Metastases-directed stereotactic body radiotherapy in combination with targeted therapy or immunotherapy: systematic review and consensus recommendations by the EORTC-ESTRO OligoCare consortium.

Stereotactic body radiotherapy (SBRT) for patients with metastatic cancer, especially when characterised by a low tumour burden (ie, oligometastatic disease), receiving targeted therapy or immunotherapy has become a frequently practised and guideline-supported treatment strategy. Despite the increasing use in routine clinical practice, there is little information on the safety of combining SBRT with modern targeted therapy or immunotherapy and a paucity of high-level evidence to guide clinical management. A systematic literature review was performed to identify the toxicity profiles of combined metastases-directed SBRT and targeted therapy or immunotherapy. These results served as the basis for an international Delphi consensus process among 28 interdisciplinary experts who are members of the European Society for Radiotherapy and Oncology (ESTRO) and European Organisation for Research and Treatment of Cancer (EORTC) OligoCare consortium. Consensus was sought about risk mitigation strategies of metastases-directed SBRT combined with targeted therapy or immunotherapy; a potential need for and length of interruption to targeted therapy or immunotherapy around SBRT delivery; and potential adaptations of radiation dose and fractionation. Results of this systematic review and consensus process compile the best available evidence for safe combination of metastases-directed SBRT and targeted therapy or immunotherapy for patients with metastatic or oligometastatic cancer and aim to guide today's clinical practice and the design of future clinical trials.

Phase II open-label study investigating apalutamide in patients with biochemical progression after radical prostatectomy.

Apalutamide, a competent inhibitor of the androgen receptor, has shown promising clinical efficacy results for patients with advanced prostate cancer. Here, we describe the rationale and design for the SAVE trial, a multi-center, Phase II study, wherein 202 men with biochemical progression after radical prostatectomy are randomly assigned 1:1 to apalutamide plus salvage radiotherapy (SRT) or androgen-deprivation therapy with an luteinizing hormone-releasing hormone agonist or antagonist plus SRT. The primary objective is to compare sexual function between the two treatment arms based on the expanded prostate cancer index-26 sexual domain score at nine months after start of hormonal treatment. The key secondary objectives are to assess quality of life, to evaluate the safety profile and the short-term efficacy of apalutamide in combination with SRT. ClinicalTrials.gov identifier: NCT03899077.

Urethra-Sparing Prostate Cancer Stereotactic Body Radiation Therapy: Sexual Function and Radiation Dose to the Penile Bulb, the Crura, and the Internal Pudendal Arteries From a Randomized Phase 2 Trial.

PURPOSE: Erectile dysfunction (ED) is a common side effect after prostate cancer stereotactic body radiation therapy (SBRT). We aimed to assess the correlation between the dose to the penile bulb (PB), internal pudendal arteries (IPA), and crura with the development of ED after ultrahypofractionation as part of a phase 2 clinical trial of urethra-sparing prostate SBRT. METHODS AND MATERIALS: Among the 170 patients with localized prostate cancer from 9 centers included in the trial, 90 men with Common Terminology Criteria for Adverse Events version 4.03 grade 0 to 1 ED (ED-) at baseline treated with 36.25 Gy in 5 fractions were selected for the present analysis. Doses delivered to the PB, crura, and IPA were analyzed and correlated with grade 2 to 3 ED (ED+) development. The effect on quality of life, assessed by the European Organisation for Research and Treatment of Cancer (EORTC QLQ-PR25) questionnaire, was reported. RESULTS: After a median follow-up of 6.5 years, 43% (n = 39) of the patients developed ED+, and 57% (n = 51) remained ED-. The dose delivered to the crura was significantly higher in ED+ patients than in ED- patients (7.7 vs 3.6 Gy [P = .014] for the Dmean and 18.5 vs 7.2 Gy [P = .015] for the D2%, respectively). No statistically significant difference between ED+ and ED- patients was observed for the dose delivered to the PB and IPA. The median ED+-free survival was worse in patients receiving a crura Dmean ≥ 4.7 versus < 4.7 Gy (51.5% vs 71.7%, P = .005) and a crura D2% > 12 versus ≤ 12 Gy (54.9% vs 68.9%, P = .015). No ED+-free survival differences were observed for doses delivered to the PB and IPA. Decline in EORTC QLQ-PR25 sexual functioning was significantly more pronounced in patients with higher doses to the crura. CONCLUSIONS: By keeping a Dmean and D2% to crura below 4.7 and 12 Gy, respectively, the risk of developing ED+ after prostate SBRT may be significantly reduced.

