Prevalence and prognosis of low-volume, oligorecurrent, hormone-sensitive prostate cancer amenable to lesion ablative therapy.

OBJECTIVES: To describe the anatomical patterns of prostate cancer (PCa) recurrence after primary therapy and to investigate if patients with low-volume disease have a better prognosis as compared with their counterparts. MATERIALS AND METHODS: Patients eligible for an 18-F choline positron-emission tomography (PET)-computed tomography (CT) were enrolled in a prospective cohort study. Eligible patients had asymptomatic biochemical recurrence after primary PCa treatment and testosterone levels >50 ng/mL. The number of lesions was counted per scan. Patients with isolated local recurrence (LR) or with ≤3 metastases (with or without LR) were considered to have low-volume disease and patients with >3 metastases to have high-volume disease. Descriptive statistics were used to report recurrences. Cox regression analysis was used to investigate the influence of prognostic variables on the time to developing castration-resistant PCa (CRPC). RESULTS: In 208 patients, 625 sites of recurrence were detected in the lymph nodes (N1/M1a: 30%), the bone (18%), the prostate (bed; 11%), viscera (4%), or a combination of any of the previous (37%). In total, 153 patients (74%) had low-volume recurrence and 55 patients (26%) had high-volume recurrence. The 3-year CRPC-free survival rate for the whole cohort was 79% (95% confidence interval 43-55), 88% for low-volume recurrences and 50% for high-volume recurrences (P < 0.001). Longer PSA doubling time at time of recurrence and low-volume disease were associated with a longer time to CRPC. CONCLUSIONS: Three out of four patients with PCa with a 18-F choline PET-CT-detected recurrence have low-volume disease, potentially amenable to local therapy. Patients with low-volume disease have a better prognosis as compared with their counterparts. Lymph node recurrence was the most dominant failure pattern.

Surveillance or metastasis-directed Therapy for OligoMetastatic Prostate cancer recurrence (STOMP): study protocol for a randomized phase II trial.

BACKGROUND: Metastases-directed therapy (MDT) with surgery or stereotactic body radiotherapy (SBRT) is emerging as a new treatment option for prostate cancer (PCa) patients with a limited number of metastases (≤3) at recurrence - so called "oligometastases". One of the goals of this approach is to delay the start of palliative androgen deprivation therapy (ADT), with its negative impact on quality of life. However, the lack of a control group, selection bias and the use of adjuvant androgen deprivation therapy prevent strong conclusions from published studies.The aim of this multicenter randomized phase II trial is to assess the impact of MTD on the start of palliative ADT compared to patients undergoing active surveillance. METHODS/DESIGN: Patients with an oligometastatic recurrence, diagnosed on choline PET/CT after local treatment with curative intent, will be randomised in a 1:1 ratio between arm A: active surveillance only and arm B: MTD followed by active surveillance. Patients will be stratified according to the location of metastasis (node vs. bone metastases) and PSA doubling time (≤3 vs. > 3 months). Both surgery and SBRT are allowed as MDT. Active surveillance means 3-monthly PSA testing and re-imaging at PSA progression. The primary endpoint is ADT-free survival. ADT will be started in both arms at time of polymetastatic disease (>3 metastatic lesions), local progression or symptoms. The secondary endpoints include progression-free survival, quality of life, toxicity and prostate-cancer specific survival. DISCUSSION: This is the first randomized phase 2 trial assessing the possibility of deferring palliative ADT with MDT in oligometastatic PCa recurrence. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01558427.

Positron emission tomography-guided, focal-dose escalation using intensity-modulated radiotherapy for head and neck cancer.

