Lluís Escudé

Hypofractionated boost to the dominant tumor region with intensity modulated stereotactic radiotherapy for prostate cancer: a sequential dose escalation pilot study.

PURPOSE To evaluate the feasibility, tolerability, and preliminary outcomes in patients with prostate cancer treated according to a hypofractionated dose escalation protocol to boost the dominant tumor-bearing region of the prostate. METHODS AND MATERIALS After conventional fractionated external radiotherapy to 64 to 64.4 Gy, 50 patients with nonmetastatic prostate cancer were treated with an intensity-modulated radiotherapy hypofractionated boost under stereotactic conditions to a reduced prostate volume to the dominant tumor region. A rectal balloon inflated with 60 cc of air was used for internal organ immobilization. Five, 8, and 8 patients were sequentially treated with two fractions of 5, 6, or 7 Gy, respectively (normalized total dose in 2 Gy/fraction [NTD(2 Gy)] < 100 Gy, low-dose group), whereas 29 patients received two fractions of 8 Gy each (NTD(2 Gy) > 100 Gy, high-dose group). Androgen deprivation was given to 33 patients. Acute and late toxicities were assessed according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG/EORTC) scoring system. RESULTS Two patients presented with Grade 3 acute urinary toxicity. The 5-year probabilities of >or=Grade 2 late urinary and late low gastrointestinal (GI) toxicity-free survival were 82.2% +/- 7.4% and 72.2% +/- 7.6%, respectively. The incidence and severity of acute or late toxicities were not correlated with low- vs. high-dose groups, pelvic irradiation, age, or treatment with or without androgen deprivation. The 5-year biochemical disease-free survival (b-DFS) and disease-specific survival were 98% +/- 1.9% and 100%, respectively. CONCLUSION Intensity-modulated radiotherapy hypofractionated boost dose escalation under stereotactic conditions was feasible, and showed excellent outcomes with acceptable long-term toxicity. This approach may well be considered an alternative to high-dose-rate brachytherapy.

Dosimetric implications of changes in patient repositioning and organ motion in conformal radiotherapy for prostate cancer

PURPOSE To assess the influence of patient repositioning and organ motion on dose distribution within the prostate and the seminal vesicles (clinical target volume, (CTV)). MATERIAL AND METHODS Nine patients were simulated and treated in the supine position, with an empty bladder, and without immobilization devices. While on treatment, patients underwent weekly pelvic computed tomography (CT) scans under conditions identical to those at simulation. Patients were aligned using lasers on anterior and lateral skin tattoos, onto which lead markers were placed. After each CT scan (n=53) the CTV was redefined by contouring, and a new isocenter was obtained. A six-field technique was used. The field margins around the CTV were 20 mm in the cranio-caudal axis, and 13 mm in the other axes, except in the lateral fields where a 10 mm posterior margin was used. Dose-volume histograms (DVHs) for each organ were compared with those determined at simulation, using the notion of the proportional change in the area under the CTV-DVH curve resulting from a change in treatment plan (cDVH). RESULTS The reproducibility of the dose distribution was good for the prostate (%cDVH, mean+/-SD: -0.97+/-2.11%) and less than optimal for the seminal vesicles (%cDVH, mean+/-SD: -4.66+/-10.45%). When correlating prostate %cDVH variations with displacements of the isocenter in the Y axis (antero-posterior) the %cDVH exceeded (-)5% in only two dosimetries, both with an isocenter shift of >10 mm. For the seminal vesicles, however, ten out of 53 dosimetries showed a %cDVH exceeding (-) 5%. In nine of these ten dose distribution studies the posterior shift of the isocenter exceeded 8 mm. CONCLUSIONS Precise targeting of prostate radiotherapy is primarily dependent on careful daily set-up and on random changes in rectal geometry. Margins no less than 10 mm around the prostate and at least 15 mm around the seminal vesicles are probably necessary to insure adequate target coverage with a six-field technique.

