A novel concept to include uncertainties in the evaluation of stereotactic body radiation therapy after 4D dose accumulation using deformable image registration.

PURPOSE: To use four-dimensional (4D) dose accumulation based on deformable image registration (DIR) to assess dosimetric uncertainty in lung stereotactic body radiation therapy (SBRT) treatment planning. A novel concept, the Evaluation Target Volume (ETV), was introduced to achieve this goal. METHODS: The internal target volume (ITV) approach was used for treatment planning for 11 patients receiving lung SBRT. Retrospectively, 4D dose calculation was done in Pinnacle v9.10. Total dose was accumulated in the reference phase using DIR with MIM. DIR was validated using landmarks introduced by an expert radiation oncologist. The 4D and three-dimensional (3D) dose distributions were compared within the gross tumor volume (GTV) and the planning target volume (PTV) using the D95 and Dmin (calculated as Dmin,0.035cc ) metrics. For lung involvement, the mean dose and V20 , V10 , and V5 were used in the 3D to 4D dose comparison, and Dmax (D0.1cc ) was used for all other organs at risk (OAR). The new evaluation target volume (ETV) was calculated by expanding the GTV in the reference phase in order to include geometrical uncertainties of the DIR, interobserver variability in the definition of the tumor, and uncertainties of imaging and delivery systems. D95 and Dmin,0.035cc metrics were then calculated on the basis of the ETV for 4D accumulated dose distributions, and these metrics were compared with those calculated from the PTV for 3D planned dose distributions. RESULTS: The target registration error (TRE) per spatial component was below 0.5 ± 2.1mm for all our patients. For five patients, dose degradation above 2% (>4% in 2 patients) was found in the PTV after 4D accumulation and attributed to anatomical variations due to breathing. Comparison of D95 and Dmin,0.035cc metrics showed that the ETV (4D accumulated dose) estimated substantially lower coverage than the PTV (3D planning dose): in six out of the 11 cases, and for at least for one of the two metrics, coverage estimated by ETV was at least 5% lower than that estimated by PTV. Furthermore, the ETV approach revealed hot and cold spots within its boundaries. CONCLUSIONS: A workflow for 4D dose accumulation based on DIR has been devised. Dose degradation was attributed to respiratory motion. To overcome limitations in the PTV for the purposes of evaluating DIR-based 4D accumulated dose distributions, a new concept, the ETV, was proposed. This concept appears to facilitate more reliable dose evaluation and a better understanding of dosimetric uncertainties due to motion and deformation.

Correction: Hypofractionated radiation therapy and temozolomide in patients with glioblastoma and poor prognostic factors. A prospective, single-institution experience.

[This corrects the article DOI: 10.1371/journal.pone.0217881.].

Hypofractionated radiation therapy and temozolomide in patients with glioblastoma and poor prognostic factors. A prospective, single-institution experience.

BACKGROUND: Hypofractionated radiation therapy is a feasible and safe treatment option in elderly and frail patients with glioblastoma. The aim of this study was to evaluate the effectiveness of hypofractionated radiation therapy with concurrent temozolomide in terms of feasibility and disease control in primary glioblastoma patients with poor prognostic factors other than advanced age, such as post-surgical neurological complications, high tumor burden, unresectable or multifocal lesions, and potential low treatment compliance due to social factors or rapidly progressive disease. MATERIAL AND METHODS: GTV included the surgical cavity plus disease visible in T1WI-MRI, FLAIR-MRI and in the MET-uptake. The CTV was defined as the GTV plus 1.5-2 cm margin; the PTV was the CTV+0.3 cm margin. Forty, fourty-five, and fifty grays in 15 fractions were prescribed to 95% of PTV, CTV, and GTV, respectively. Treatment was delivered using IMRT or the VMAT technique. Simultaneously, 75 mg/m2/day of temozolomide were administered. RESULTS: Between January 2010 and November 2017, we treated a total of 17 patients. The median age at diagnosis was 68-years; median KPS was 50-70%. MGMT-methylation status was negative in 5 patients, and 8 patients were IDH-wildtype. Eight of 18 patients were younger than 65-years. Median tumor volume was 26.95cc; median PTV volume was 322cc. Four lesions were unresectable; 6 patients underwent complete surgical resection. Median residual volume was 1.14cc. Progression-free survival was 60% at 6 months, 33% at 1-year and 13% at 2-years (median OS = 7 months). No acute grade 3-5 toxicities were documented. Symptomatic grade 3 radiation necrosis was observed in one patient. CONCLUSIONS: Patients with poor clinical factors other than advanced age can be selected for hypofractionated radiotherapy. The OS and PFS rates obtained in our series are similar to those in patients treated with standard fractionation, assuring good treatment adherence, low rates of toxicity and probable improved cost-effectiveness.