PURPOSE: To assess the feasibility of intensity-modulated radiotherapy (IMRT) using positron emission tomography (PET)-guided dose escalation, and to determine the maximum tolerated dose in head and neck cancer. METHODS AND MATERIALS: A Phase I clinical trial was designed to escalate the dose limited to the [(18)-F]fluoro-2-deoxy-D-glucose positron emission tomography ((18)F-FDG-PET)-delineated subvolume within the gross tumor volume. Positron emission tomography scanning was performed in the treatment position. Intensity-modulated radiotherapy with an upfront simultaneously integrated boost was employed. Two dose levels were planned: 25 Gy (level I) and 30 Gy (level II), delivered in 10 fractions. Standard IMRT was applied for the remaining 22 fractions of 2.16 Gy. RESULTS: Between 2003 and 2005, 41 patients were enrolled, with 23 at dose level I, and 18 at dose level II; 39 patients completed the planned therapy. The median follow-up for surviving patients was 14 months. Two cases of dose-limiting toxicity occurred at dose level I (Grade 4 dermitis and Grade 4 dysphagia). One treatment-related death at dose level II halted the study. Complete response was observed in 18 of 21 (86%) and 13 of 16 (81%) evaluated patients at dose levels I and II (p < 0.7), respectively, with actuarial 1-year local control at 85% and 87% (p = n.s.), and 1-year overall survival at 82% and 54% (p = 0.06), at dose levels I and II, respectively. In 4 of 9 patients, the site of relapse was in the boosted (18)F-FDG-PET-delineated region. CONCLUSIONS: For head and neck cancer, PET-guided dose escalation appears to be well-tolerated. The maximum tolerated dose was not reached at the investigated dose levels.

Implementation of biologically conformal radiation therapy (BCRT) in an algorithmic segmentation-based inverse planning approach.

The development of new biological imaging technologies offers the opportunity to further individualize radiotherapy. Biologically conformal radiation therapy (BCRT) implies the use of the spatial distribution of one or more radiobiological parameters to guide the IMRT dose prescription. Our aim was to implement BCRT in an algorithmic segmentation-based planning approach. A biology-based segmentation tool was developed to generate initial beam segments that reflect the biological signal intensity pattern. The weights and shapes of the initial segments are optimized by means of an objective function that minimizes the root mean square deviation between the actual and intended dose values within the PTV. As proof of principle, [(18)F]FDG-PET-guided BCRT plans for two different levels of dose escalation were created for an oropharyngeal cancer patient. Both plans proved to be dosimetrically feasible without violating the planning constraints for the expanded spinal cord and the contralateral parotid gland as organs at risk. The obtained biological conformity was better for the first (2.5 Gy per fraction) than for the second (3 Gy per fraction) dose escalation level.

Definition and delineation of the clinical target volume for rectal cancer.

PURPOSE: Optimization of radiation techniques to maximize local tumor control and to minimize small bowel toxicity in locally advanced rectal cancer requires proper definition and delineation guidelines for the clinical target volume (CTV). The purpose of this investigation was to analyze reported data on the predominant locations and frequency of local recurrences and lymph node involvement in rectal cancer, to propose a definition of the CTV for rectal cancer and guidelines for its delineation. METHODS AND MATERIALS: Seven reports were analyzed to assess the incidence and predominant location of local recurrences in rectal cancer. The distribution of lymphatic spread was analyzed in another 10 reports to record the relative frequency and location of metastatic lymph nodes in rectal cancer, according to the stage and level of the primary tumor. RESULTS: The mesorectal, posterior, and inferior pelvic subsites are most at risk for local recurrences, whereas lymphatic tumor spread occurs mainly in three directions: upward into the inferior mesenteric nodes; lateral into the internal iliac lymph nodes; and, in a few cases, downward into the external iliac and inguinal lymph nodes. The risk for recurrence or lymph node involvement is related to the stage and the level of the primary lesion. CONCLUSION: Based on a review of articles reporting on the incidence and predominant location of local recurrences and the distribution of lymphatic spread in rectal cancer, we defined guidelines for CTV delineation including the pelvic subsites and lymph node groups at risk for microscopic involvement. We propose to include the primary tumor, the mesorectal subsite, and the posterior pelvic subsite in the CTV in all patients. Moreover, the lateral lymph nodes are at high risk for microscopic involvement and should also be added in the CTV.

[18F]fluoro-deoxy-glucose positron emission tomography ([18F]FDG-PET) voxel intensity-based intensity-modulated radiation therapy (IMRT) for head and neck cancer.