Cancer-specific dose and fractionation schedules in stereotactic body radiotherapy for oligometastatic disease: An interim analysis of the EORTC-ESTRO E2-RADIatE OligoCare study.

BACKGROUND AND INTRODUCTION: Optimal dose and fractionation in stereotactic body radiotherapy (SBRT) for oligometastatic cancer patients remain unknown. In this interim analysis of OligoCare, we analyzed factors associated with SBRT dose and fractionation. MATERIALS AND METHODS: Analysis was based on the first 1,099 registered patients. SBRT doses were converted to biological effective doses (BED) using α/ß of 10 Gy for all primaries, and cancer-specific α/ß of 10 Gy for non-small cell lung and colorectal cancer (NSCLC, CRC), 2.5 Gy for breast cancer (BC), or 1.5 Gy for prostate cancer (PC). RESULTS: Of the interim analysis population of 1,099 patients, 999 (99.5 %) fulfilled inclusion criteria and received metastasis-directed SBRT for NSCLC (n = 195; 19.5 %), BC (n = 163; 16.3 %), CRC (n = 184; 18.4 %), or PC (n = 457; 47.5 %). Two thirds of patients were treated for single metastasis. Median number of fractions was 5 (IQR, 3-5) and median dose per fraction was 9.7 (IQR, 7.7-12.4) Gy. The most frequently treated sites were non-vertebral bone (22.8 %), lung (21.0 %), and distant lymph node metastases (19.0 %). On multivariate analysis, the dose varied significantly for primary cancer type (BC: 237.3 Gy BED, PC 300.6 Gy BED, and CRC 84.3 Gy BED), and metastatic sites, with higher doses for lung and liver lesions. CONCLUSION: This real-world analysis suggests that SBRT doses are adjusted to the primary cancers and oligometastasis location. Future analysis will address safety and efficacy of this site- and disease-adapted SBRT fractionation approach (NCT03818503).

Every-Other-Day Versus Once-a-Week Urethra-Sparing Prostate Stereotactic Body Radiation Therapy: 5-Year Results of a Randomized Phase 2 Trial.

PURPOSE: The objective of this study was to present the 5-year results from a prospective, multicenter, phase 2 randomized trial of every-other-day (EOD) versus once-a-week (QW) urethra-sparing stereotactic body radiation therapy for localized prostate cancer. METHODS AND MATERIALS: Between 2012 and 2015, 170 patients with cT1c-3aN0M0 prostate cancer from 9 European institutions were randomized to 36.25 Gy in 5 fractions (6.5 Gy/fraction to the urethra) delivered either EOD (arm A, n = 84) or QW (arm B, n = 86). The median follow-up was 78 months (interquartile range, 66-89 months) and 77 months (interquartile range, 66-82 months) for arms A and B, respectively. RESULTS: Among the 165 patients treated and retained for the final analysis (arm A, n = 82; arm B, n = 83), acute toxicity (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 scale) was mild or absent, with no differences between arms. The 5-year grade 2 or greater genitourinary toxicity-free survival was 75.9% and 76.1% for arms A and B, respectively (P = .945), whereas the 5-year grade 2 or greater gastrointestinal toxicity-free survival was 89% and 92% for arms A and B, respectively (P = .596). No changes in European Organisation for Research and Treatment of Cancer QLQ-PR25 scores were observed in both arms for genitourinary, gastrointestinal, and sexual domains at 5-year follow-up compared with baseline. At the last follow-up, biochemical failure was observed in 14 patients in the EOD arm and in 7 patients in the QW arm, with a 5-year biochemical relapse-free survival rate of 92.2% and 93% for arms A and B, respectively (P = .13). CONCLUSIONS: Stereotactic body radiation therapy for prostate cancer with a 10% dose reduction to urethra was associated with a minimal effect on urinary function and quality of life regardless of an EOD or QW fractionation schedule. Biochemical control so far has been encouraging and much alike in both study arms, although longer follow-up is probably needed to assess the true value of overall treatment time on disease outcome.