Influence of rectal volume changes during radiotherapy for prostate cancer: A predictive model for mild-to-moderate late rectal toxicity

PURPOSE To assess the rectal volume changes during radiotherapy for prostate cancer, to estimate an average rectal dose distribution profile during treatment, and to correlate these parameters with mild-to-moderate late rectal toxicity. MATERIALS AND METHODS Nine patients with localized prostate cancer underwent virtual CT simulation using a six-field conformal 18-MV photon technique. During treatment, patients underwent weekly pelvic CT scans under simulation conditions. Dosimetries were run with each CT data set using the same beam parameters as in the initial treatment plan. The influence of weekly rectal volume changes on the dose-volume histogram (DVH) profiles was studied. A polynomial function correlating the initial rectal volume with the mean percentage of change in the rectal volume during treatment was used to define a correction factor for rectal DVHs. The model was validated using data from 100 patients treated with 74 Gy according to the same technique. Areas under the curve of the initial rectal DVHs were correlated with toxicity (Radiation Therapy Oncology Group Grade 0 vs. 1-2, Students t test), with or without the use of the above correction factor. RESULTS A trend for enlargement of the rectal volume during treatment was observed for most patients in the study with small rectal volumes (<75 cm(3)) at simulation, resulting in an increase in the integral rectal dose by a factor ranging from 1.3 to 2.1. Corrected, but not uncorrected, rectal DVH profiles were strongly predictive of Grade 0 vs. 1-2 late rectal morbidity. CONCLUSIONS Correcting the area under the curve of the rectal DVH at simulation by a factor that takes into account the projected volume changes during treatment correlates significantly with the probability of mild-to-moderate late rectal toxicity (Grade 1-2). This reliable predictor for mild-to-moderate late rectal morbidity may also be a practical tool for treatment planning.

Intraoperative radiotherapy for recurrent and/or residual colorectal cancer

Intraoperative radiotherapy (IORT) is an attractive boosting modality in the combined treatment of recurrent and/or residual colorectal cancer. Twenty seven patients treated with IORT are analysed. Residual disease following resection of the primary tumor was treated in 11 cases (group I). Localized recurrent disease without previous radiotherapy was treated in 11 cases (group II). IORT was used in five additional patients with local recurrences in previously irradiated areas (group III). The treatment program consisted of maximal tumor resection, IORT (10-30 Gy) to the area of residual disease and external beam radiotherapy (46-50 Gy). The median follow-up time for the entire series of patients is 11 months. Local tumor control rates are 90% in group I, 63% in group II and 60% in group III. Toxicity and complications related to IORT observed in this initial experience have been pelvic pain (29%) and lower extremity neuropathy (3%). These early clinical results suggest that the IORT combined with surgery and external beam radiotherapy is feasible in primary and recurrent disease. Local control rates obtained in patients not suitable for curative surgery are encouraging.

Intraoperative radiotherapy during lung cancer surgery: Technical description and early clinical results

A phase I-II study of intraoperative radiotherapy (IORT) for Stage III lung cancer was performed in 34 patients during a period of 58 months. Loco-regional treatment included tumor resection if technically feasible, IORT boost of electron beams using moderate single doses (10-15 Gy) to tumor bearing areas and external photon beam irradiation (46-50 Gy in 5 weeks) using conventional fields. Indications for this study were unresectable hiliar tumors (14, 41%), and mediastinal, hiliar and/or chest wall residual disease following resection (20, 59%). Thirty-four procedures, with 40 IORT fields, have been analyzed to describe the relevant technical aspects and the toxicity. IORT was delivered using acrylic transparent cones of different diameters. Surgical approach consisted in a lateral thoracotomy in all patients (21 right side and 13 left side). Tissues included within the IORT field were: tumor or residual tumor tissues (34, 100%), collapsed lung parenchyma and main bronchus not surgically manipulated (14, 41%), bronchial stump and vascular suture following resection (19, 55%), mediastinal structures (20, 58%), and brachial plexus (1, 3%). The bronchial suture was covered with pleural or pericardial flap after IORT in 10 cases (29%). Life threatening toxicity related to IORT consisted in broncho-pleural fistula (1, 3%) and massive hemoptysis (1, 3%). Other reversible toxic events were acute pneumonitis (12, 85%) and esophagitis (10, 50%). Long term asymptomatic lung fibrosis was detected in 11 cases (32%). Median survival time for the entire group has been 12 months. With a median follow-up time of 12 months the freedom from thoracic recurrence rate is 30% (65% in cases with tumor resection). Projected actuarial survival rates at 4 years were 28% for resected group and 7% for unresected cases. This experience supports IORT as a feasible alternative modality to be used in the management of locally advanced lung cancer. Tolerance of thoracic organs to moderate doses of IORT appeared to be adequate and local control is achieved in certain patients. These results deserve further investigation and confirmation trials.