Delta-24-RGD combined with radiotherapy exerts a potent antitumor effect in diffuse intrinsic pontine glioma and pediatric high grade glioma models.

Pediatric high grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPGs), are aggressive tumors with a dismal outcome. Radiotherapy (RT) is part of the standard of care of these tumors; however, radiotherapy only leads to a transient clinical improvement. Delta-24-RGD is a genetically engineered tumor-selective adenovirus that has shown safety and clinical efficacy in adults with recurrent gliomas. In this work, we evaluated the feasibility, safety and therapeutic efficacy of Delta-24-RGD in combination with radiotherapy in pHGGs and DIPGs models. Our results showed that the combination of Delta-24-RGD with radiotherapy was feasible and resulted in a synergistic anti-glioma effect in vitro and in vivo in pHGG and DIPG models. Interestingly, Delta-24-RGD treatment led to the downregulation of relevant DNA damage repair proteins, further sensitizing tumors cells to the effect of radiotherapy. Additionally, Delta-24-RGD/radiotherapy treatment significantly increased the trafficking of immune cells (CD3, CD4+ and CD8+) to the tumor niche compared with single treatments. In summary, administration of the Delta-24-RGD/radiotherapy combination to pHGG and DIPG models is safe and significantly increases the overall survival of mice bearing these tumors. Our data offer a rationale for the combination Delta-24-RGD/radiotherapy as a therapeutic option for children with these tumors. SIGNIFICANCE: Delta-24-RGD/radiotherapy administration is safe and significantly increases the survival of treated mice. These positive data underscore the urge to translate this approach to the clinical treatment of children with pHGG and DIPGs.

The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models.

Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032).

Intercellular Adhesion Molecule-1 and Vascular Cell Adhesion Molecule Are Induced by Ionizing Radiation on Lymphatic Endothelium.

PURPOSE/OBJECTIVES: The goal of this study was to assess the effects of ionizing radiation on the expression of the integrin ligands ICAM-1 and VCAM that control leucocyte transit by lymphatic endothelial cells. MATERIALS/METHODS: Confluent monolayers of primary human lymphatic endothelial cells (LEC) were irradiated with single dose of 2, 5, 10 or 20 Gy, with 6 MeV-x-rays using a Linear-Accelerator. ICAM-1 and VCAM expression was determined by flow cytometry. Human tissue specimens received a single dose of 20 Gy with 15 MeV-x-rays. MC38, B16-OVA or B16-VEGF-C tumors grown in C57BL/6 mice were irradiated with single dose of 20Gy using a Linear-Accelerator fitted with a 10mm Radiosurgery collimator. Clinical samples were obtained from patients previous and 4 weeks after complete standard radiotherapy. ICAM-1 and VCAM expression was detected in all tissue specimens by confocal microscopy. To understand the role of TGFß in this process anti-TGFß blocking mAb were injected i.p. 30min before radiotherapy. Cell adhesion to irradiated LEC was analyzed in adhesion experiments performed in the presence or in the absence of anti- TGFß and /or anti-ICAM1 blocking mAb. RESULTS: We demonstrate that lymphatic endothelial cells in tumor samples experience induction of surface ICAM-1 and VCAM when exposed to ionizing radiation in a dose- and time-dependent manner. These effects can be recapitulated in cultured LEC, and are in part mediated by TGFß. These data are consistent with increases in ICAM-1 and VCAM expression on LYVE-1+ endothelial cells in freshly explanted human tumor tissue and in mouse transplanted tumors after radiotherapy. Finally, ICAM-1 and VCAM expression accounts for enhanced adherence of human T lymphocytes to irradiated LEC. CONCLUSION: Our results show induction of ICAM-1 and VCAM on LVs in irradiated lesions and offer a starting point for elucidating the biological and therapeutic implications of targeting leukocyte traffic in combination to immunotherapy.