Once-a-week or every-other-day urethra-sparing prostate cancer stereotactic body radiotherapy, a randomized phase II trial: 18 months follow-up results.

BACKGROUND: To present the 18 months results from a prospective multicenter phase II randomized trial of short vs protracted urethra-sparing stereotactic body radiotherapy (SBRT) for localized prostate cancer (PCa). METHODS: Between 2012 and 2015, a total of 170 PCa patients were randomized to 36.25 Gy in 5 fractions (6.5 Gy × 5 to the urethra) delivered either every other day (EOD, arm A, n = 84) or once a week (QW, arm B, n = 86). Genitourinary (GU) and gastrointestinal (GI) toxicity (CTCAE v4.0 scale), IPSS, and QoL scores were assessed at baseline, at the 5th fraction (5fx), 12th weeks (12W), and every 6 months after SBRT. The primary endpoint was biochemical control at 18 months and grade ≥ 3 toxicity (including grade ≥ 2 for urinary obstruction/retention) during the first 3 months. RESULTS: Among the 165 patients analyzed, the toxicity stopping rule was never activated during the acute phase. Maximum acute grade 2 GU toxicity rates at 5fx were 17% and 19% for arms A and B, respectively, with only 2 cases of grade 2 GI toxicity at 5fx in arm A. At month 18, grade ≥ 2 GU and GI toxicity decreased below 5% and 2% for both arms. No changes in EORTC QLQ-PR25 scores for GU, GI, and sexual domains were observed in both arms between baseline and month 18. Four biochemical failures were observed, 2 in each arm, rejecting the null hypothesis of an unfavorable response rate ≤ 85% in favor of an acceptable ≥ 95% rate. CONCLUSIONS: At 18 months, urethra-sparing SBRT showed a low toxicity profile, with minimal impact on QoL and favorable biochemical control rates, regardless of overall treatment time (EOD vs QW).

Urethra-Sparing Stereotactic Body Radiation Therapy for Prostate Cancer: Quality Assurance of a Randomized Phase 2 Trial.

PURPOSE: To present the radiation therapy quality assurance results from a prospective multicenter phase 2 randomized trial of short versus protracted urethra-sparing stereotactic body radiation therapy (SBRT) for localized prostate cancer. METHODS AND MATERIALS: Between 2012 and 2015, 165 patients with prostate cancer from 9 centers were randomized and treated with SBRT delivered either every other day (arm A, n = 82) or once a week (arm B, n = 83); 36.25 Gy in 5 fractions were prescribed to the prostate with (n = 92) or without (n = 73) inclusion of the seminal vesicles (SV), and the urethra planning-risk volume received 32.5 Gy. Patients were treated either with volumetric modulated arc therapy (VMAT; n = 112) or with intensity modulated radiation therapy (IMRT; n = 53). Deviations from protocol dose constraints, planning target volume (PTV) homogeneity index, PTV Dice similarity coefficient, and number of monitor units for each treatment plan were retrospectively analyzed. Dosimetric results of VMAT versus IMRT and treatment plans with versus without inclusion of SV were compared. RESULTS: At least 1 major protocol deviation occurred in 51 patients (31%), whereas none was observed in 41. Protocol violations were more frequent in the IMRT group (P < .001). Furthermore, the use of VMAT yielded better dosimetric results than IMRT for urethra planning-risk volume D98% (31.1 vs 30.8 Gy, P < .0001), PTV D2% (37.9 vs 38.7 Gy, P < .0001), homogeneity index (0.09 vs 0.10, P < .0001), Dice similarity coefficient (0.83 vs 0.80, P < .0001), and bladder wall V50% (24.5% vs 33.5%, P = .0001). To achieve its goals volumetric modulated arc therapy required fewer monitor units than IMRT (2275 vs 3378, P <.0001). The inclusion of SV in the PTV negatively affected the rectal wall V90% (9.1% vs 10.4%, P = .0003) and V80% (13.2% vs 15.7%, P = .0003). CONCLUSIONS: Protocol deviations with potential impact on tumor control or toxicity occurred in 31% of patients in this prospective clinical trial. Protocol deviations were more frequent with IMRT. Prospective radiation therapy quality assurance protocols should be strongly recommended for SBRT trials to minimize potential protocol deviations.