Boosting the tumor bed from deep-seated tumors in early-stage breast cancer: A planning study between electron, photon, and proton beams

PURPOSE To assess the potential dosimetric advantages and drawbacks of photon beams (modulated or not), electron beams (EB), and protons as a boost for the tumor bed in deep-seated early-stage breast cancer. MATERIAL AND METHODS Planning CTs of 14 women with deep-seated tumors (i.e., > or =4 cm depth) were selected. The clinical target volume (CTV) was defined as the area of architectural distortion surrounded by surgical clips. The planning treatment volume (PTV) was the CTV plus 1cm margin. A dose of 16 Gy in 2 Gy fractions was prescribed. Organs at risk (OARs) were heart, lungs, breasts, and a 5-mm thick skin segment on the breast surface. Dose-volume metrics were defined to quantify the quality of concurrent treatment plans assessing target coverage and sparing of OAR. The following treatment techniques were assessed: photon beams with either static 3D-conformal, dynamic arc (DCA), static gantry intensity-modulated beams (IMRT), or RapidArc (RA); a single conformal EB; and intensity-modulated proton beams (IMPT). The goal for this planning effort was to cover 100% of the CTV with 95% of the prescribed dose and to minimize the volume inside the CTV receiving >107% of the dose. RESULTS All techniques but DCA and EB achieved the planning objective for the CTV with an inhomogeneity ranging from 2% to 11%. RA showed the best conformity, EB the worst. Contra-lateral breast and lung were spared by all techniques with mean doses <0.5 Gy (zero for protons). The ipsi-lateral lung received a mean dose <10% of that prescribed with photon beams and <2% with IMPT, increasing to 17% with EB. The heart, in left-sided breast tumors, received also the highest dose with EB. The skin was best protected with RA with a mean dose of 5.4 Gy and V(15Gy)=2.4%. CONCLUSIONS Boosting the tumor bed in early-stage breast cancer with optimized photon or proton beams may be preferred to EB especially for deep-seated targets. The marked OAR (i.e., ipsi-lateral breast, lung, heart, and skin surface) dose-sparing effect may allow for a potential long-term toxicity risk reduction and better cosmesis. DCA or RA may also be considered alternative treatment options for patients eligible for accelerated partial breast irradiation trials.

Twice-Weekly Hypofractionated Intensity-Modulated Radiotherapy for Localized Prostate Cancer With Low-Risk Nodal Involvement: Toxicity and Outcome From a Dose Escalation Pilot Study

PURPOSE To evaluate the toxicity and preliminary outcome of patients with localized prostate cancer treated with twice-weekly hypofractionated intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS Between 2003 and 2006, 82 prostate cancer patients with a nodal involvement risk ≤20% (Roach index) have been treated to the prostate with or without seminal vesicles with 56 Gy (4 Gy/fraction twice weekly) and an overall treatment time of 6.5 weeks. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicities were scored according to the Radiation Therapy Oncology Group (RTOG) grading system. Median follow-up was 48 months (range, 9-67 months). RESULTS All patients completed the treatment without interruptions. No patient presented with Grade ≥3 acute GU or GI toxicity. Of the patients, 4% presented with Grade 2 GU or GI persistent acute toxicity 6 weeks after treatment completion. The estimated 4-year probability of Grade ≥2 late GU and GI toxicity-free survival were 94.2% ± 2.9% and 96.1% ± 2.2%, respectively. One patient presented with Grade 3 GI and another patient with Grade 4 GU late toxicity, which were transitory in both cases. The 4-year actuarial biochemical relapse-free survival was 91.3% ± 5.9%, 76.4% ± 8.8%, and 77.5% ± 8.9% for low-, intermediate-, and high-risk groups, respectively. CONCLUSIONS In patients with localized prostate cancer, acute and late toxicity were minimal after dose-escalation administering twice-weekly 4 Gy to a total dose of 56 Gy, with IMRT. Further prospective trials are warranted to further assess the best fractionation schemes for these patients.