Multicatheter breast implant during breast conservative surgery: Novel approach to deliver accelerated partial breast irradiation.

PURPOSE: To assess the safety, feasibility, and efficacy of free-hand intraoperative multicatheter breast implant (FHIOMBI) and perioperative high-dose-rate brachytherapy (PHDRBT) in early breast cancer. METHODS AND MATERIALS: Patients with early breast cancer candidates for breast conservative surgery (BCS) were prospectively enrolled. Patients suitable for accelerated partial breast irradiation (APBI) (low or intermediate risk according GEC-ESTRO criteria) received PHDRBT (3.4 Gy BID × 10 in 5 days). Patients not suitable for APBI (high risk patients according GEC-ESTRO criteria) received PHDRBT boost (3.4 Gy BID × 4 in 2 days) followed by whole breast irradiation. RESULTS: From June 2007 to November 2014, 119 patients were treated and 122 FHIOMBI procedures were performed. Median duration of FHIOMBI was 25 minutes. A median of eight catheters (range, 4-14) were used. No severe intraoperative complications were observed. Severe early postoperative complications (bleeding) were documented in 2 patients (1.6%), wound healing complications in 3 (2.4%), and infection (mastitis or abscess) in 2 (1.6%). PHDRBT was delivered as APBI in 88 cases (72.1%) and as a boost in 34 (27.8%). The median clinical target volume T was 40.8 cc (range, 12.3-160.5); median D90 was 3.32 Gy (range, 3.11-3.85); median dose homogeneity index was 0.72 (range, 0.48-0.82). With a median followup of 38.4 months (range, 8.7-98.7) no local, elsewhere, or regional relapses were observed; there was only one distant failure in PHDRBT boost. No major (acute or late) RTOG grade 3 or higher were documented in any of the 119 patients treated with PHDRBT. Cosmetic outcome in APBI patients was excellent or good in (87.0%) and fair or poor in (11.9%) while in boost patients was excellent or good in (76.4%) and fair in (23.5%). CONCLUSION: The FHIOMBI-PHDRBT program does not add complications to conservative surgery. It allows precise selection of APBI patients and offers excellent results in disease control and cosmetics. It also offers logistic advantages because it dramatically shortens the time of local treatment and avoids further invasive procedures.

Salvage surgery and radiotherapy including intraoperative electron radiotherapy in isolated locally recurrent tumors: Predictors of outcome.