Helical tomotherapy with simultaneous integrated boost for high-risk and lymph node-positive prostate cancer: early report on acute and late toxicity.

The use of whole pelvic radiotherapy (WPRT) for high-risk and lymph node-positive prostate cancer (PC) remains controversial. The purpose of this study was to evaluate the acute toxicity associated with helical tomotherapy in the treatment of high-risk and lymph node-positive prostate cancer. To do so, twenty-eight patients were treated to a dose of 54 Gy in daily fractions of 1.8 Gy to the pelvic lymph node area, while the prostate and the seminal vesicles received a simultaneous integrated boost (SIB) to a dose of 70.5 Gy. A SIB to a dose of 60 Gy was delivered to the involved lymph node region(s) in 8 patients with pelvic lymph node metastases. All patients received concurrent hormonal treatment. The incidence of grade 2 and 3 acute gastrointestinal (GI) toxicity was 7% and 0% respectively. Grade 2 and 3 acute genito-urinary (GU) side effects were observed in 14% and 4% of the patients respectively. No grade 4 side effects occurred. No increased toxicity was observed in the 8 lymph node-positive patients receiving a simultaneous pelvic nodal dose escalation. In conclusion, WPRT with a SIB to the prostate and seminal vesicles by helical tomotherapy resulted in a favourable toxicity profile. Pelvic nodal dose escalation in node-positive patients is feasible without increasing toxicity.

The use of molecular imaging to evaluate radiation fields in the adjuvant setting of breast cancer: a feasibility study.

PURPOSE: To evaluate standard radiation fields in locally advanced breast cancer using the information of a preoperative FDG-PET showing lymph node involvement. PATIENTS AND METHODS: In 15 consecutive patients, referred for postoperative radiotherapy, a standard simulation was performed. Planning CT was fused semiautomatically with preoperative FDG-PET, and thoracic wall/breast (clinical target volume [CTV]), lungs, and location(s) of axillary nodal involvement on FDG-PET (PET(ax)) were delineated. A dose computation was performed using the standard field simulation (plan-). If plan-resulted in inadequate dose delivery to PET(ax), a plan adaptation was performed to improve this deficit (plan+). Mean dose-volume histograms (DVHs) were made of the relevant structures for both plan- and plan+. Student's paired t-test was performed on all mean reference values. RESULTS: In 13 patients an image fusion could be performed. Dose computation showed underdosage to the PET(ax) in eleven out of 13 patients. After plan adaptation, the dose delivered to PET(ax) could be increased, with a statistically significant difference (p < 0.01) in favor of plan+ for all reference values on the DVHs. This was achieved without changes in dose delivery to CTV or lungs. CONCLUSION: Standard radiation portals in postoperative radiation therapy in breast cancer with lymph node involvement do not automatically result in an adequate dose delivery to the region of highest biological activity. With these preliminary results in a small series it was found feasible to correct this without compromising the dose to the CTV or lungs for patients in whom a preoperative FDG-PET shows nodal involvement.

A feasibility study of image-guided hypofractionated conformal arc therapy for inoperable patients with localized non-small cell lung cancer.

We treated 36 cases of stage I/II non-small cell lung cancer in inoperable patients. Treatments were planned to a total isocenter dose of 60Gy (8x7.5Gy) based on a dynamic field shaping arc, employing one arc to span as much area as possible and if needed additional weighted segments. The 2 year infield progression free probability is 65%. Disease-specific survival is 75% at 2 years. No patients experienced grade 3-4 toxicity.

Comparison of 6 MV and 18 MV photons for IMRT treatment of lung cancer.