Hypofractionated Extracranial Stereotactic Radiotherapy Boost For Gynecologic Tumors: A Promising Alternative To High-Dose Rate Brachytherapy

The purpose of this study is to report toxicity and outcome results in patients with gynaecological tumours treated with a final boost using extra-cranial stereotactic radiotherapy (SRT) with a linac-based micro-multileaf collimator technique as an alternative to high-dose rate brachytherapy (HDR-BT). Since January 2002, 26 patients with either endometrial (n = 17) or cervical (n = 9) cancer were treated according to this protocol: 45–50.4 Gy external radiotherapy (RT) to the pelvic ± para-aortic regions followed by a final SRT boost of 2 × 7 Gy to the vaginal vault (4–7 day interval between fractions). Median age was 62 years (37–74 range). Fifteen patients were diagnosed with adenocarcinoma, 7 with squamous-cell carcinoma, and 4 with sarcoma. FIGO stage I (n = 17), stage II (n = 7), and stage III (n = 2). Toxicity was scored according to RTOG/EORTC criteria. No severe (>grade-3) acute urinary or low-gastrointestinal (GI) toxicity was observed during treatment and up to 3 months after treatment completion. Moderate (grade ≤ 3) acute urinary or low-GI toxicity was observed in 23% and 35% of patients, respectively. After a median follow-up of 47 months (4–77, range), late urinary, low-GI, and sexual ≥grade-2 (worst score) has been reported in 4%, 12% and 29.4% of patients, respectively. The 3-year loco-regional failure-free and overall survival rates were 96% and 95%, respectively. Preliminary results on feasibility, tolerance, and outcome with SRT are encouraging and may be considered a sound alternative to HDR-BT for gynecologic tumors.

Stereotactic radiotherapy for ocular melanoma: initial experience using closed eyes for ocular target immobilization.

To assess the reliability and target positioning reproducibility with eyes closed in uveal melanoma patients treated with a micromultileaf-based linear accelerator dedicated for stereotactic radiotherapy. Five consecutive patients treated with curative radiotherapy for uveal melanoma were monitored for positioning reproducibility with resimulation CT scans performed every two days while on treatment (23 resimulation CTs available). All patients underwent MRIs of the orbits before simulation to help to define the target and organs at risk (e.g., lenses, optic nerves, ciliary bodies, and lacrimal glands) in the simulation CT (MRI-to-CT bone registration). Patients were simulated, resimulated, and treated with eyes closed. Patient #1 was treated with 5 daily fractions while patients #2 to #5, were treated with 10 daily fractions. We chose the lens of the tumor-bearing eye as the structure to be controlled, assuming that correct repositioning of the lens should be a valid surrogate for correctness of target repositioning. Displacements (mean and standard deviations, SD) of the lens in the three axes were measured for each patient. Systematic and standard errors were calculated. Planning target volume (PTV) margins were estimated according to McKenzie et al. [Phys Med Biol 45, 3331-3342 (2000)]. For both AP-PA and left-right shifts calculated SD were always below 1 mm, except for patient #4, who was treated with a non-customized bolus that pushed the globe backwards in a random fashion. In ideal set-up conditions PTV margins around the target were estimated to be 3 mm. Asking patients to close their eyes is a simple and reliable immobilization procedure when treating ocular tumors with stereotactic radiotherapy. Margins of 3 mm around the target may be necessary to safely treat these tumors under ideal set-up conditions.

Multicentre validation of IMRT pre-treatment verification: comparison of in-house and external audit.

BACKGROUND AND PURPOSE We performed a multicentre intercomparison of IMRT optimisation and dose planning and IMRT pre-treatment verification methods and results. The aims were to check consistency between dose plans and to validate whether in-house pre-treatment verification results agreed with those of an external audit. MATERIALS AND METHODS Participating centres used two mock cases (prostate and head and neck) for the intercomparison and audit. Compliance to dosimetric goals and total number of MU per plan were collected. A simple quality index to compare the different plans was proposed. We compared gamma index pass rates using the centres equipment and methodology to those of an external audit. RESULTS While for the prostate case, all centres fulfilled the dosimetric goals and plan quality was homogeneous, that was not the case for the head and neck case. The number of MU did not correlate with the plan quality index. Pre-treatment verifications results of the external audit did not agree with those of the in-house measurements for two centres: being within tolerance for in-house measurements and unacceptable for the audit or the other way round. CONCLUSIONS Although all plans fulfilled dosimetric constraints, plan quality is highly dependent on the planner expertise. External audits are an excellent tool to detect errors in IMRT implementation and cannot be replaced by intercomparison using results obtained by centres.