PURPOSE: To evaluate the influence of equivalent dose (EQD2) in clinical outcomes of patients with isolated locally recurrent tumors (ILRT), treated with salvage surgery and intra-operative electron beam radiation therapy (IOERT). METHODS AND MATERIALS: We retrospectively reviewed 128 patients with non-metastatic ILRT of different tissues (soft tissue sarcomas, head and neck, uterine, and colorectal). Patients had received salvage surgery (R0/R1/R2) and IOERT. Previously not irradiated patients had received additional external beam radiation therapy (EBRT). RESULTS: IOERT was delivered at a median dose of 15 Gy (range, 5-25 Gy). Seventy-five patients (60.9%) received additional EBRT of 46 Gy. Median EQD2 of salvage program was 62 Gy and median EQD2 of exclusive IORT was 31.2 Gy. Median follow-up was 19.2 months (range: 1.3-220). Thirty-one patients (24.2%) developed severe (grade 3-5) complications. New locoregional recurrence was documented in 86 (67.2%) of the 123 cases. Five-year rates were 31% for locoregional control, 57% for distant metastasis-free and 31% for overall survival. On multivariate analysis, R0-1 vs. R2 resection (HR 2.2, 95 CI: 1.2-4.1) was statistically significant for locoregional recurrence and EQD2 ⩾62 Gy for survival (HR 2.2, 95 CI: 1.1-4.1). CONCLUSIONS: Surgical radicality (gross macroscopic resection) and radiation dose (EQD2 ⩾62 Gy in radiation salvage program) are the dominant prognostic factors beside ILRT histology. Modest rates of long-term disease control are expected when both factors are fulfilled.

Salvage wide resection with intraoperative electron beam therapy or HDR brachytherapy in the management of isolated local recurrences of soft tissue sarcomas of the extremities and the superficial trunk.

PURPOSE: To assess the toxicity and efficacy of salvage wide resection (SWR) with intraoperative electron beam radiation therapy (IOERT) or perioperative high-dose-rate brachytherapy (PHDRB) in previously unirradiated patients (PUP) vs. previously irradiated patients (PIP) with isolated local recurrence of soft tissue sarcomas (STS) of the extremities and the superficial trunk. METHODS AND MATERIALS: PUP received SWR and IOERT/PHDRB with external beam radiation therapy. PIP received SWR and IOERT/PHDRB only. RESULTS: Fifty patients were analyzed retrospectively. PUP (n = 24; 48%) received IOERT (n = 13) or PHDRB (n = 11). PIP (n = 26; 52%) received IOERT (n = 10) or PHDRB (n = 16). Reintervention because of complications was not required in PUP. Nine of 26 (34%) PIP required reintervention (p = 0.01). After a median followup of 3.7 years (range, 0.2-18.3), the 5-year rates of locoregional control, distant control, and overall survival were 54%, 66%, and 56%, respectively. Five-year locoregional control was higher in PUP than in PIP (81% vs. 26%, p = 0.01) and in the extremity locations compared with trunk locations (68% vs. 28%, p = 0.001). Five-year overall survival was superior in unifocal vs. multifocal presentations (70% vs. 36%, p = 0.03) and for tumor sizes <4 vs. ≥4 cm (74% vs. 50%, p = 0.05). CONCLUSIONS: Prior irradiation is the main determinant of locoregional control in patients with isolated local recurrence of STS. The locoregional control rates in PUP were similar to those described in primary STS. In PIP, SWR + IOERT/PHDRB reirradiation yielded modest locoregional control rates and was associated with significant morbidity, especially in PHDRB cases.

Voxel-based analysis of dual-time-point 18F-FDG PET images for brain tumor identification and delineation.