BACKGROUND AND PURPOSE: To compare 6 MV and 18 MV photon intensity modulated radiotherapy (IMRT) for non-small cell lung cancer. MATERIALS AND METHODS: Doses for a cohort of 10 patients, typical for our department, were computed with a commercially available convolution/superposition (CS) algorithm. Final dose computation was also performed with a dedicated IMRT Monte Carlo dose engine (MCDE). RESULTS: CS plans showed higher D(95%) (Gy) for the GTV (68.13 vs 67.36, p=0.004) and CTV (67.23 vs 66.87, p=0.028) with 18 than with 6 MV photons. MCDE computations demonstrated higher doses with 6 MV than 18 MV in D(95%) for the PTV (64.62 vs 63.64, p=0.009), PTV(optim) (65.48 vs 64.83, p=0.014) and CTV (66.22 vs 65.64, p=0.027). Dose inhomogeneity was lower with 18 than with 6 MV photons for GTV (0.08 vs 0.09, p=0.007) and CTV (0.10 vs 0.11, p=0.045) in CS but not MCDE plans. 6 MV photons significantly (D(33%); p=0.045) spared the esophagus in MCDE plans. Observed dose differences between lower and higher energy IMRT plans were dependent on the individual patient. CONCLUSIONS: Selection of photon energy depends on priority ranking of endpoints and individual patients. In the absence of highly accurate dose computation algorithms such as CS and MCDE, 6 MV photons may be the prudent choice.

The magnetic resonance detected intraprostatic lesion in prostate cancer: planning and delivery of intensity-modulated radiotherapy.

BACKGROUND AND PURPOSE: Local relapse after radiotherapy for prostate cancer mostly originates at the original tumor location. Dose escalation reduces local relapse rates. It may be of benefit to focus the highest dose to the intraprostatic lesion (GTVMRI) using intensity-modulated radiotherapy (IMRT). Therefore, the visualization of the GTVMRI and its inclusion into computer optimization is mandatory. MATERIALS AND METHODS: Fifteen patients with prostatic adenocarcinoma were referred for IMRT. All these patients had a palpable lesion on digital rectal examination (DRE) and/or a PSA >10.0 ng/ml. A T2-weighted MR examination of the prostate was performed in order to detect a GTV(MRI) and correlate the location of the GTV(MRI) with the site of the tumour-containing cylinder (biopsy). Two IMRT plans were compared: a plan without the inclusion of the GTV(MRI) (IMRT-CONV) versus a plan including the GTV(MRI) into the plan optimization (IMRT-GTV(MRI)). For comparison, both physical and biological endpoints of the GTV(MRI), CTV, PTV and rectum were taken into account. After the finalization of the planning study, the IMRT-GTV(MRI) plans were clinically delivered using step-and-shoot IMRT. Acute gastro-intestinal (GI) and genito-urinary (GU) toxicity were recorded. RESULTS: In all cases, the location of the GTV(MRI) corresponded with the site of the tumor containing biopsy cylinder. The mean and median distance of the GTV(MRI) to the anterior rectal wall was 3 and 2mm, respectively (range: 0-12 mm). For the GTV(MRI), its inclusion in the optimization led to a significant increase of all physical endpoints (P<0.01), without compromising the dose to the CTV, PTV and rectum. Mean GTV(MRI) dose was 78.3 Gy (IMRT-GTV(MRI)) versus 76.9 Gy (IMRT-CONV) (P<0.00001). All IMRT treatments were successfully delivered within 6 min. We did not observe grade 3 acute GI toxicity. One patient developed grade 3 GU toxicity (nocturia), that disappeared after administration of medication. Grade 2 GI and GU toxicity was observed in, respectively, four and six patients. CONCLUSION: Using T2-weighted MR, the visualization of an intraprostatic lesion is feasible. The inclusion of the GTV(MRI) into planning optimization leads to a modest increase in dose, without compromising the dose to the CTV, PTV and organs at risk. The clinical delivery of these plans runs without problems. Acute toxicity is mild.

Evaluation of the Sinmed Mastercouch as replacement for a standard couch.

