance 
BioMed Research International  2014;2014:781340.
External beam radiation therapy with conventional fractionation to a total dose of 76–80 Gy represents the most adopted treatment modality for prostate cancer. Dose escalation in this setting has been demonstrated to improve biochemical control with acceptable toxicity using contemporary radiotherapy techniques. Hypofractionated radiotherapy and stereotactic body radiation therapy have gained an increasing interest in recent years and they have the potential to become the standard of care even if long-term data about their efficacy and safety are not well established. Strong radiobiological basis supports the use of high dose for fraction in prostate cancer, due to the demonstrated exceptionally low values of α/β. Clinical experiences with hypofractionated and stereotactic radiotherapy (with an adequate biologically equivalent dose) demonstrated good tolerance, a PSA control comparable to conventional fractionation, and the advantage of shorter time period of treatment. This paper reviews the radiobiological findings that have led to the increasing use of hypofractionation in the management of prostate cancer and briefly analyzes the clinical experience in this setting.
PMCID: PMC4066864  PMID: 24999475
25.  Salvage radiotherapy for lymph node recurrence after radical surgery in cervical cancer 
Journal of Gynecologic Oncology  2012;23(3):168-174.
This study was to evaluate the treatment outcomes and prognostic factors of patients treated with salvage radiotherapy for the treatment of isolated lymph node recurrence of cervical cancer.
Between 1990 and 2009, 22 cervical cancer patients with lymph node recurrence who had previously undergone radical hysterectomy and pelvic lymph node dissection were treated with salvage radiotherapy with (n=18) or without (n=4) chemotherapy. Of the 22 patients, 10 had supraclavicular lymph node recurrence, 9 had para-aortic lymph node, and 3 had inguinal lymph node. The median total radiotherapy dose was 60 Gy (range, 40 to 70 Gy). Initial pathologic findings, latent period to lymph node recurrence and other clinical parameters such as squamous cell carcinoma antigen (SCC-Ag) level and concurrent chemotherapy were identified as prognostic factors for survival.
The median follow-up period after salvage radiotherapy was 31.2 months (range, 12.1 to 148.9 months). The 5-year progression-free and overall survival rates of all patients were 32.7% and 30.7%, respectively. Concurrent chemoradiotherapy (p=0.009) and longer latent period to lymph node recurrence (>18 months vs. ≤18 months, p=0.019) were significant predictors of progression-free survival and SCC-Ag level at the time of recurrence (>8 ng/dL vs. ≤8 ng/dL, p=0.008) and longer latent period to lymph node recurrence (p=0.040) for overall survival. Treatment failure after salvage radiotherapy occurred in 14 (63.6%) for the 22 patients (in field, 2; out of field, 10; both in and out field, 2). Grade 3 acute skin (n=2) and hematologic toxicity (n=1) developed in 3 patients.
For isolated lymph node recurrence of cervical cancer, salvage radiotherapy with concurrent chemotherapy should be considered, especially in patients with a long-term progression-free period.
PMCID: PMC3395012  PMID: 22808359
Cervical cancer; Lymph nodes; Salvage therapy

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