UNLABELLED: We have investigated dual-time-point (18)F-FDG PET for the detection and delineation of high-grade brain tumors using quantitative criteria applied on a voxel basis. METHODS: Twenty-five patients with suspected high-grade brain tumors and inconclusive MRI findings underwent (11)C-methionine PET and dual-time-point (18)F-FDG PET. Images from each subject were registered and spatially normalized. Parametric maps of standardized uptake value (SUV) and tumor-to-normal gray matter (TN) ratio for each PET image were obtained. Tumor diagnosis was evaluated according to 4 criteria comparing standard and delayed (18)F-FDG PET images: any SUV increase, SUV increase greater than 10%, any TN increase, and TN increase greater than 10%. Voxel-based analysis sensitivity was assessed using (11)C-methionine as a reference and compared with visual and volume-of-interest analysis for dual-time-point PET images. Additionally, volumetric assessment of the tumor extent that fulfills each criterion was compared with the volume defined for (11)C-methionine PET. RESULTS: The greatest sensitivity for tumor identification was obtained with any increase of TN ratio (100%), followed by a TN increase greater than 10% (96%), any SUV increase (80%), and an SUV increase greater than 10% (60%). These values were superior to visual analysis of standard (18)F-FDG (sensitivity, 40%) and delayed (18)F-FDG PET (sensitivity, 52%). Volume-of-interest analysis of dual-time-point PET reached a sensitivity of only 64% using the TN increase criterion. Regarding volumetry, voxel-based analysis with the TN ratio increase as a criterion, compared with (11)C-methionine PET, detected 55.4% of the tumor volume, with the other criteria detecting volumes lower than 20%. Nevertheless, volume detection presented great variability, being better for metastasis (78%) and glioblastomas (56%) than for anaplastic tumors (12%). A positive correlation was observed between the volume detected and the time of acquisition of the delayed PET image (r = 0.66, P < 0.001), showing volumes greater than 75% when the delayed image was obtained at least 6 h after (18)F-FDG injection. CONCLUSION: Compared with standard (18)F-FDG PET studies, quantitative dual-time-point (18)F-FDG PET can improve sensitivity for the identification and volume delineation of high-grade brain tumors.

Use of customized-mold brachytherapy in the management of malignancies arising in the maxillary antrum after maxillectomy: a dosimetric analysis.

PURPOSE: To explore the feasibility of a intraoral mold high-dose rate (HDR) brachytherapy in the treatment of tumors arising in the maxillary antrum after maxillectomy and to describe the dosimetric profile of HDR brachytherapy in such an unusual location. METHODS AND MATERIALS: A customized mold with four 6-French catheters was designed and produced in transparent acrylic resin. The catheters formed a soft loop that allowed the passage of the HDR source. CT-based dose evaluation in several volumes of interest, including the gross tumor volume (GTV) and several organs at risk (OARs), such as the skin of the cheek, eyeball, lens, optic nerve, optic chiasm, and spinal cord was performed. RESULTS: Treatments were delivered uneventfully. A favorable OAR/GTV ratio was observed. The GTV D(90) was covered by the 3.8 Gy isodose (95% of the prescription isodose of 4 Gy) and the doses received by the OARs varied between 4% and 43% of the prescription isodose for the V1 cc of spinal cord and eyeball, respectively. The only structure that could not be adequately spared was the skin overlying the tumoral lesion that received between 94% and 107% of the prescription isodose (1.0 and 0.5 cm(2) of skin, respectively). CONCLUSIONS: Intraoral mold-based HDR brachytherapy can be used to treat tumors involving the maxillary antrum provided that access is possible through a previous maxillectomy. A dose reduction of 4-43% in several OARs, such as the spinal cord, pituitary gland, optic chiasm, optic nerve, eyeball, and lens, is obtained.

A phase II trial of less than 7 weeks of concomitant cisplatin-paclitaxel chemoradiation in locally advanced cervical cancer.

OBJECTIVES: This study was undertaken to determine the tolerability of a 7-week schedule of external beam radiation therapy, high-dose-rate brachytherapy, and weekly cisplatin and paclitaxel in patients with locally advanced carcinoma of the cervix. METHODS: Twenty-nine patients with International Federation of Gynecology and Obstetrics stages IB2 to IVa cervical cancer were treated with 40 mg/m per week of intravenous (i.v.) cisplatin and 50 mg/m per week of i.v. paclitaxel combined with 45 Gy of pelvic external beam radiation therapy and 30 Gy of high-dose-rate brachytherapy. RESULTS: Eleven patients (37.9%) were able to complete the 6 scheduled cycles of chemotherapy. The median number of weekly chemotherapy cycles administered was 5 (range, 2-7). Thirty-five (20.1%) of 174 cycles of chemotherapy were not given because of toxicity. The median dose intensity of cisplatin was 31 mg/m per week (95% confidence interval [CI], 25.2-36.8); that of paclitaxel was 44 mg/m per week (95% CI, 39.9-48.3). Twenty-two patients (78.6%) were able to complete the planned radiation course in less than 7 weeks. Median radiation treatment length was 45 days (95% CI, 43.4-46.6). After a median follow-up of 48 months, 7 patients (24.1%) experienced severe (Radiation Therapy Oncology Group grade 3 or higher) late toxicity. No fatal events were observed. Seven patients have failed, 1 locally and 6 at distant sites. The 8-year local/pelvic control rate was 95.7%, and the 8-year freedom from systemic failure rate was 76.1%. Eight-year actuarial disease-free survival and overall survival were 63.1% and 75.9%, respectively. CONCLUSIONS: This study demonstrated unacceptable toxicity of combining the stated doses of concurrent cisplatin and paclitaxel chemotherapy with definitive radiotherapy for patients with advanced cervical cancer. Additional phase I/II trials are recommended to clearly establish the recommended phase II dose for these drugs.