BACKGROUND AND PURPOSE: Introducing into practice a new carbon-fibre couch necessitates its evaluation with regard to the present clinical situation. MATERIALS AND METHODS: In this study, a geometric and dosimetric evaluation has been made for the Sinmed Mastercouch as a replacement for the Elekta C-arm couch with Mylar-tennis racket combination. Geometrically, feasible gantry angles with regard to collision and beam intersection were discriminated as function of isocentric table rotation for 10 treatment isocentres. Dosimetrically, the build-up distortion and attenuation by the aforementioned tabletops and a carbon-fibre tabletop of an Elekta Precise simulator was measured. Finally, the clinical implications of these influences were assessed for a 3-field prostate treatment in three configurations: Mastercouch, C-arm couch and no-intersection situation. RESULTS: With regard to collision, the largest advantages are observed for the Mastercouch with the Omega-shaped treatment module compared to the C-arm couch for isocentres located in the upper part of the body, thanks to its shape and the absence of any metal. Dosimetrically, one has to take into account the build-up loss and attenuation by beam intersection with Mastercouch and the carbon-fibre edges of the tennis racket (C-arm couch). The clinical relevance of these dosimetric aspects depends on the dose delivered by the compromised beams.

Setup accuracy of the Novalis ExacTrac 6DOF system for frameless radiosurgery.

PURPOSE: Stereotactic radiosurgery using frame-based positioning is a well-established technique for the treatment of benign and malignant lesions. By contrast, a new trend toward frameless systems using image-guided positioning techniques is gaining mainstream acceptance. This study was designed to measure the detection and positioning accuracy of the ExacTrac/Novalis Body (ET/NB) for rotations and to compare the accuracy of the frameless with the frame-based radiosurgery technique. METHODS AND MATERIALS: A program was developed in house to rotate reference computed tomography images. The angles measured by the system were compared with the known rotations. The accuracy of ET/NB was evaluated with a head phantom with seven lead beads inserted, mounted on a treatment couch equipped with a robotic tilt module, and was measured with a digital water level and portal films. Multiple hidden target tests (HTT) were performed to measure the overall accuracy of the different positioning techniques for radiosurgery (i.e., frameless and frame-based with relocatable mask or invasive ring, respectively). RESULTS: The ET/NB system can detect rotational setup errors with an average accuracy of 0.09° (standard deviation [SD] 0.06°), 0.02° (SD 0.07°), and 0.06° (SD 0.14°) for longitudinal, lateral, and vertical rotations, respectively. The average positioning accuracy was 0.06° (SD 0.04°), 0.08° (SD 0.06°), and 0.08° (SD 0.07°) for longitudinal, lateral and vertical rotations, respectively. The results of the HTT showed an overall three-dimensional accuracy of 0.76 mm (SD 0.46 mm) for the frameless technique, 0.87 mm (SD 0.44 mm) for the relocatable mask, and 1.19 mm (SD 0.45 mm) for the frame-based technique. CONCLUSIONS: The study showed high detection accuracy and a subdegree positioning accuracy. On the basis of phantom studies, the frameless technique showed comparable accuracy to the frame-based approach.

Daily megavoltage computed tomography in lung cancer radiotherapy: correlation between volumetric changes and local outcome.

PURPOSE: To assess the predictive or comparative value of volumetric changes, measured on daily megavoltage computed tomography during radiotherapy for lung cancer. PATIENTS AND METHODS: We included 80 patients with locally advanced non-small-cell lung cancer treated with image-guided intensity-modulated radiotherapy. The radiotherapy was combined with concurrent chemotherapy, combined with induction chemotherapy, or given as primary treatment. Patients entered two parallel studies with moderately hypofractionated radiotherapy. Tumor volume contouring was done on the daily acquired images. A regression coefficient was derived from the volumetric changes on megavoltage computed tomography, and its predictive value was validated. Logarithmic or polynomial fits were applied to the intratreatment changes to compare the different treatment schedules radiobiologically. RESULTS: Regardless of the treatment type, a high regression coefficient during radiotherapy predicted for a significantly prolonged cause-specific local progression free-survival (p = 0.05). Significant differences were found in the response during radiotherapy. The significant difference in volumetric treatment response between radiotherapy with concurrent chemotherapy and radiotherapy plus induction chemotherapy translated to a superior long-term local progression-free survival for concurrent chemotherapy (p = 0.03). An enhancement ratio of 1.3 was measured for the used platinum/taxane doublet in comparison with radiotherapy alone. CONCLUSION: Contouring on daily megavoltage computed tomography images during radiotherapy enabled us to predict the efficacy of a given treatment. The significant differences in volumetric response between treatment strategies makes it a possible tool for future schedule comparison.

Prospective, risk-adapted strategy of stereotactic body radiotherapy for early-stage non-small-cell lung cancer: results of a Phase II trial.