BACKGROUND AND PURPOSE: Focused dose escalation may improve local control in head and neck cancer. Planning results of [(18)F]fluoro-deoxy-glucose positron emission tomography ([(18)F]FDG-PET) voxel intensity-based intensity-modulated radiation therapy (IMRT) were compared with those of PET contour-based IMRT. PATIENTS AND METHODS: PET contour-based IMRT aims to deliver a homogeneous boost dose to a PET-based subvolume of the planning target volume (PTV), called PTV(PET). The present PET voxel intensity-based planning study aims to prescribe the boost dose directly as a function of PET voxel intensity values, while leaving the dose distribution outside the PTV unchanged. Two escalation steps (2.5 and 3 Gy/fraction) were performed for 15 patients. RESULTS: PTV(PET) was irradiated with a homogeneous dose in the contour-based approach. In the voxel intensity-based approach, one or more sharp dose peaks were created inside the PTV, following the distribution of PET voxel intensity values. CONCLUSIONS: While PET voxel intensity-based IMRT had a large effect on the dose distribution within the PTV, only small effects were observed on the dose distribution outside this PTV and on the dose delivered to the organs at risk. Therefore both methods are alternatives for boosting subvolumes inside a selected PTV.

Postoperative intensity-modulated radiotherapy in sinonasal carcinoma: clinical results in 39 patients.

BACKGROUND: Carcinoma of the paranasal sinuses is rare. Standard therapeutic modalities consist of surgery and radiotherapy (RT). Because of the often advanced stage and the vicinity of optic structures, RT-induced ocular toxicity is a feared side effect of conventional RT. Intensity-modulated radiotherapy (IMRT) is a relatively new technique, which is implemented with the hypothesis that, compared with conventional RT, it would result in a lower rate of ocular toxicity for an equal local control (LC). METHODS: Between 1998 and 2003, 39 consecutive patients received postoperative irradiation by means of IMRT for an adenocarcinoma (n = 31) or squamous cell carcinoma (n = 8) of the paranasal sinuses (n = 36) or nasal cavity (n = 3). T-classification was T2 in 41%, T3 in 15%, T4a in 23%, and T4b in 21% of patients. Invasion through the cribriform plate was seen in 11 patients. Orbital invasion was present in 36% of patients. The median delivered dose was 70 gray (Gy) (range, 60-70 Gy). The authors compared the overall survival (OS) and LC of the patients with a historic cohort (HC) (n = 30), treated with conventional or 3-dimensional conformal RT. RESULTS: The median follow-up was 31 months. The actuarial OS rates were 68% at 2 years and 59% at 4 years. The actuarial LC rates were 73% at 2 years and 68% at 4 years. Invasion through the cribriform plate was a significant prognostic factor for LC and OS, with a median time to local disease recurrence of 7 months if present, and a 2-year LC rate of 90% if not present. In the comparison between the IMRT and HC groups, no significant differences were found for LC and OS. Acute toxicity was mild. Two patients developed decreased vision after RT. No RT-induced blindness was observed. CONCLUSIONS: Postoperative IMRT for sinonasal carcinoma resulted in good LC, with a low acute toxicity and no RT-induced blindness.

Automatic generation of a plan optimization volume for tangential field breast cancer radiation therapy.

BACKGROUND AND PURPOSE: Dose homogeneity is one of the objectives during computer planning of postoperative radiotherapy of the conserved breast. For three-dimensional (3-D) optimization of the dose distribution using serial CT scan images, suitable volumes have to be delineated. The purpose of this study was to develop a computer-generated delineation of a plan optimization volume (POV) and an irradiated volume (IV) and to automate their use in a fast dose homogeneity optimization engine. PATIENTS AND METHODS: Simulation was performed according to our standard procedure which involves the positioning of a lead collar around the palpable breast to facilitate the definition of gantry angle, collimator angle and field aperture for tangential wedged photon beams. In a change to the standard procedure an anterolateral radiograph was taken with its axis orthogonal to the central plane of the two tangential half-beams. Images from a serial CT scan were acquired in treatment position, and the geometric data of the three simulated beams were used by a computer program to generate the POV and IV. For each patient, weights of wedged and unwedged beams were optimized by either human heuristics using only the central slice (2-D), the whole set of CT slices (3-D), or by a computer algorithm using the POV, IV and lung volume with constrained matrix inversion (CMI) as optimization method. The resulting dose distributions were compared. RESULTS: The total planning procedure took, on average, 44 min of which < 7 min were needed for human interactions, compared to about 52 min for the standard planning at Ghent University Hospital, Belgium. The simulation time is increased by 2-3 min. The method provides 3-D information of the dose distribution. Dose homogeneity and minimum dose inside the POV and maximum dose inside the IV were not significantly different for the three optimization techniques. CONCLUSION: This automated planning method is capable of replacing the contouring of the clinical target volume as well as the trial-and-error procedure of assigning weights of wedged and unwedged beams by an experienced planner.