Phase II trial of radiation dose escalation with conformal external beam radiotherapy and high-dose-rate brachytherapy combined with long-term androgen suppression in unfavorable prostate cancer: feasibility report.

PURPOSE: To determine the feasibility of combined long-term luteinizing hormone-releasing hormone agonist-based androgen suppressive therapy (AST) and dose escalation with high-dose-rate (HDR) brachytherapy for high-risk (HRPC) or very-high-risk prostate cancer (VHRPC). METHODS AND MATERIALS: Between January 2001 and October 2006, 134 patients (median age, 70 years) with either National Comprehensive Cancer Network criteria-defined HRPC (n = 47, 35.1%) or VHRPC (n = 87, 64.9%) were prospectively enrolled in this Phase II trial. Tumor characteristics included a median pretreatment prostate-specific antigen level of 14.6 ng/mL, a median clinical stage of T2c, and a median Gleason score of 7. Three-dimensional conformal radiotherapy (54 Gy in 30 fractions) was followed by HDR brachytherapy (19 Gy in 4 b.i.d. treatments). Androgen suppressive therapy started 0-3 months before three-dimensional conformal radiotherapy and continued for 2 years. RESULTS: One implant was repositioned with a new procedure (0.7%). Five patients (3.7%) discontinued AST at a median of 13 months (range, 6-18 months) because of disease progression (n = 1), hot flashes (n = 2), fatigue (n = 1), and impotence (n = 1). After a median follow-up of 37.4 months (range, 24-90 months), the highest Radiation Therapy Oncology Group-defined late urinary toxicities were Grade 0 in 47.8%, Grade 1 in 38.1%, Grade 2 in 7.5%, and Grade 3 in 6.7% of patients. Maximal late gastrointestinal toxicities were Grade 0 in 73.1%, Grade 1 in 16.4%, Grade 2 in 7.5%, and Grade 3 in 2.9% of patients. There were no Grade 4 or 5 events. CONCLUSIONS: Intermediate-term results show that dose escalation with HDR brachytherapy combined with long-term AST is feasible and has a toxicity profile similar to that reported by previous HDR brachytherapy studies.

Phase I-II trial of perioperative high-dose-rate brachytherapy in oral cavity and oropharyngeal cancer.