PURPOSE: Validation of a prospective, risk-adapted strategy for early-stage non-small-cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS: Patients with a T1-3N0M0 (American Joint Committee on Cancer 6th edition) NSCLC were accrued. Using the Radiation Therapy Oncology Group definition, patients were treated to a total dose of 60,Gy in three fractions for peripherally located lesions and four fractions for centrally located lesions. The primary endpoint was toxicity, graded according to the Radiation Therapy Oncology Group acute and late morbidity scoring system, and the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. Secondary endpoints were local control and survival. RESULTS: A total of 40 patients were included, 17 with a centrally located lesion. The lung toxicity-free survival estimate at 2 years was 74% and was related to the location (central vs. peripheral) and the size of the target volume. No dose volumetric parameters could predict the occurrence of lung toxicity. One patient died because of treatment-related toxicity. The 1-year and 2-year local progression-free survival estimates were 97% and 84%, respectively, and were related to stage (T1 vs. T2) related (p = 0.006). Local failure was not more frequent for patients treated in four fractions. The 1-year local progression-free survival estimate dropped below 80% for lesions with a diameter of more than 4 cm. CONCLUSION: The proposed risk-adapted strategy for both centrally and peripherally located lesions showed an acceptable toxicity profile while maintaining excellent local control rates. The correlation between local control and tumor diameter calls for the inclusion of tumor stage as a variable in future study design.

Toxicity and outcome results of a class solution with moderately hypofractionated radiotherapy in inoperable Stage III non-small cell lung cancer using helical tomotherapy.

PURPOSE: To prospectively assess the feasibility, toxicity, and local control of a class solution protocol of moderately hypofractionated tomotherapy in Stage III, inoperable, locally advanced non-small-cell lung cancer patients. METHODS AND MATERIALS: Eligible patients were treated according to a uniform class solution (70.5 Gy in 30 fractions) with fixed constraints and priorities using helical tomotherapy. Toxicity monitoring was performed using the Radiation Therapy Oncology Group criteria and the National Cancer Institute Common Terminology Criteria and Adverse Events (CTCAE) version 3.0. Pulmonary function tests were performed at the start and repeated at 3 months after treatment. RESULTS: Our class solution resulted in a deliverable plan in all 40 consecutive patients. Acute Grade 3 lung toxicity was seen in 10% of patients. Two patients died during acute follow-up with pulmonary toxicity. Correlations were found between changes in pulmonary function test results and mean lung dose or the lung volume receiving 20 Gy (V(20)). The correlation was strongest for lung diffusion capacity for carbon monoxide. A V(20) of >27% and >32% were predictive for Grades 2 and 3 acute lung toxicity respectively (p < 0.05). Late Grade 3 toxicity was exclusively pulmonary, with an incidence of 16%. Overall Grade 3 lung toxicity correlated with a mean lung dose of >18 Gy and a median lung dose of >5 Gy (p < 0.05). Median survival was 17 months, and the 1-year and 2-year local progression-free survivals were 66% and 50%, respectively. CONCLUSION: The current class solution using moderately hypofractionated helical tomotherapy in patients with locally advanced non-small-cell lung cancer is feasible. Toxicity was acceptable and in line with other reports on intensity-modulated radiotherapy. The local progression-free survival was encouraging considering the unselected population.

Volumetric imaging by megavoltage computed tomography for assessment of internal organ motion during radiotherapy for cervical cancer.

PURPOSE: To assess the internal organ motion of the cervix and uterus by megavoltage computed tomography (MVCT) during intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Ten patients with Stage IIB-IVA cervical cancer underwent daily MVCT imaging. Internal organ motion was evaluated on 150 pretreatment MVCT images by measuring shifts in their boundaries between the MVCT and kilovoltage (kV) planning CT scan in the anterior, posterior, left and right lateral, and superior and inferior direction. Additional intrafractional patient movement was evaluated on 50 posttreatment MVCT images. RESULTS: Measured cervical motion (mean +/- SD) was 0.4 +/- 10.1 mm in the anterior, -3.0 +/- 6.9 mm in the posterior direction, -3.5 +/- 4.9 mm in the left and 0.2 +/- 4.5 mm in the right lateral direction, 2.2 +/- 8.0 mm in the superior and 0.5 +/- 5.0 mm in the inferior direction. Compared to the cervix, larger uterine motion was observed. Patient movement during treatment was limited to 1.1 +/- 1.3 mm, -0.3 +/- 1.6 mm, and 0.2 +/- 2.3 mm in anteroposterior, laterolateral and superoinferior direction respectively. CONCLUSIONS: MVCT imaging can be used to study patient setup accuracy and cervical and uterine motion during IMRT. This data may be used to refine treatment margins.