Clinical implementation of intensity-modulated arc therapy (IMAT) for rectal cancer.

PURPOSE: In rectal cancer, combined radiotherapy and chemotherapy, either pre- or postoperatively, is an accepted treatment. Late small bowel (SB) toxicity is a feared side effect and limits radiation-dose escalation in a volume-dependent way. A planning strategy for intensity- modulated arc therapy (IMAT) was developed, and IMAT was clinically implemented with the aim to reduce the volume of SB irradiated at high doses and thus reduce SB toxicity. We report on the treatment plans of the first 7 patients, on the comparison of IMAT with conventional 3D planning (3D), and on the feasibility of IMAT delivery. METHODS AND MATERIALS: Seven patients, who were referred to our department for preoperative (n = 4) or postoperative (n = 3) radiotherapy for rectal cancer, gave written consent for IMAT treatment. All patients had a planning CT in prone position. The delineation of the clinical target volume was done after fusion of CT and MRI, with the help of a radiologist. For the IMAT plan, arcs were generated using an anatomy-based segmentation tool. The optimization of the arcs was done by weight optimization (WO) and leaf position optimization (LPO), both of which were adapted for IMAT purposes. The 3D plans used one posterior and two lateral wedged beams, of which the outlines were shaped to the beam's-eye view projection of the planning target volume (PTV). Beam WO was done by constrained matrix inversion. For dose-volume histogram analysis, all plans were normalized to 45 Gy as median PTV dose. Polymer gel dosimetry (PGD) on a humanoid phantom was used for the validation of the total chain (planning to delivery). IMAT treatments were delivered by an Elekta SliPlus linear accelerator using prototype software with the same interlock class as in clinical mode. RESULTS: The IMAT plan resulted in 3 to 6 arcs, with a mean delivery time of 6.3 min and a mean of 456 monitor units (MU) for a 180 cGy fraction. The minimal dose in the PTV was not significantly different between 3D and IMAT plans. Inhomogeneity was highest for the IMAT plans (14.1%) and lowest for the 3D plans (9.9%). Mean dose to the SB was significantly lower for the IMAT plans (12.4 Gy) than for the 3D plans (17.0 Gy). The volume of SB receiving less than any dose level was lower for the IMAT plans than for 3D plans. Integral dose was lower in the IMAT plans than for the 3D plans (respectively 244 J and 262 J to deliver 45 Gy). Differences between the PGD measured dose and the calculated dose were as small for IMAT as for 3D treatments. CONCLUSION: IMAT plans are deliverable within a 5-10-minute time slot, and result in a lower dose to the SB than 3D plans, without creating significant underdosages in the PTV. PGD showed that IMAT delivery is as accurate as 3D delivery.

Intensity-modulated radiation therapy for head and neck cancer.

In head and neck cancer, intensity-modulated radiation therapy (IMRT) makes the use of electron beams for irradiation of the posterior neck obsolete, inherently performs missing tissue compensation, and allows concave and intentionally nonhomogeneous dose distributions. By clinical use of these physical characteristics, salivary or lacrimal glands, optic pathway and auditory structures can be selectively underdosed and good evidence of decreased radiation toxicity is available. Evidence for increased local control is still lacking. Recurrences are mainly located in the high-dose-prescription regions, suggesting the need for even higher doses in these areas. Image-aided design of IMRT dose distribution is an area of intense research. New positron emission tomography and magnetic resonance imaging developments might allow definition of volumes inside the tumor where treatment failure is most likely to occur. If these volumes are small, focused dose escalation of large magnitude can be attempted and the hypothesis of improved local control by IMRT can be tested.

Whole abdominopelvic radiotherapy (WAPRT) using intensity-modulated arc therapy (IMAT): first clinical experience.