BACKGROUND: To determine the feasibility of combined perioperative high-dose-rate brachytherapy (PHDRB) and intermediate-dose external beam radiation therapy (EBRT) as an alternative to full-dose adjuvant EBRT in patients with unirradiated squamous cell cancer (SCC) of the oral cavity and oropharynx. METHODS AND MATERIALS: Forty patients were treated with surgical resection and PHDRB. PHDRB dose was 4Gy b.i.d.x4 (16Gy) for R0 resections and 4Gy b.i.d.x6 (24Gy) for R1 resections, respectively. External beam radiotherapy (45Gy in 25 fractions) was added postoperatively. Patients with Stage III, IVa tumors, and some recurrent cases received concomitant cisplatin-paclitaxel chemotherapy during EBRT. RESULTS: The rate of protocol compliance was 97.5%. Eleven patients (27.5%) developed RTOG Grade 3 or greater toxicity. Four patients (10%) presented complications requiring a major surgical procedure (RTOG 4), and one patient died of bleeding (RTOG 5). Three complications (7.5%) occurred in the perioperative period, and 8 (20.0%) occurred more than 3 months after the completion of the treatment program. Severe complications were more frequent in posteriorly located implants than in anterior implants (p=0.035). After a median follow-up of 50 months for living patients (range, 2.5-86.1+), the 7-year actuarial rates of local and locoregional control were 86% and 82%, respectively; and the 7-year disease-free survival and overall survival rates were 50.4% and 52.3%, respectively. CONCLUSIONS: PHDRB can be integrated into the management of patients with resected cancer of the oral cavity who are candidates to receive postoperative radiation or chemoradiation. The local control and toxicity rates were similar to those expected after standard chemoradiation. PHDRB was associated with high toxicity in posterior locations, and the scheduled PHDRB dose was shifted to the closest lower level.

An independent algorithm to check the monitor units calculation in radiosurgery.

Double checking of the monitor units (MU) is an important step in the quality assurance (QA) process in radiosurgery. In this paper we propose the use of an independent algorithm constructed using the ellipsoid which best fits the measurements taken with the bubble head frame. The monitor units calculated by this independent algorithm and the commercial planning system were compared in 40 patients treated with radiosurgery (57 isocenters, 320 arcs). The average relative difference was -0.2% +/- 2.1 (k=1). These results are better for the variance, -0.4% +/- 1.8 (k=1), when all the depths of the bubble head frame are measured and no arcs are calculated by extrapolation or when only one of these factors appear. If there are missing values in the bubble head frame measurements and the model is extrapolated, the variance of the results is greater, 0.4% +/- 3.9 (k=1). The algorithm is reliable as a QA tool for linac radiosurgery.

Phase I-II trial of concurrent capecitabine and oxaliplatin with preoperative intensity-modulated radiotherapy in patients with locally advanced rectal cancer.

PURPOSE: To identify the maximal tolerated dose level of preoperative intensity-modulated radiotherapy combined with capecitabine and oxaliplatin and to evaluate the efficacy. PATIENTS AND METHODS: Patients with rectal T3-T4 and/or N0-N+ rectal cancer received capecitabine 825 mg/m(2) twice daily Monday through Friday and oxaliplatin 60 mg/m(2) intravenously on Days 1, 8, and 15, concurrently with intensity-modulated radiotherapy. The radiation dose was increased in 5.0-Gy steps in cohorts of 3 patients starting from 37.5 Gy in 15 fractions (dose level [DL] 1). DL2 and DL3 were designed to reach 42.5 Gy in 17 fractions and 47.5 Gy in 19 fractions, respectively. RESULTS: No dose-limiting toxicity was observed at DL1 or DL2. Of the 3 patients treated at DL3, 1 presented with Grade 3 diarrhea, which was considered a dose-limiting toxicity, and 3 additional patients were added. Of the 6 patients treated at DL3, no new dose-limiting toxicities were observed, and DL3 was identified as the recommended dose in this study. Eight additional patients were treated at 47.5 Gy. Grade 2 proctitis was the most frequent adverse event (40%); Grade 3 diarrhea occurred in 2 patients (10%). All patients underwent surgery, and 17 patients (85%) underwent R0 resection. Four patients (20%) presented with a histologic response of Grade 4, 11 (55%) with Grade 3+, 2 (15%) with Grade 3, and 2 patients (10%) with Grade 2. CONCLUSION: The maximal tolerated dose in this study was 47.5 Gy. The high rates of pathologic response of Grade 3+ and 4 must be confirmed through the accrual of new patients in the Phase II study.

Paclitaxel, cisplatin, and vinorelbine combination chemotherapy in metastatic non-small-cell lung cancer.