Toxicity report of a phase 1/2 dose-escalation study in patients with inoperable, locally advanced nonsmall cell lung cancer with helical tomotherapy and concurrent chemotherapy.

BACKGROUND: The objective of the current study was to evaluate the feasibility and toxicity of radiation dose escalation with concurrent chemotherapy using helical tomotherapy (HT) in patients with inoperable, locally advanced, stage III nonsmall cell lung cancer (LANSCLC) (grading determined according to the American Joint Committee on Cancer 6th edition grading system). METHODS: This phase 1/2 study was designed to determine the maximum tolerated dose (MTD) of radiotherapy in patients with LANSCLC administered concurrently with docetaxel and cisplatin. Radiotherapy was delivered using HT. A dose per fraction escalation was applied starting at 2 grays (Gy), with an increase of 6% per dose cohort (DC). The Radiation Therapy Oncology Group acute radiation morbidity score was used to monitor pulmonary, esophageal, and cardiac toxicity. RESULTS: Dose escalation was performed in 34 patients over 5 DCs to a dose per fraction of 2.48 Gy. No differences were observed in acute toxicity between the different DCs. However, a significant increase in late lung toxicity in DC IV, which received a fraction size of 2.36 Gy, necessitated a halt in further dose escalation with the MTD defined as 2.24 Gy per fraction. The overall incidence of acute grade > or =3 esophageal and pulmonary toxicity was 24% and 3%, respectively (grading determined according to the Radiation Therapy Oncology Group-European Organisation for Research and Treatment of Cancer toxicity scoring system). The overall incidence of late lung toxicity was 21%, but the incidence was an acceptable 13% in DCs I, II, and III. The local response rate was 61% on computed tomography images. CONCLUSIONS: The use of HT to 67.2 Gy with concurrent cisplatin/docetaxel was feasible and resulted in acceptable toxicity. A full phase 2 study has been initiated to establish the true local response rate at the MTD of 2.24 Gy per fraction.

Volumetric response analysis during chemoradiation as predictive tool for optimizing treatment strategy in locally advanced unresectable NSCLC.

PURPOSE: To study the feasibility of measuring volumetric changes in the primary tumor on megavoltage-computed tomography (MVCT) during chemoradiation and to examine the correlation with local response. PATIENTS AND METHODS: Fifteen consecutive patients with stage III, inoperable, locally advanced non-small cell lung cancer (NSCLC) were treated in a prospective dose escalation study protocol of concurrent chemoradiation. They were monitored for acute toxicity and evaluated with daily MVCT imaging. The volumetric changes were fitted to a negative exponential resulting in a regression coefficient (RC). Local response evaluation was done with positron emission tomography using the radio-labeled glucose analogue F18 fluorodeoxyglucose (FDG-PET). RESULTS: The mean volume decrease (+/-standard deviation) was 73% (+/-18%). With a mean treatment time of 42days this treatment schedule resulted in a mean decrease of 1.74%/day. Of the 13 evaluable patients seven developed a metabolic complete remission (MCR). The mean RC of the patients with MCR is 0.050 versus a mean RC of 0.023 in non-responders (p=0.0074). Using a proposed cut-off value for the RC of 0.03 80% of the non-responders will be detected correctly while misclassifying 16.4% of patients who will eventually achieve an MCR. The total cumulative percentage of esophageal grade 3 or more toxicity was 46.7%. CONCLUSION: The RC derived from volumetric analysis of daily MVCT is prognostic and predictive for local response in patients treated with chemoradiation for a locally advanced NSCLC. Because this treatment schedule is toxic in nearly half of the patient population, MVCT is a tool in the implementation of patient-individualized treatment strategies.