PURPOSE: Whole abdominopelvic radiation therapy (WAPRT) is a treatment option in the palliation of patients with relapsed ovarian cancer. With conventional techniques, kidneys and liver are the dose- and homogeneity-limiting organs. We developed a planning strategy for intensity-modulated arc therapy (IMAT) and report on the treatment plans of the first 5 treated patients. METHODS AND MATERIALS: Five consecutive patients with histologically proven relapsed ovarian cancer were sent to our department for WAPRT. The target volumes and organs at risk (OAR) were delineated on 0.5-cm-thick CT slices. The clinical target volume (CTV) was defined as the total peritoneal cavity. CTV and kidneys were expanded with 0.5 cm. In a preset range of 8 degrees interspaced gantry angles, machine states were generated with an anatomy-based segmentation tool. Machine states of the same class were stratified in arcs. The optimization of IMAT was done in several steps, using a biophysical objective function. These steps included weight optimization of machine states, leaf position optimization adapted to meet the maximal leaf speed constraint, and planner-interactive optimization of the start and stop angles. The final control points (machine states plus associated cumulative monitor unit counts) were calculated using a collapsed cone convolution/superposition algorithm. For comparison, two conventional plans (CONV) were made, one with two fields (CONV2), and one with four fields (CONV4). In these CONV plans, dose to the kidneys was limited by cerrobend blocks. The IMAT and the CONV plans were normalized to a median dose of 33 Gy to the planning target volume (PTV). Monomer/polymer gel dosimetry was used to assess the dosimetric accuracy of the IMAT planning and delivery method. RESULTS: The median volume of the PTV was 8306 cc. The mean treatment delivery time over 4 patients was 13.8 min. A mean of 444 monitor units was needed for a fraction dose of 150 cGy. The fraction of the PTV volume receiving more than 90% of the prescribed dose (V(90)) was 9% higher for the IMAT plan than for the CONV4 plan (89.9% vs. 82.5%). Outside a build-up region of 0.8 cm and 1 cm away from both kidneys, the inhomogeneity in the PTV was 15.1% for the IMAT plans and 24.9% for the CONV4 plans (for CONV2 plans, this was 34.9%). The median dose to the kidneys in the IMAT plans was lower for all patients. The 95th percentile dose for the kidneys was significantly higher for the IMAT plans than for the CONV4 and CONV2 plans (28.2 Gy vs. 22.2 Gy and 22.6 Gy for left kidney, respectively). No relevant differences were found for liver. The gel-measured dose was within clinical planning constraints. CONCLUSION: IMAT was shown to be deliverable in an acceptable time slot and to produce dose distributions that are more homogeneous than those obtained with a CONV plan, with at least equal sparing of the OARs.

Intensity modulated radiation therapy for oropharyngeal and oral cavity tumors: clinical use and experience.

Background and purpose. Intensity modulated radiation therapy (IMRT) offers an opportunity to generate dose distributions highly conformal to the target volume. Head and neck cancer patients, referred for radiotherapy, may be good candidates to benefit from IMRT. This paper discusses the clinical implementation of IMRT for oropharyngeal and oral cavity tumors, and reports the clinical results of the 14 patients treated with this technique at Ghent University Hospital (GUH). Patients and Methods. Between May 1999 and May 2001, 14 patients were treated with IMRT at GUH for oropharyngeal or oral cavity tumors. Two groups of patients can be distinguished. The first group consists of eight patients re-irradiated with IMRT for a locoregional relapse. The second group of six patients were treated with IMRT for a primary tumor. For the first group, IMRT was used to treat the relapse by generating a concave dose distribution, i.e. to combine a homogeneous target re-irradiation with a dose to the spinal cord as low as possible. For the second group, IMRT was applied in order to achieve a more homogeneous dose distribution inside the PTV and to preserve parotid gland function. Results. The majority of the patients of group 1 (6/8) relapsed in field within four months after the end of the re-irradiation, with a median overall survival of 7 months. For group 2, two patients died shortly after the end of the IMRT treatment, the other four patients are free of tumor relapse with a median follow-up of 5 months (1-13 months). The acute toxicity due to radiation was acceptable for both patient groups. Dysphagia and pain was more present in group 1. Regarding late complications for the group of re-irradiations (group 1), no myelitis, carotid rupture or cranial nerve palsy was observed. One patient of group 1 developed osteoradionecrosis of the mandible and feeding tube dependency was present for another patient. No fatal late complications were observed in this group. For the first two patients of group 2, sparing of the parotid function was not a treatment objective. For the other patients of group 2, the mean dose to the contralateral parotid gland ranged from 17 to 25 Gy, which resulted in a decrease of subjective symptoms of xerostomia compared to patients treated with conventional radiotherapy. Conclusions. The implementation of IMRT for oropharyngeal and oral cavity tumors results in a homogeneous target irradiation and allows to re-irradiate locoregional relapses with acceptable adverse effects. Sparing of the parotid gland by IMRT is feasible, although this may be significantly influenced by the delineation method of the elective lymph node regions.