Vinorelbine-cisplatin combination chemotherapy is a standard approach for the treatment of advanced non-small-cell lung cancer (NSCLC). The addition of paclitaxel as a third therapeutic agent seems promising. The aim of the present study was to evaluate the activity and toxicity of this new regimen. Forty-six nonselected and chemotherapy-naive patients with stage IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 2 were treated every 4 weeks with paclitaxel (135 mg/m2 given iv in 3 hours) and cisplatin (120 mg/m2 given iv in 6 hours) on day 1 and vinorelbine (30 mg/m2 given iv in 30 minutes) on days 1 and 15. All patients were evaluated for toxicity and response according to the intent-to-treat principle. An objective response was observed in 39% of the patients (95% CI: 25% to 55%). World Health Organization grade III to IV neutropenia, thrombocytopenia, and anemia occurred in 43%, 2%, and 17%, respectively. There was one treatment-related death. Nonhematologic toxicities were mild, mainly grade III nausea and vomiting in 20% of the patients. After a median follow-up period of 54 months, the median progression-free survival was 14.3 weeks and the median overall survival was 31.3 weeks. This three-drug chemotherapy combination is feasible, well tolerated, and shows activity in metastatic NSCLC.

Front-line paclitaxel/cisplatin-based chemotherapy in brain metastases from non-small-cell lung cancer.

OBJECTIVE: Paclitaxel-cisplatin is considered to be a standard therapy for metastatic non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the activity and toxicity of this combination with vinorelbine or gemcitabine as front-line therapy in brain metastases from NSCLC. METHODS: Twenty-six chemotherapy-naive patients with an ECOG performance status of 0-2 were treated with paclitaxel (135 mg/m(2)) on day 1, cisplatin (120 mg/m(2)) on day 1, and either vinorelbine (30 mg/m(2)) on days 1 and 15 or gemcitabine (800 mg/m(2)) on days 1 and 8. Whole-brain irradiation was offered early in case of progression and later as consolidation treatment. RESULTS: All patients were evaluated for toxicity and 25 for response. An intracranial response rate was observed in 38% of the patients (95% CI: 22-59%). WHO grade 3-4 neutropenia and thrombocytopenia occurred in 31 and 4% of the patients, respectively. There was one treatment-related death. Non-hematological toxicities were mild. After a median follow-up of 46 months, the median overall survival for all patients was 21.4 weeks and the median time to progression was 12.8 weeks. CONCLUSIONS: Paclitaxel and cisplatin combined with vinorelbine or gemcitabine as front-line therapy in brain metastases seem to achieve responses similar to those for extracranial disease, suggesting a meaningful role in this setting.

Radiation therapy after high-dose chemotherapy with peripheral blood stem cell support for high-risk breast cancer.

Multidisciplinary treatment in high-risk breast cancer improves survival and local control. The feasibility and patterns of failure after several induction and high-dose consolidation regimens of chemotherapy were evaluated in this study. Between November 1990 and January 1997, 65 patients with histologically proven breast cancer American Joint Committee on Cancer stages II-III with four or more axillary lymph nodes positive or locally advanced breast cancer underwent high-dose chemotherapy (HDC) with peripheral stem cell support after surgery and induction chemotherapy. All patients were subsequently treated with radiotherapy (up to total doses of 50-60 Gy), which included the ipsilateral axilla and supraclavicular fossa and the chest wall or breast. A minimum follow-up period of 2 years from the completion of radiotherapy was required for analysis. Local control (LC), disease-free survival (DFS), overall survival (OS), and toxicity were evaluated. With a median follow-up of 62 months (range: 32-107 months), LC was 89%, and 5-year OS and DFS were 78% and 63%, respectively. Symptomatic pneumonitis developed in six patients (9%); only one patient had her radiotherapy interrupted because of hematologic toxicity. No treatment-related mortality was observed. Radiation therapy after HDC provides excellent local control rates without excessive toxicity. Delaying the start of irradiation until recovery from HDC does not seem to increase local failure rates.